malaria_pathogenesis 1.presentation for msc

go through it. for pharma chemistry

1. Malaria Pathogenesis and
Clinical Presentation

2. Plasmodiumspecies which
infect humans
Plasmodium vivax(tertian)
Plasmodium ovale(tertian)
Plasmodium falciparum(tertian)
Plasmodium malariae(quartian)

3. Exo-
erythrocytic
(hepatic) cycle
Sporozoites
Mosquito Salivary
Gland
Malaria Life
Cycle
Life Cycle
Gametocytes
Oocyst
Erythrocytic
Cycle
Zygote
Schizogony
Sporogony
Hypnozoites
(for P. vivax
and P. ovale)

4. Malaria Transmission Cycle
Parasite undergoes
sexual reproduction in
the mosquito
Some merozoites
differentiate into male or
female gametocyctes
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts
Dormant liver stages
(hypnozoites) of P.
vivax and P. ovale
Exo-erythrocytic (hepatic) Cycle:
Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood
MOSQUITO HUMAN
Sporozoires injected
into human host during
blood meal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands

5. Components of the Malaria Life Cycle
Mosquito Vector
Human Host
Sporogonic cycle
Infective Period
Mosquito bites
gametocytemic
person
Mosquito bites
uninfected
person
Prepatent Period
Incubation Period
Clinical Illness
Parasites visible
Recovery
Symptom onset

6. Exo-erythrocytic (tissue) phase
•Blood is infected with sporozoites about 30
minutes after the mosquito bite
•The sporozoites are eaten by macrophages
or enter the liver cells where they multiply –
pre-erythrocytic schizogeny
•P. vivaxand P. ovalesporozoites form
parasites in the liver called hypnozoites

7. Exo-erythrocytic (tissue) phase
•P. malariaeor P. falciparum sporozoites do
not form hypnozites, develop directly into
pre-erythrocytic schizonts in the liver
•Pre-erythrocytic schizogeny takes 6-16 days
post infection
•Schizonts rupture, releasing merozoites
which invade red blood cells (RBC) in liver

8. Relapsing malaria
•P. vivax and P. ovale hypnozoites remain
dormant for months
•They develop and undergoe pre-erythrocytic
sporogeny
•The schizonts rupture, releasing merozoites
and produce clinical relapse

9. Exo-
erythrocytic
(hepatic) cycle
Sporozoites
Mosquito Salivary
Gland
Malaria Life
Cycle
Life Cycle
Gametocytes
Oocyst
Erythrocytic
Cycle
Zygote
Schizogony
Sporogony
Hypnozoites
(for P. vivax
and P. ovale)

10. Exo-erythrocytic (tissue) phase
•P. vivax and P. ovale hypnozoites remain
dormant for months
•They develop and undergoe pre-erythrocytic
sporogeny
•The schizonts rupture, releasing merozoites
and producing clinical relapse

11. Erythrocytic phase
•Pre-patent period –interval between date of
infection and detection of parasites in peripheral
blood
•Incubation period –time between infection and
first appearance of clinical symptoms
•Merozoites from liver invade peripheral (RBC)
and develop causing changes in the RBC
•There is variability in all 3 of these features
depending on species of malaria

12. Erythrocytic phase
stages of parasite in RBC
•Trophozoites are early stages with ring form the
youngest
•Tropohozoite nucleus and cytoplasm divide
forming a schizont
•Segmentation of schizont’s nucleus and
cytoplasm forms merozoites
•Schizogeny complete when schizont ruptures,
releasing merozoites into blood stream, causing
fever
•These are asexual forms

13. Erythrocytic phase
stages of parasite in RBC
•Merozoites invade other RBCs and
schizongeny is repeated
•Parasite density increases until host’s
immune response slows it down
•Merozoites may develop into gametocytes,
the sexual forms of the parasite

14. Schizogenic periodicity and fever
patterns
•Schizogenic periodicity is length of asexual
erythrocytic phase
–48 hours in P.f., P.v., and P.o.(tertian)
–72 hours in P.m. (quartian)
•Initially may not see characteristic fever pattern if
schizogeny not synchronous
•With synchrony, periods of fever or febrile
paroxsyms assume a more definite 3 (tertian)-or
4 (quartian)-day pattern

15. Clinical presentation
•Early symptoms
–Headache
–Malaise
–Fatigue
–Nausea
–Muscular pains
–Slight diarrhea
–Slight fever, usually not intermittent
•Could mistake for influenza or gastrointestinal
infection

16. Clinical presentation
•Acute febrile illness, may have periodic febrile
paroxysms every 48 –72 hours with
•Afebrile asymptomatic intervals
•Tendency to recrudesce or relapse over months to
years
•Anemia, thrombocytopenia, jaundice,
hepatosplenomegaly, respiratory distress
syndrome, renal dysfunction, hypoglycemia,
mental status changes, tropical splenomegaly
syndrome

17. Clinical presentation
•Early symptoms
–Headache
–Malaise
–Fatigue
–Nausea
–Muscular pains
–Slight diarrhea
–Slight fever, usually not intermittent
•Could mistake for influenza or gastrointestinal
infection

18. Clinical presentation
•Signs
–Anemia
–Thrombocytopenia
–Jaundice
–Hepatosplenomegaly
–respiratory distress syndrome
–renal dysfunction
–Hypoglycemia
–Mental status changes
–Tropical splenomegaly syndrome

19. Types of Infections
•Recrudescence
–exacerbation of persistent undetectable parasitemia, due
to survival of erythrocytic forms, no exo-erythrocytic
cycle (P.f., P.m.)
•Relapse
–reactivation of hypnozoites forms of parasite in liver,
separate from previous infection with same species (P.v.
and P.o.)
•Recurrence or reinfection
–exo-erythrocytic forms infect erythrocytes, separate
from previous infection (all species)
•Can not always differentiate recrudescence from
reinfection

20. Clinical presentation
•Varies in severity and course
•Parasite factors
–Species and strain of parasite
–Geographic origin of parasite
–Size of inoculum of parasite
•Host factors
–Age
–Immune status
–General health condition and nutritional status
–Chemoprophylaxis or chemotherapy use
•Mode of transmission
–Mosquito
–Bloodborne, no hepatic phase (transplacental,
needlestick, transfusion, organ donation/transplant)

21. Malarial Paroxysm
•Can get prodrome 2-3 days before
–Malaise, fever,fatigue, muscle pains, nausea, anorexia
–Can mistake for influenza or gastrointestinal infection
–Slight fever may worsen just prior to paroxysm
•Paroxysm
–Cold stage -rigors
–Hot stage –Max temp can reach 40-41
o
C,
splenomegaly easily palpable
–Sweating stage
–Lasts 8-12 hours, start between midnight and midday

22. Malarial Paroxysm
•Periodicity
–Days 1 and 3 for P.v., P.o., (and P.f.) -tertian
–Usually persistent fever or daily paroxyms for
P.f.
–Days 1 and 4 for P.m. -quartian

23. Presentation of P.v.
•Lack classical paroxysm followed by
asymptomatic period
•Headache,dizziness, muscle pain, malaise,
anorexia, nausea, vague abdominal pain, vomiting
•Fever constant or remittent
•Postural hypotension, jaundice, tender
hepatosplenomegaly

24. Common features of P.vivax
infections
•Incubation period in non-immunes 12-17 days but
can be 8-9 months or longer
•Some strains from temperate zones show longer
incubation periods, 250-637 days
•First presentation of imported cases –1 month –
over 1 year post return from endemic area
•Typical prodromal and acute symptoms
–Can be severe
–However, acute mortality is very low

25. Common features of
P.vivaxinfections
•Most people of West African descent are
resistant to P.v.
–Lack Duffy blood group antigens needed for
RBC invasion
•Mild –severe anemia, thrombocytopenia,
mild jaundice, tender hepatosplenomegaly
•Splenic rupture carries high mortality
–More common with P.v.than with P.f.

26. Common features of
P.vivaxinfections
•Relapses
–60% untreated or inadequately treated will
relapse
–Time from primary infection to relapse varies
by strain
–Treat blood stages as well as give terminal
prophylaxis for hypnozoites

27. Common features of
P. ovale infections
•Clinical picture similar to P.v.but
•Spontaneous recovery more common
•Fewer relapses
•Anemia and splenic enlargement less severe
•Lower risk of splenic rupture
•Parasite often latent and easily suppressed by
more virulent species of Plasmodia
•Mixed infection with P.o.usually in those exposed
in tropical Africa

28. Common features of
P. malariae infections
•Clinical picture similar to P.v.but prodrome
may be more severe
•Incubation period long –18-40 days
•Anemia less pronounced than P.v.
•Gross splenomegaly but risk of rupture less
common than in P.v.
•No relapse –no hepatic phase or persisting
hepatic cycle

29. Common features of
P. malariae infections
•Undetectable parasitemia may persist with
symptomatic recrudescences
–Frequent during first year
–Then longer intervals up to 52 years
•Asymptomatic carriers may be detected at time of
blood donation or in cases of congenital
transmission
•Parasitemia rarely > 1%, all asexual stages can be
present
•Can cause nephrotic syndrome, prognosis is poor

30. Features of P.falciparumcases
•Lack classical paroxysm followed by
asymptomatic period
•Headache,dizziness, muscle pain, malaise,
anorexia, nausea, vague abdominal pain, vomiting
•Fever constant or remittent
•Postural hypotension, jaundice, tender
hepatosplenomegaly
•Can progress to severe malaria rapidly in non-
immune patients
•Cerebral malaria can occur with P.f.
•Parasites can sequester in tissues, not detected on
peripheral smear

31. Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Pre-
erythroctic
stage (days)
6-8 9 14-16 5.5-7
Pre-patent
period (days)
11-13 10-14 15-16 9-10
Incubation
period (days)
15 (12-17)
or up to 6-
12 months
17 (16-18)
or longer
28 (18-40)
or longer
12 (9-14)
Erythrocytic
cycle (hours)
48 (about)50 72 48

32. Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Paraitemia
per μl
Average
Maximum
20,000
50,000
9,000
30,000
6,000
20,000
20,000-
50,000
2,000,000
Primary
attack*
Mild-
severe
Mild Mild Severe in
non-
immunes
Febrile
paroxysms
(hours)
8-12 8-12 8-10 16-36 or
longer

33. Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Invasion
requirements
Duffy –ve
blood
group
? ? ?
Relapses ++ ++ - -
Recrude-
scences
+ + - -

34. Some characteristics of infection with
four species of human Plasmodia
P.v. P.o. P.m. P.f.
Period of
recurrence **
VariableVariableVery longshort
Duration of
untreated
infection
(years)
1.5-5 Probably
same as
P.v.
3-50 1-2
*The severity of infection and the degree of parasitemia are greatly influenced by the immune response. Chemoprphylaxis
May suppress an initial attack for weeks or months.
** Patterns of infection and of relapses vary greatly in different strains.
Bruce-Chwatt’ Essential Malariology, 3
rd
rev ed. 1993

35. Congenital malaria
•Transplacental infection
–Can be all 4 species
–Commonly P.v.and P.f.in endemic areas
–P.m.infections in nonendemic areas due to long
persistence of species
•Neonate can be diagnosed with parasitemia within
7 days of birth or longer if no other risk factors for
malaria (mosquito exposure, blood transfusion)
•Fever, irritability, feeding problems, anemia,
hepatosplenomegaly, and jaundice
•Be mindful of this problem even if mother has not
been in malarious area for years before delivery

36. Immunity
•Influenced by
–Genetics
–Age
–Health condition
–Pregnancy status
–Intensity of transmission in region
–Length of exposure
–Maintenance of exposure

37. Immunity
•Innate
–Red cell polymorphisms associated with some
protection
•Hemoglobin S sickle cell trait or disease
•Hemoglobin C and hemoglobin E
•Thalessemia –α and β
•Glucose –6 –phosphate dehydrogenase deficiency
(G6PD)
–Red cell membrane changes
•Absence of certain Duffy coat antigens improves
resistance to P.v.

38. Immunity
•Acquired
–Transferred from mother to child
•3-6 months protection
•Then children have increased susceptibility
–Increased susceptibility during early childhood
•Hyper-and holoendemic areas
–By age 5 attacks usually < frequent and severe
–Can have > parasite densities with fewer symptoms
•Meso-or hypoendemic areas
–Less transmission and repeated attacks
–May acquire partial immunity and be at higher risk for
symptomatic disease as adults

39. Immunity
•Acquired
–No complete immunity
•Can be parasitemic without clinical disease
–Need long period of exposure for induction
–May need continued exposure for maintenance
–Immunity can be unstable
•Can wane as one spends time outside endemic area
•Can change with movement to area with different
endemicity
•Decreases during pregnancy, risk improves with
increasing gravidity

41. Antimalarial
drugs

42. Plasmodium species which
infect humans
Plasmodium vivax (tertian):
Plasmodium ovale (tertian)
Plasmodium falciparum (tertian)
Plasmodium malariae (quartan)
Plasmodium knowlesi:

43. Sir RonaldRoss

45. Schizogony
(asexual)
Man : Intermediate host
Mosquito : Definitive host
Life cycle of the malarial
parasite
True causalprophylactics
Causal
prophylactics
Supressives
Gametocidal
Sporonticide
Sporogeny
(sexual)

46. •Classification of antimalarialdrugs
–Therapeuticclassification
–Chemical classification

47. Therapeuticclassification
•Causal prophylaxis: (Primary tissue
schizonticides)
–Destroy parasite in liver cells and prevent invasion of
erythrocytes
–Primaquine, proguanil
•Supressives Prophylaxis:
–Supress the erythrocytic phase and thus attack of
malarial fever can be used as prophylactics
–Chloroquine, proguanil, mefloquine, doxycycline

48. Therapeuticclassification
•Clinical cure: erythrocytic schizonticides
–used to terminate an episode of malarial fever
•Fast acting high efficacy
–Chloroquine, quinine, mefloquine,
atovaquone, artemisinin
•Slow acting low efficacy drugs
–Proguanil, pyrimethamine, sulfonamides,
tetracyclines

49. Therapeuticclassification
•Radical curatives:
–Eradicate all forms of P.vivax & P.ovale from the body
–Supressive drugs + hypnozoitocidal drugs
–For vivax: primaquine 15 mg daily for 14 days
•Gametocidal:
–Destroy gametocytes and prevent transmission
–Primaquine, artemisinin–againstall plasmodia
–Chloroquine, quinine –Pl Vivax
–Proguanil,pyrimethamine–prevent
development of sporozoites

50. Chemical
classification
•4 aminoquinolines:
–Chloroquine, Hydroxychloroquine, Amodiaquine, Pyronari
dine
•8 aminoquinolines:
–Primaquine, Tafenoquine, Bulaquine
•Cinchona alkaloids:
–Quinine, Quinidine
•Quinoline methanol:
–Mefloquine
•Biguanides
–Proguanil, Chlorproguanil

51. Chemical
classification
•Diaminopyrimidines
–Pyrimethamine
•Sulfonamides
–Sulfadoxine,dapsone
•Tetracyclines:
–tetracycline, doxycycline
•Naphthoquinone:
–Atovaquone
•Sesquiterpene lactones:
–Artesunate, artemether,arteether

52. •Chloroquine:
–Synthesized by Germans in 1934 (resochin)
–d & l isomers,d isomer is less toxic
–Cl at position 7 confers maximal antimalarial
efficacy

53. Hemoglobin Globin utilized by
malarial parasite
Heme (highly toxicformalariaparasite)
(+)HemePolymerase
Chloroquine
Quinine,
mefloquine(-)
Hemozoin (Not toxic toplasmodium)
Mechanism of
action

54. Pharmacologicalactions
1.Antimalarial activity:
–High against erythrocytic forms of
vivax, ovale, malariae& sensitive strains of
falciparum
–Gametocytes of vivax
–No activity against tissue schizonts
–Resistance develops due to efflux mechanism
1.Other parasitic infections:
–Giardiasis,taeniasis,extrainstestinal
amoebiasis
2.Other actions:
–Depressant action on myocardium, direct relaxant
effect on vascular smooth
muscles, antiinflammatory, antihistaminic , local

55. Pharmacokinetics
•Well absorbed, tmax 2-3 hrs , 60 % protein
bound
•Concentratedin liver , spleen, kidney, lungs ,
leucocytes
•Selective accumulation in retina:occular
toxicity
•T1/2 = 3-10 daysincreases from few days
to weeks

56. Adverse drugreactions
•Intolerance:
–Nausea, vomiting, anorexia
–skin rashes, angioneurotic edema,
photosensitivity, pigmentation, exfoliative
dermatititis
–Long term therapy may cause bleaching of hair
–Rarely thrombocytopenia, agranulocytosis,
pancytopenia

57. Adverse drugreactions
•Occular toxicity: High dose prolonged therapy
–Temporary loss of accommodation
–Lenticular opacities, subcapsular cataract
–Retinopathy: constriction of arteries, edema, blue
black pigmentation , constricted field of vision.
•CNS:
–Insomnia, transient depression seizures, rarely
neuromyopathy& ototoxicity
•CVS:
–ST & T wave abnormalities, abrupt fall in BP &
cardiac arrest in children reported

58. Dosage
•600 mg of basestat
•300 mg base after 8hours
•150 mg of base BD for 2days
•200 mg oral tablet of chloroquine phosphate
consists of 150 mg base

59. Chloroquine is administered in
loading dose in malaria
•Chloroquine is well absorbed after oral
administration. It is extensively tissue bound
and sequestrated by tissues particularly liver,
spleen, kidney it has got large apparent
volume of distribution
•So it is given in loading dose to rapidly achieve
the effective plasma conc.

60. Therapeuticuses
1.Hepaticamoebiasis:
2.Giardiasis
3.Clonorchis sinensis
4.Rheumatoidarthritis
5.Discoid LupusErythematosus
6.Control manifestation of leprareaction
7.Infectiousmononucleosis

61. •Hydroxychloroquine:
–Less toxic, properties &usessimilar
•Amodiaquine:
–As effective aschloroquine
–Pharmacological actionssimilar
–Chloroquine resistant strains may beeffective
–Adverse events: GIT,headache
, photosensitivity, rarelyagranulocytosis
–Not recommended forprophylaxis
•Pyronaridine: effective in resistantcases

62. Quinine
•1820 Pelletier & caventou isolated quinine
from cinchonabark.
•Mechanism of action:
–Similar to chloroquine

63. Pharmacologicalactions
1.Antimalarial action:
–Erythrocytic formsof all malarial parasites including
resistant falciparum strains .
–Gametocidal for vivax & malariae
2.Local irritant effect:
–Local pain sterile abcess.
3.Cardiovascular:
–depresses myocardium, ↓ excitability, ↓ conductivity,
↑ refractory period, profound hypotension IV.
4.Miscellaneousactions:
–Mild analgesic, antipyretic activity , stimulation of
uterine smooth muscle, curaremimitic effect

64. Adverse drugreactions
Cinchonism:
•Tinnitus, nausea& vomiting
•Headache mental confusion, vertigo,
difficulty in hearing & visual disturbances
•Diarrhoea , flushing & marked perspiration
•Still higher doses , exagerated symptoms
with delirium , fever, tachypnoea,
respiratory depression , cyanosis.

65. Adverse drugreactions
•Idiosyncrasy : similar to cinchonism but
occurs in therapeutic doses
•Cardiovascular toxicity: cardiac arrest,
hypotension ,fatal arrhytmias
•Black water fever:
•Hypoglycemia:

66. Uses
•Malaria:
–uncomplicated resistant falciparum malaria
–Cerebral malarial
•Myotonia congenita: 300 to 600 mg BD/ TDS
•Nocturnal muscle cramps: 200 –300 mg
before sleeping
•Spermicidal in vaginal creams
•Varicose veins: along with urethane causes
thrombosis & fibrosis of varicose vein mass

67. –Interfereswith oxygen transportsystem
•Primaquine:
–Mechanism of action:
Primaquine
Converted to
electrophiles
Generates reactive
oxygen species

68. Antimalarial
action
•Liver hypnozoites
•Weak action against erythrocytic stage of
vivax, so used with supressives in radical cure
•No action against erythrocytic stage of
falciparum
•Hasgametocidalactionandismosteffective
antimalarialtopreventtransmissiondisease
againstall4species

69. Adverseeffects
•Gastrointestinal:
–epigastric
distress, abdominal cramps ,
•Hemopoetic:
–mild
anemia, methaemoglobinem ia,
cyanosis, hemolytic anemia in
G6PD deficiency
•Avoided during
pregnancy,G6PD deficient

70. Uses
•Primary use is radical cure of relapsing malaria
15 mg daily for 14 days with dose of
chloroquine
•Falciparum malaria 45 mg of single dose with
chloroquine curative dose to kill gametes &
cut down transmission of malaria.

71. •Tafenoquine:
–More active slowly metabolized analog of
primaquine, has advantage that it can be given on
weekly basis.
•Bulaquine:
–Congener of primaquine developed in india
–Comparable antirelapse activity when used for 5
days
–Partly metabolized to primaquine
–Better tolerated in G6PD deficiency

72. Mefloquine
•Quinoline methanol derivative developed to
deal with chloroquine resistant malaria
•Rapidly acting erythrocytic schizonticide ,
slower than chloroquine & quinine
•Effective against chloroquine sensitive &
resistant plasmodia
•Mechanism of action similar to chloroquine

73. Pharmacokinetics
•Good but slow oral absorption
•High protein binding
•Concentrated in liver, lung, intestine
•Extensive metabolism in liver, primarily
secreted in bile , under goes enterohepatic
circulation
•Long t1/2 = 2 –3 weeks

74. Adverseevents
•GIT:
–bitter in taste, nausea, vomiting , abdominal pain ,
diarrhoea
•Neuropsychiatric disturbances:
–anxiety, hallucinations, sleep disturbances,
psychosis, errors in operating machinery,
convulsions
•CVS:
–Bradycardia, sinus arhythmia, & QT prolongation
•Teratogenicity:
–Avoided in firsttrimester
•Miscellaneous:
–allergic skin reactions, hepatitis & blooddyscrasias

75. Uses
•Effective drug for MDR falciparum
1.T/t of uncomplicated falciparum in MDR malaria
should be used along with artesunate (ACT)
2.Prophylaxis in MDR areas 250 mg perweek
started 2-3 weeks before to asses side effects
•Due to fear of development of drug
resistance mefloquine should not be used as
drug for prophylaxis in residents of endemic
area

76. Halofantrine
•Quinoline methanol
•Used in chloroquine resistant malaria since
1980
•Erratic bioavailabilty, lethal cardiotoxicity &
cross resistance to mefloquine limited its use
•Now a days used only when no other
alternative available
•Adverse events; Nausea, vomiting, QT
prolongation , diarrhoea, itching , rashes
•C/I: along with
quinine, chloroquine, antidepressants, antips
ychotics

77. Atovaquone
•Synthetic napthoquinone
•Rapidly acting erythrocytic schizonticide for
plasmodium falciparum & other plasmodia
•MOA: Collapses mitochondrial membrane &
interferes ATP production
•Proguanil potentiates action of atovaquone
and prevents development of resistance
•Also used in P. Jivoreci & Toxoplasma gondii
infections

78. Dihydrofolate reductaseinhibitors
•Proguanil :
–Biguanide converted to cycloguanil active
compound
–Act slowly on erythrocytic stage of vivax &
falciparum
–Prevents development of gametes
Adverse effects:
Stomatitis, mouth ulcers, larger doses depression
of myocardium , megaloblastic anemia
Not a drug for acute attack
Causal prophylaxis: 100 –200 mg daily

79. Pyrimethamine
•Diaminopyrimidine more potent than proguanil
& effective against erythrocytic forms ofall
species.
•Tasteless so suitable for children
Adverse events: megaloblastic
anemia, thrombocytopenia, agranulocytosis.

80. Sulfadoxine-pyrimethamine
•Sequential blockade
•sulfadoxine 500 mg + pyrimethamine 25 mg, 3
tablets once for acute attack
•Not recommended for prophylaxis
•Use:
–single dose treatment of uncomplicated
chloroquine resistant falciparum malaria
–patients intolerant to chloroquine
–First choice treatment for toxoplasmosis

81. Artemisini
n
•Artemisinin is the active principle of the plant
artimisia annua
•Sesquiterpine lactone derivative
•Most potent and rapid acting blood
schizonticides
•Short duration of action
•high recrudescence rate
•Poorly soluble in water & oil

82. Artemisinin
derivatives
•Artesunate
•Artemether
•Arteether

83. PLANT-ARTEMISIA
ANNUA

84. Mechanism ofaction
•These compounds have presence of endoperoxide
bridge
•Endoperoxide bridge interacts with heme in parasite
•Heme iron cleaves this endoperoxide bridge
•There is generation of highly reactive free radicals which
damage parasite membrane by covalently binding to
membrane proteins

85. Antimalarial
action
Artemisinin
Artemisinin
Conventional
Treatment

86. Artesunate
•Water soluble ester ofdihydroartemisinin
•Dose: can be given oral, IM,IV,rectal
–Oral
•100 mg BD on day1
•50 mg BD day 2 to day5
–Parenteral
•120 mg on day 1(2.4mg/kgBD)
•60 mgOD (2.4mg/kg)for 7 days

87. Artemether
•Methyl ether ofdihydroartemisinin
•Dose:
•Oral &IM
•80 mg BD on day 1 (3.2mg/kg)
•80 mg OD (1.6 mg/kg) for 7days

88. Arteether
•Ethyl ether of dihydroartemisinin
•Therapeutically equivalent to quinine in
cerebral malaria
•A longer t
1/2 & more lipophilic than
artemether favouring accumulation in brain
•Dose:3.2 mg/kg on day1 followed by 1.6
mg/kg daily for next 4 days

89. Adverseevents
•Leucopenia
•Hypersensitivity: Drug fever, itching
•GIT: nausea, vomiting, abdominal pain
(common)
•ECG changes: ST-T changes, QT prolongation
•Abnormal bleeding, dark urine
•Reticulocytopenia

90. Artemisinin based combination
therapy (ACT)
•Artemisinin compunds are shorter acting drugs
•Monotherapy needs to be extended beyond
disappearance of parasite to prevent
recrudescence
•This can be prevented by combining 3-5 day
regimen of artemisin compounds with one long
acting drug like mefloquine 15 mg/kg single
dose
•Indicated by WHO in acute uncomplicated
resistant falciparum malaria

91. Why combinationtherapy
•Rapid clinical & parasitologicalcure
•High cure rates and low relapserates
•Absence ofresistance
•Good tolerabilityprofile

92. ACT Regimens in
use
•Artesunate –Sulfadoxine, pyrimethamine:
–Adopted as first line in india under NMP
–ARTESUNATE 100 mg BD for 3 days with S-P, 3
tablets
•Artesunate Mefloquine:
–By combining artesunate further spread of
mefloquine resistance can be prevented
–Artesunate 100 mg BD for 3 days, + mefloquine
750 mg on second day & 500 mg on third day

93. Artemether &lumefantrine
•Lumefantrine is highly effective , long acting
oral erythrocytic schizonticide related to
mefloquine
•Highly lipophilic onset delayed , peak 6 hrs
•Available as fixed dose combination
•80 mg artemether BD WITH 480 mg
lumefantrine BD for 3 days
Other ACTs:
–DHA –Piperaquine, Artesunate-pyronaridine

94. Tetracyclines
•Slow but potent action on erythrocytic stage
of all MP & Pre-erythrocytic stage of
falciparum
•Always used in combination with quinine or S-
P for treatment of chloroquine resistant
malaria

95. Management ofMalaria

96. Prophylaxis of
malaria
•Indication:
•Duration :1-2 weeks before to 4 weeks
after returning from endemic area
•Drug regimens:
–Chloroquine sensitive malaria: 300 mg / week
–Chloroquine resistant malaria:
•Mefloquine 250 mg once a week ,
•Doxycycline 100 mg daily ,
•Atovaquone + proguanil daily

97. Drugs not allowed for
prophylaxis
•Quinine , artemisinincompounds
–Shorter acting, highertoxicity
•Pyrimethaminesulfadoxine
•Amodiaquine

98. •Tab. Chloroquine phosphate 250 mg
–Contains 150 mg of base
–Give 4 tablets stat , 2 tablets after 8 hours and , 1
tablet BD for 2 days
•Patients who cannot take orally
–3.5 mg/kg IM every 6 hrs for 3 days
•Tab primaquine 15 mg OD for 14 days in
Plasmodium vivax, ovale
•Primaqine 45 mg single dose for falciparum
after chloroquine (gametocidal)
Acute attack of chloroquine
sensitive malaria:

99. Acute attack of chloroquine
resistant malaria
A.Pts who can take orally:
–3tabletsof(Pyrimethamine+sulfadoxine)single
dosefollowedbyquinine600mgTDSfor2daysor
–Tab Quinine 600 mg TDS X3 days with Cap
doxycycline100 mg BD for 7 days or
–Quinine 3 days with mefloquine or
–(Atovaquone 250 mg + proguanil 100 mg) 4
tab(Single dose ) for 3 days or
–artesunate 100 mg BD x 3 days with Sulfadoxine-
pyrimethamineor mefloquine

100. •Pts who cannot take orally
–Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline
over 4 hrs then
–10 mg/kg in dextrose saline over 2 hrs every 8 hrly
till patient is able to swallow
–Then quinine 600 mg TDS for 7 days &
tetracycline/ doxycycline
Or
–artemether / arteether injection

101. When should resistance be
suspected
•All pts with complication
•Any pt who has already received chloroquine
last 1 month
•Hb continues to fall in absence of bleeding &
asexual forms persist along with symptoms
after 48 hrs of treatment

102. Severe and complicated
falciparum malaria•Hyperparasitaemia
•Hyperpyrexia
•Fluid electrolyte disturbances,acidosis
•Hypoglycemia
•Cardiovascularcollapse
•Jaundice, severeanaemia
•Spontaneousbleeding
•Pulmonaryedema
•Renalfailure
•Hemoglobinuria, black waterfever
•Cerebralmalaria

103. Treatment of severe and
complicated falciparum
malaria
•Artesunate 2.4 mg/kg IV/IM, BD on day1
then 2.4 mg/kg daily for 7 days OR
•Artemether 3.2 mg/kg IM on day 1then
1.6 mg/kg daily for 7 daysOR
•Arteether 3.2 mg/kg IM on day1, followed by
1.6 mg/kg daily for next 4 days
–Switchover to 3 Day oralACT in between
whenever patient can take oral medication

104. O
R
•Quinine: 20 mg quinine salt/kg on admission
(i.v. infusion in 5% dextrose/dextrose saline
over a period of 4 hours) followed by
maintenance dose of 10 mg/kg body weight 8
hourly.
–When ever patient can swallow orallyswitch
over to oral quinine 10 mg/kg 8 hrly and complete 7
days course

105. •Malaria in children:
–Quinine parenteral high toxicity / oral well
tolerated
–Primaquine avoided in neonates
–Mefloquine not used in children below 15 kg
weight
•Acute malaria in pregnant women
–Chloroqune in usual doses
–Mefloquine C/I in first trimester
–Primaquine/ tetracycline avoided
–Anemia: folic acid & iron

106. Practicepoints
•Most antimalarials are bitter in taste give
along with milk or fruit juice
•If vomiting occurs within hour of drug repeat
full dose, in case of mefloquine repeat half
dose
•If vomiting after 1 hour no need to repeat
•Postural hypotension : quinine, chloroquine

107. Drugs used in chloroquine
resistant malaria
•Mefloquine
•Quinine
•Sulfadoxinepyrimethamine
•Artemisinincompounds

109. Sedative-Hypnotic Drugs
-----prescribed to cause sedation (for patients with anxiety)
or to encourage sleep (for patients with insomnia)

111. Chemical classification
•Benzodiazepines: diazepam (安定), nitrazepam (硝西泮),
oxazepam (奥沙西泮 ), estazolam (艾司唑仑 ), triazolam (三唑仑),
flunitrazepam (氟硝西泮 )，etc (with same nucleus and different
substituents)
•Barbiturates: pentobarbital(戊巴比妥 ), phenobarbital (苯巴比妥
), thiopental (硫喷妥), etc
•Others: buspirone (丁螺环酮 ), chloral hydrate (水合氯醛 ),
meprobamate (甲丙氨酯 ), etc
•Antipsychotic, antidepressant drugs and certain antihistaminic
agents

112. 1.ADME
(1)Oralabsorption
(2)Lipid solubility-dependent distribution (across
BBB), placental penetrability (effect on fetus)
(3)Hepaticmetabolism---activemetabolites
(4)Urinaryexcretion
A.Benzodiazepines

113. 1.ADME
(5)Classificationaccordingtoactionduration
Short-acting:triazolam,laorazepam,oxazepam,etc
Medium andlong-acting:diazepam,nitrazepam,
chlordiazepoxide,flurazepametc
A.Benzodiazepines

114. Disassociation of effect and half-life time

115. 2.Pharmacologicaleffectsandclinicaluses
(1)Reductionofanxiety:atsmalldoses,usedas
anxiolytics(notworkonschizophrenia)
(2)Sedative-hypnoticeffects
--atrelativelyhigherdoses
--noanestheticeffect
--noenzymeinduction
--noremarkableeffectonREM,decreaseslowwavesleep
--usedforinsomniaandpreanestheticmedication(as
adjuvanttoanesthetics)
A.Benzodiazepines

116. (3) Antiepileptic and anticonvulsant effects
epilepsy,status epilepticus (i.v.), convulsion
(4) Centrally acting muscle relaxant effect
--relaxing the spasticity of skeletal muscle, probably
by increasing presynaptic inhibition in the spinal cord.
--used for the treatment of skeletal muscle spasms
caused by central or peripheral diseases.
A.Benzodiazepines

117. (5) Others
--dose-dependentanterogradeamnesiceffects(i.v.）
-forunpleasantexaminationortherapy(cardioversion,
endoscope,etc)
--respiratoryandCVSeffects(centralinhibition)
--alleviatethewithdrawsyndromes
A.Benzodiazepines

118. Graded dose-dependentdepressive effect of sedative-
hypnotics on central nervous system function
Benzodiazepi
nes

119. 3.Mechanismsofactions
(1)Sitesofaction:mainlyactsonlimbicsystem
(anxielytic)andmidbrainreticularformation
(hypnotic).
(2)InteractionwithGABA
Areceptor
-----increasethefrequencyofGABA-induced
channel-openingevents
-----GABAdependentefficacy
A.Benzodiazepines

121. 4.Adverseeffects
(1)Centraldepression
Mostcommon:drowsinessandconfusion
ataxia;cognitiveimpairment(hangovereffect)
AntagonizedbyBZreceptorantagonistflumazenil
AdditivewithotherCNSdepressantdrugs
(2) Tolerance: lethal dose is not altered
(3)Dependence:compulsivemisuse
Withdrawalsyndrome(shorteractingagents):restlessness,
anxiety,weakness,orthostatichypotensionandgeneralized
seizures
A.Benzodiazepines

122. (3)Others
RespiratoryandCVSreactions
Teratogeniceffects(PregnancyCategoryDorX)
(4) Contraindications
Myastheniagravis(重症肌无力 )
Infants<6months
Pregnantandlactationmothers
Elderlywithheart/lung/liver/kidneydysfunction
Workersrequiringmentalalertnessandfinemotor
coordination
A.Benzodiazepines

123. 1.ADME
-hepaticenzymeinducer
-alkalizingurine(sodiumbicarbonate):excretion
2.Pharmacologicaleffectsandclinicaluses
(1)Sedative-hypnoticeffects-REMdecrease
(2) Antiepileptic and anticonvulsant effects
(3) Preanesthetic medication
B.Barbiturates

124. •increase the
duration of the
GABA-gated
chloride ion channel
openings
•GABA-mimetic at
high dose –GABA
independent efficacy

125. 3.Adverseeffects
(1)Centraldepression:after(hangover)effect
(2) Tolerance and dependence: long-term uses, REM
rebound
(3)Porphyria(enhancesporphyrinsynthesis):
anemia,photosensitiveskininjury
(4)Acutepoisoning
---supportingtherapies:oxygeninhalation,unblocked
respiratorytract(tracheotomy),centralstimulants
---alkalizingurine
---hemodialysis
B.Barbiturates

126. Marilyn Monroe (1926-1962)

127. Graded dose-dependentdepressive effect of sedative-
hypnotics on central nervous system function
Benzodiazepi
nes
Barbiturates

128. •Chloralhydrate
Sedative-hypnotic effects
Anticonvulsant effect:children (anal administration)
•Meprobamate:sedative,hypnotive,anxiolytic
•Buspirone:anxiolytic,minimalabuseliability
C.Other sedative-hypnotic drugs

129. •Antipsychotics
•Antidepressant drugs
•Antihistaminic agents
•Ethanol
•Melatonin (pineal hormone)
C.Other sedative-hypnotic drugs

130. Summary of clinical uses of sedative-
hypnotics

132. LOCAL ANDGENERAL
ANAESTHESIA

133. INTRODUCTIO
N
ANAESTHESIA :
GENERAL
ANAESTHESIA
LOCAL
ANAESTHESIA

134. What is Anaesthesia
???
Anesthesia –is a reversible condition of comfort and
quiescence for a patient within the physiological limit
before, during and after performance of a procedure.
Generalanesthesia–forsurgicalprocedureto
renderthepatientunaware/unresponsivetothe
painfulstimuli.
Drugs producing General Anaesthesia –are called General
Anaesthetics.
Local anesthesia -reversible inhibition of impulse
generation and propagation in nerves. In sensory
nerves, such an effect is desired when painful
procedures must be performed, e.g., surgical or
dental operations.
Drugs producing Local Anaesthesia –are called Local
Anaesthetics e.g. Procaine, Lidocaine and Bupivacaine etc.

135. LOCALANAESTHETICS

136. DIFFERENCE BETWEEN GENERAL
ANAESTHESIA & LOCAL ANAESTHESIA
FEATURES Gen.AnaesthsiaLocalAnaesthsia
Site of action
Area of body involved
Consciousness
Care of vital functions
CNS
Whole body
Lost
Essential
Peripheral nerves
Restricted area
Unaltered
Usually not needed
Risky
Possible
Safer
Notpossible
Poor health patients
Use in non cooperative
patients
Major surgery
Minor surgery
Preferred
Notpreferred
Cannot bepreferred
preferred

137. LOCAL
ANAESTHETICS
DEFINITION: are drugs which, when
applied directly to peripheral nervous
tissue, block the nerve conduction and
abolish all sensations in the part supplied
by the nerve without loss of
consciousness.

138. FEATURES OF LOCAL
ANAESTHETICS
Should have quick onset of action
Should not be irritating to skin & mucous membranes
Duration of action must be long enough to allow desired
surgery to be completed
Should be effective on both injection & local application
Should have low Systemic toxicity

139. Should not cause any permanent damage on any
tissue.
Should be relatively free from producing allergic
reaction.
Should be stable in solution and readily undergo
biotransformation.
No LA in use today satisfy all of these criteria
, however all anesthetics do meet a majority
of them.
Contd…

140. Chemistr
y
All local anesthetics are weak bases,they have
amphiphilic property
Consist of hydrophilic secondary or tertiary amine on
one side
Lipophilic aromatic residue on other side
Two are joined by an alkyl chain through an ester or
amide linkage

141. Based on linkage they can
be
classifiedas

142. ADVANTAGE OF AMIDE LAsOVER
ESTERLAs
Produce more intense and longer lasting
anaesthesia .
Bind to α
1 acid glycoprotein in plasma.
Not hydrolysed by plasma esterases.
Rarely causes hypersensitivity reaction.

143. CLASSIFICATION
1.INJECTABLEANAESTHETIC :
 SHORTDURATIONLOW POTENCY,
procaine
chloroprocaine


INTERMEDIATE POTENCY AND DURATION
Lidocaine prilocaine
HIGH POTENCY, LONG DURATION
tetracaine bupivacaine ropivacaine dibucaine

144. 2.SURFACEANAESTHETIC:
INSOLUBLE
benzocaine
butylaminobenzoate
oxethazaine
SOLUBLE
cocaine
lidocaine
tetracaine
benoxinate

145. MECHANISM OF ACTION OFLAs


146. MECHANISM OF ACTION OFLAs
LA blocks the nerve conduction by reducing entry
of Na+ through the voltage gated channels
Due to this, they block the initiation & propagation
of nerve impulse.
At higher doses it also blocks
1.Voltage gated Ca
2+ channels
2.K
+ channels

147. PHARMACOKINETIC
S
Absorption
Local anesthetics are absorbed when ingested.
Some local anesthetics may be absorbed in toxic
amounts after topical use.
Absorption after an injection depends on drug
solubility in lipid and in water, tissue vascularity
and local anesthetic and vasoconstrictor
effects on local circulation.

148. Distribution: amides-wide distribution –I.V-lipophilics
taken up by highly perfused organs-then moderately
perfused
Ester type-short plasma half life
Metabolism and excretion
Esters are hydrolyzed by plasma and liver esterases.
Longer-acting esters are often metabolized more
slowly..Patients with altered pseudo-
cholinesterase activity may be highly sensitive to
these drugs.
Amides are metabolized in the liver by cyp450.-N-
dealkylation then hydrolysis except prilocaine-
hydrolysis first-o toludine-can cause
methhamoglobinemia

149. Patients with severe hepatic damage or advanced
congestive heart failure may be unusually sensitive to
these drugs.
Some amides are partially excreted unchanged in the
urine.
Acidification can enhance excretion PK properties of
amide LAs :

150. PRECAUTIONS AND INTERACTIONS
Aspirate lightly to avoid intravascular injection.
Inject the LA slowly &take care not to exceed the
maximum safe dose, especially in children.
Propranolol may reduce metabolism of lidocaine and
other amide LAs by reducing hepatic blood flow.
Vasoconstrictor (Adr) containing LA should be
avoided for patients with ischemic heart disease,
cardiac arrhythmia, uncontrolled hypertension those
receiving β-blockers or tricyclic antidepressants

151. Techniques of LocalAnaesthesia

152. Surface
Anaesthesia

153. Application of a local anesthetic to nose, mouth, throat,
tracheobronchial tree, esophagus.
Onset & duration depends on the site, the drug, its
concentration and form.
Absorption of soluble LAs from mucous membrane is
rapid.

154. Infiltration
Anaesthesia

155. Injection of LA directly into tissue under theskin.
used primarily for surgical procedures.
LAs most frequently used are lidocaine(1%), bupivacaine
(0.25%), etidocaine(0.5-1%), ropivacaine(0.5-1%),
mepivacaine(1-3%) and prilocaine(1-4%).
mix with adrenaline (1:20000) to prolong theaction.

156. Conductionblock:

157. Injected around nerve trunkssothatarea distalto
injection is anaesthetised andparalyzed.
-Choice of LA and concentration is mainlydetermined
by the required duration ofaction.
-Lidocaine for intermediate duration ofaction
-longer lasting anesthesia bupivacaine may be
selected.

158. -
Field block:
producedbyinjectingtheLAsubcutaneouslyinthe
surroundingareaofnervesothatallnervescoming
toparticularfieldareblocked.
-herniorrhaphy, appendicectomy, dental procedures,
scalp stitching, operations on forearms and legs etc.
-
-Larger area can be anaesthetized with lesser drug
compared to infiltration.

159. NerveBlock:
local anesthetic is injected around a nerve that leads to
the operative site.
Usually more concentrated forms of local anesthetic
solutions are used
eg: radial nerve block, ulner nerve block so on.
Nerve block lasts than field block or infiltration
anaesthesia.
Lidocaine (1.5%), mepivacaine(1.5%), bupivacaine (0.25-
0.35%) can be used.

160. Epidural
Anaesthesia.

161. spinal dural space is filled with semi liquid fatthrough
which nerve roottravel.
Injected in this space-acts primarily on nerveroots
and small amountspermeates through intravertebral
foramina to produce multiple paravertebralblocks.
used to produce analgesia or anaesthesia insurgical
andobstretric.
Divided into 3 categories depending on site ofaction:
1.Thoracic:
2.Lumbar:
3.Caudal:

162. Spinal
Anaesthesia.

163. Injected into the subarachnoid space between L2-3 or
L3-4 of the spinal cord .
Suitable LA like lidocaine(3-5%), bupivacaine (0.5-
0.8%), tetracaine(0.3-0.5%).
Primary site of action is caudaequinaratherthan
spinal cord.
Used to anaesthetize lower abdomen and hindlimbs.

164. Use of hyperbaric(in7.5-10% glucose) or hypobaric (in
distilled water) solution of LA.
proper positioning of the patient is also limitingthe
block to the desired level.
Advantages over general anaesthesia are:
Safer


Produces good analgesia and muscle relaxationwithout
loss ofconsciousness.
Cardiac, pulmonary, renal disease and diabetic pose
lessproblem.

165. complication of spinalanaesthesia:





Respiratory paralysis
Hypotension
Headache
Cauda equina syndrome
Septic meningitis
Contraindications:



Hypotension & hypovolemia
Infant & childrens-control of level is difficult
Vertebral abnormalities -kyphosis

166. Intravenous regionalanaesthesia

167. Also referred as Bier’s block & used for upper limb and
orthopedic procedures.
Regional analgesia produced within 2-5min and last till 5-
10min.
Only ¼of the injected drug enters systemic
circulation when tourniquet is removed.
Bradycardia can occur and bupivacaine should not be
used because of higher cardio toxicity.

168. Generalanaesthetics
(Defn.)

•General Anaesthetics are the drugs
which produce reversible loss of all
modalities of sensation and consciousness,
or simply, a drug that brings about a
reversible loss of consciousness.
Remember !!! These drugs are generally
administered by an anesthesiologist in order to
induce or maintain general anesthesia to
facilitate surgery.
General anaesthetics are –mainly inhalation or
intravenous.
Balanced Anaesthesia: A combination of IV
anaesthetics and inhaled anaesthetics.

169. What are the Drugs used as GA?
(Classification)
Inhalation:
1.Gas: NitrousOxide
2.Volatileliquids:






Ether
Halothane
Enflurane
Isoflurane
Desflurane
Sevoflurane




Intravenous:
1.Inducing agents:
Thiopentone, Methohexitone
sodium, propofol and
etomidate
1.Benzodiazepines (slower
acting):
Diazepam, Lorazepam, Midazolam
1.Dissociative anaesthesia:
Ketamine
1.Neurolept analgesia:
Fentanyl

170. Mechanisms of
GA


For inhalation anesthetics –Minimum Alveolar Concentration (MAC)
–1 (one) MAC is defined as the minimum alveolar concentration that
prevents movement in response to surgical stimulation in 50% of
subjects. Correlates with oil/gas partition coefficient
Practically –



Alveolar concentrations can be monitored continuously by measuring end-tidal
anesthetic concentration using spectrometry
End point (immobilization) –can me measured. Other end points –Verbal
commands or memory etc.


For Intravenous agents –Potency of IV agent is defined as the free
plasma concentration (at equilibrium) that produces loss of response to
surgical incision in 50% of subjects.
Difficult to measure:


no available method to measure blood or plasma concentration
continuously
Free concentration at site of action cannot be determined
(MAC explains only capacity of anaesthetics to enter in CNS
and attain sufficient concentration, but not actual MOA)

171. Mechanisms of
GA


For inhalation anesthetics –Minimum Alveolar Concentration (MAC)
–1 (one) MAC is defined as the minimum alveolar concentration that
prevents movement in response to surgical stimulation in 50% of
subjects. Correlates with oil/gas partition coefficient
Practically –



Alveolar concentrations can be monitored continuously by measuring end-tidal
anesthetic concentration using spectrometry
End point (immobilization) –can me measured. Other end points –Verbal
commands or memory etc.


For Intravenous agents –Potency of IV agent is defined as the free
plasma concentration (at equilibrium) that produces loss of response to
surgical incision in 50% of subjects.
Difficult to measure:


no available method to measure blood or plasma concentration
continuously
Free concentration at site of action cannot be determined
(MAC explains only capacity of anaesthetics to enter in CNS
and attain sufficient concentration, but not actual MOA)

172. Modern theory on Mechanismof
GeneralAnesthesia
Mainly acts via interaction with membrane proteins
Different agents -different molecular mechanism
Major sites: Thalumus & RAS, Hippocampus and Spinal
cord
Major targets –ligand gated (not voltage gated) ion
channels
Importantone –GABAA receptor gated Cl¯ channel
complexes; examples –many inhalation anesthetics,
barbiturates, benzodiazepines and propofol


Potentiate the GABA to open the Cl¯ channels
Also direct activation of Cl¯ channel by some inhaled anesthetics and
Barbiturates

173. 4 (Four) Stages and signs!!!
•Traditional Description of signs and stages
of GA -Also called Guedel`s sign
•Typically seen in case of Ether
•Slow action as very much lipid soluble
•Descending depression of CNS
•Higher to lower areas of brain are involve
•Vital centers located in medulla are paralyzed last

174. Stagesof
GA
Stage I: Stage of Analgesia
Starts from beginning of anaesthetic inhalation and
lasts upto the loss of consciousness
Pain is progressively abolished during this stage
Patient remains conscious, can hear and see, and
feels a dream like state
Reflexes and respiration remain normal
It is difficult to maintain -use is limited to short
procedures only

175. stages of GA –
contd.
Stage II: Stage of Delirium andExcitement:








From loss of consciousness to beginning of regular respiration
Excitement -patient may shout, struggle and hold his breath Muscle
tone increases, jaws are tightly closed.
Breathing is jerky; vomiting, involuntary micturition or defecation may
occur.
Heart rate and BP may rise and pupils dilate due to sympathetic
stimulation.
No stimulus or operative procedure carried out during this stage.
Breatholding are commonly seen.Potentially dangerous responses
can occur during this stage including vomiting, laryngospasm and
uncontrolled movement.
This stage is not found with modern anaesthesia –preanaesthetic
medication, rapid induction etc.

176. stages ofGA
–contd.
Stage III: Stage of Surgical anaesthesia
Extends from onset of regular respiration to
cessation of spontaneous breathing. This has
been divided into 4 planes:
Plane 1: Roving eye balls. This plane ends when
eyes become fixed.
Plane 2: Loss of corneal and laryngeal reflexes.
Plane 3: Pupil starts dilating and light reflex is
lost.
Plane 4: Intercostal paralysis, shallow abdominal
respiration, dilated pupil.

177. stages of GA –
contd.
Stage IV: Medullary / respiratory paralysis
Cessation of breathing failure
of circulation death
Pupils:widely dilated
Muscles are totally flabby
Pulse is imperceptible
BP is very low.

178. Properties of
G
A
ForPatient:
-
-
Pleasant, non-irritating and should not cause nausea or
vomiting
Induction and recovery should be fast


For Surgeon:
-analgesia, immobility and muscle relaxation
-nonexplosive and noninflammable
For the anaesthetist:
1.Margin of safety: No fall in BP
2.Heart, liver and other organs: No affect
3.Potent
4.Cheap, stable and easily stored
5.Should not react with rubber tubing or soda lime
6.Rapid adjustment of depth of anaesthesia should be
possible

180. 1. Diethyl ether (C2H5 –O –C2H5)
Colourless, highly volatile liquid with a
pungent odour. Boiling point = 35ºC
Produces irritating vapours and are
inflammable and explosive.
Pharmacokinetics:
-85to90percentiseliminatedthroughlung
andremainderthroughskin,urine,milkand
sweat
-Can cross the placental barrier

181. Ether –
contd.
Advantages
-Can be used without
complicated apparatus
-Potent anaesthetic and
good analgesic
-Muscle relaxation
-Wide safety of margin
-Respiratory stimulation
and bronchodilatation
-Does not sensitize the
heart to adrenaline
-No cardiac arrythmias
-Can be used in
delivery
-Less likely hepato or
nephrotoxicity
Disadvantages
-Inflammable and
explosive
-Slow induction and
unpleasant
-Struggling, breath
holding,salivationand
secretions(drowning)-
atropine
-Slow recovery –nausea
& vomiting
-Cardiac arrest
-Convulsion in children
-Cross tolerance –ethyl
alcohol

182. 2.Nitrousoxide/laughinggas(N2O)
NH4NO3 (s) → 2 H2O (g) + N2O (g)
Colourless, odourless inorganic gas with
sweet taste
Noninflammable and nonirritating, but of low
potency
Very potent analgesic, but not potent
anaesthetic
Carrier and adjuvant to other anaesthetics –
70% + 25-30% + 0.2-2%
As a single agent used wit O2 in dental
extraction and in obstetrics

183. Nitrousoxide–
contd.
Advantages:
-Non-inflammable and
nonirritant
-Rapid induction and
recovery
-Very potent analgesic
(low concentration)
-No effect on heart rate and
respiration –mixture
advantage
-No nausea and vomiting
–post anaesthetic not marked
-Nontoxic to liver, kidney
and brain







Disadvantages:
Not potent alone
(supplementation)
Not good muscle relaxant, not
Hypoxia, unconsciousness cannot
be produced without hypoxia
Inhibits methionine synthetase
(precursor to DNA synthesis)
Inhibits vitamin B-12 metabolism
Dentists, OR personnel, abusers
at risk
Gas filled spaces expansion
(pneumothorax) -dangerous

184. 3.
Halothane
Fluorinated volatile liquid with sweet odour, non-
irritant non-inflammable and supplied in amber
coloured bottle
Potent anaesthetic (if precise control), 2-4% for
induction and 0.5-1% for maintenance
Boiling point -50ºC
Pharmacokinetics: 60 to 80% eliminated unchanged.
20% retained in body for 24 hours and metabolized
Delivered by the use of a special vapourizer
Not good analgesic or relaxants
Potentiates NM blockers

185. Halothane –
contd.
Advantages:
-
-
-
-
-
-
Non-inflammable and non-
irritant
Abolition of Pharyngeal
and laryngeal reflexes –
bronchodilatation –
preferred in asthmatics
Potent and speedy
induction & recovery
Controlled hypotension
Inhibits intestinal and
uterine contractions –
external or internal version
Popular anaesthetic in
developig countries -can
be used in children for
induction and maintenance
and adult maintenance
Disadvantages:
-
-
-
-
-
-
-
-
-
-
-
Special apparatus -vapourizer
Poor analgesic and muscle relaxation
Myocardial depression –direct depression of
Ca++ and also failure of sympathetic activity –
reduced cardiac output (more and more)
Hypotension –as depth increases and
dilatation of vascular beds
Heart rate –reduced due to vagal stimulation,
direct depression of SA node and lack of
Baroreceptor stimulation
Arrythmia -Sensitize heart to Adrenaline
Respiratory depression –shallow breathing
(PP of CO2 rises) assisted ventilation
Decreased urine formation –due to decreased
gfr
Hepatitis: 1 in 10,000
Malignant hyperthermia: Abnormal Ryanodine
receptor
Prolong labour

186. 4.
Enflurane:
Non-inflammable, with mild sweet odour and boils at
57ºC
Similar to halothane in action, except better muscular
relaxation
Depresses myocardial force of contraction and
sensitize heart to adrenaline
Induces seizure in deep anaesthesia and therefore
not used now -Epileptiform EEG
Metabolism one-tenth that of halothane--does not
release quantity of hepatotoxic metabolites
Metabolism releases fluoride ion--renal toxicity

187. 5.
Isoflurane:
Isomer of enflurane and have similar
properties but slightly more potent
Induction dose is 1.5 –3% and maintenance
dose is 1 –2%
Rapid induction (7-10 min) and recovery
By special vapourizer

188. Isoflurane –
contd.
Advantages:
-
-
-
-
-
-
-
-
-
-
Rapid induction and
recovery
Good muscle relaxation
Good coronary
vasodilatation
CO maintained, HR
increased –beta receptor
stimulation
Less Myocardial depression
than no myocardial
sensitization to adrenaline
No renal or hepatotoxicity
Low nausea and vomiting
No dilatation of pupil and no
loss of light reflex in deep
anaesthesia
No seizure and preferred in
neurosurgery
Uterine muscle relaxation
-
-
-
-
-
-
Disadvantages:
Pungent and respiratory
irritant
Special apparatus required
Respiratory depression -
prominent
Maintenance only, no
induction
Hypotension -ß adrenergic
receptor stimulation
Costly
(Desflurane and Sevoflurane -
----read yourself)

189. Intravenous
Anaesthetics
:




For induction only
Rapid induction (one arm-
brain circulation time)
For maintenance not used
Alone –supplemented with
analgesic and muscle
relaxants

•Intravenous:
Inducing agents:
•Thiopentone, Methohexitone
sodium, propofol and etomidate
•Benzodiazepines (slower
acting):
•Diazepam, Lorazepam,
Midazolam
Dissociative anaesthesia:
•Ketamine
Neurolept analgesia:
Fentanyl

190. Thiopentone
sodium
:
Barbiturate: Ultra shortacting




Water soluble Alkaline
Dose-dependent suppression of CNS activity
Dose: 3-5mg/kg iv (2.5%) solution –15 to 20 seconds
Pharmacokinetics:
-
-
Redistribution
Hepatic metabolism (elimination half-life 7-12hrs)
-CNSdepressionpersistsfor long (>12hr)

191. Thiopentone–
contd.
-
-
-
-
Rapid induction
Does not sensitize
myocardium to
adrenaline
No nausea and vomiting
Non-explosive and non-
irritant
- Short operations
(alone)Other uses: convulsion,
psychiatric patients and
narcoanalysis of cri
minals –by knocking off
guarding
Advantages: Disadvantages:
-
-
-
-
-
-
-
Depth of anaesthesia
difficult to judge
Pharyngeal and
laryngeal reflexes
persists-apnoea –
controlled ventilation
Respiratory depression
Hypotension (rapid) –
shock and hypovolemia –
CVS collapse
Poor analgesic and
muscle relaxant
Gangrene and necrosis
Shivering and delirium

192. Complicationsof
anaesthesia
:
•During anaesthesia:
Respiratory depression
Salivation, respiratory secretions
Cardiac arrhythmias
Fall in BP
Aspiration
Laryngospasm and asphyxia
Awareness
Delirium and convulsion
Fire and explosion
After anaesthesia:
Nausea and vomiting
Persisting sedation
Pneumonia
Organ damage –liver,
kidney
Nerve palsies
Emergence delirium
Cognitive defects

193. Important
!
Drugs used in General Anaesthesia
Stages of General Anaesthesia with important points
in each stage
Details of Inhalation agents, mainly Ether, Halothane
and Isoflurane
Details of Inducing agents –Thiopentone and
Propofol
Dissociative anaesthesia –short question
Preanaesthetic medication and examples of Drugs
Vivaandshortquestions-Secondgaseffect,
diffusionhypoxia,malignanthyperthermiaand
Fentanyl

195. Emetic &
Expector
ants

196. Emetics
Thesearethedrugswhichgiverisetoforced
regurgitation(emesis) bywhichthe
contentsof the stomach get expelled
through the oral cavity.
They are very important in cases ofPoisoning.

197. The emetics act by 2types:
1. Locally acting emetics:by local irritation of gastric
mucosa.
e.g. Ammonium bicarbonate, Ipecacuanha
2. Centrally acting emetics: directly on the Chemoreceptor
Trigger Zone (CTZ) in the floor of IV th ventricle in
medulla
e.g. Apomorphine & Morphine
Mechanism of
action

198. Cerebral Centers AffectingVomiting

199. Uses of
Emetics
1.Vomiting is primarily considered to be a respiratory
function,itsultimateresultwouldcausetheevacuation
ofthestomachthusemeticsproducesareflux
aactionbywhichTOXICsubstancesgetsexpelledin
caseofpoisoning.
2.Emeticsaresometimesaddedtocoughpreparations
inlowdosestostimulateflowofrespiratorytract
secretions.

200. Salt water • Warm water –mild emetic • 2 spoonful
of common salt in 1 pint of warm water
Mustard seed • 1 table spoonful ground mustard
seeds in half-pin of warm water • Strong coffee is one
of the best domestic stimulants, especially after a
narcotic poison
NaturalEmetics

201. When not to use
Emetics????
In Corrosive poisoning –acid and alkali(why?)
In CNS stimulantpoisoning
To unconsciouspatients

202. Expectora
nts
Expectorantsare“Drugsthathelpinremovingsputum
from the respiratory tract either by
increasingthefluidity(orreducingtheviscosity)of
sputum

Or
increasing the volumeof fluidsthat
haveto be expelled from the respiratory
tract by coughing.”

203. Classification of
Expectorants
According the their mechanism ofaction…
1)Sedativeexpectorant
2)Stimulant expectorant

204. Sedative
Expectorants
Thesearestomachirritantexpectorantswhich
areabletoproducetheireffectthrough
stimulationofgastricreflexes.
e.g.
Bitter drugs –Ipecac, Senega, IndianSquill
Compounds –Antimonypotassium tartrate,
Ammonium chloride,Sodiumcitrate,Potassium
iodide

205. Thesearetheexpectorantswhichbringabouta
stimulationofthesecretorycellsofthe
respiratorytractdirectlyorindirectly.
Sincethesedrugsstimulatesecretion,more
fluid in respiratory tract and sputum is diluted.
e.g.Eucalyptus,lemon,anise Active
constituents of oil like terpine hydrate, anethole
Stimulant
Expectorants

206. Psychoactive Drugs

207. Psychoactive Drugs
•Drug: a substance that on entering the body changes the
body or its functioning.
–An agonistmimics or enhances the effect of a
neurotransmitter.
–An antagonistmay occupy the receptors without activating
them, simultaneously blocking the transmitter from binding to
the receptors.
•Psychoactive drugs are those that have psychological
effects, such as anxiety relief or hallucinations.

208. Psychoactive Drugs
•Addiction:
–Preoccupation with obtaining a drug
–Compulsive use of the drug in spite of adverse consequences
–High tendency to relapse after quitting
–Typically defined as an individual showing both withdrawal and tolerance.
•Withdrawal:
–Negative reaction that occurs when drug use is stopped
•Negative = opposite of drug effect
•Negative also means “bad” to many people
–Body’s compensatory reaction.
•Tolerance:
–Individual becomes less responsive to the drug
–Requires increasing amounts of the drug to produce the same results.

209. Psychoactive Drugs: opiates
•Opiates
–Natural forms derived form the opium poppy.
–Can also be synthetically made
–Act on opiate receptors or endorphin receptors
•Several important effects:
–Analgesic(pain relieving)
–Hypnotic(sleep inducing)
–Produce a strong euphoria(sense of happiness of
ecstasy).

210. Psychoactive Drugs: opiates
•Types of opiates:
–Morphine: pain relief, surgical pain relief, cancer
•Derivatives include codeine, vicodin, oxycotin, etc...
•Synthetic or natural
–Heroin
•Synthesized from morphine; originally by C. R. Alder Wright in 1874
•Marketed as an over-the-counter analgesic until its dangers were recognized
•Now a Schedule 1 (illegal) drug.
•In 2004, Afghanistan produced roughly 87% of the world supply in illicit raw
opium.[; Mexico has increased production sixfoldfrom 2007 to 2011, making
Mexico the second largest opium producer in the world
•2-4 times more potent than morphine and is faster in its onset of action.
–Illicit heroin also made into white powder freebase form.
–Because of its lower boiling point, the freebase form of heroin is smokable.

212. Opiate drug action
•Endorphins: Endogenous opiates
–body produces its own natural opiates,
which are neuromodulators
–Released when in pain, motor exertion,
stress
–Endogenous = made by the body.
•Opiate drugs are effective because
they mimicendorphins
•Because of CNS effects and cognitive
effects, very high likelihood of abuse.

213. Psychoactive drugs:
the depressants
•Depressants: Drugs that reduce central nervous
system activity.
•Sedatives: calming drugs (hypnotic or sleep
inducing as well)
•Most common:
–Barbiturates
–Anxiolytics
–Hypnotics
–Antihistamines

214. Psychoactive drugs:
the depressants
•Anxiolytic: Anxiety-reducing drugs:
–Most common category are the Benzodiazepines ("minor
tranquilizers")
•Klonopin;
•diazepam (Valium);
•estazolam (Prosom);
•flunitrazepam (Rohypnol) ;
•lorazepam (Ativan) ;
•midazolam (Versed);
•nitrazepam (Mogadon) ;
•oxazepam (Serax) ;
•triazolam (Halcion); ;

215. Psychoactive drugs:
the depressants
•Hypnoticdrugs: induce sleep-like states: Nonbenzodiazepines:
–Zolpidem;
–Zaleplon;
–Zopiclone;
–Eszopiclone
•Antihistamines:
–Diphenhydramine (Benadryl);
–Doxylamine; Hydroxyzine; Promethazine
•Other related hypnotic drugs:
–gamma-hydroxybutyricacid (Xyrem) ; Glutethimide
–Chloral hydrate
–EthchlorvynolLevomepromazine; Chlormethiazole

216. Sedative effects on the cns
•Barbiturates
–Suppress inhibitory centers of the brain
•First act on cerebral cortex
•Then to basal ganglia areas
•Finally to brain stem
–In small amounts: act selectively on higher
cortical centers, especially those involved in
inhibiting behavior
–In low doses :produce talkativeness, increased
social interaction,
–Higher doses: sedatives and hypnotics.

217. Sedative effects on the cns
•Barbiturates include
–Amobarbital (Amytal);
–Pentobarbital (Nembutal);
–Secobarbital (Seconal) and
–Phenobarbitol (Luminal)
•Because of hypnotic effects, disrupt sleep cycles
–Rob you of REM or dream sleep
–Long term use may affect cognition as well as
upset basic physiology
–High risk of addiction

218. Benzodiazepines-an alternative to barbiturates?
•Both barbituratesand benzodiazepines
produce their effects by decreasing glutamate
activity and increasing GABA activity.
–Glutamate antagonist
–GABA agonist
•They operate at the barbiturate receptor on the
GABA
Acomplex.
•Result is increase in GABA activity and
reduction in glutamate

219. Benzodiazepines-an alternative to barbiturates?
•A few decades ago:
–Barbiturates = drug of choice for treating anxiety
–Also as most common drug for situations requiring
sedation.
•BUT: high liability potential for addiction and
high rate of accidental or intentional death.

220. Benzodiazepines-an alternative to barbiturates?
•Benzodiazepines: largelyreplaced barbiturates
–Produce anxiety reduction
–Also induce sedation and muscle relaxation.
–operate at the benzodiazepine receptor on the GABA
A
complex.
•At first, thought non-addictive
–Today know that are highly addictive
–Are less likely to cause death with overdose unless mixed
with another sedative such as alcohol or sleeping pills.

221. Psychoactive drugs:
Alcohol
•Ethanol, or alcohol:
–is a drug fermented from fruits, grains, and other plant products.
–Is a DEPRESSANT
•It acts at many brain sites to produce
–euphoria,
–anxiety reduction,
–sedation,
–poor motor coordination,
–cognitive impairment
•Why is it a depressant?
–Depresses CNS
–Inhibits areas of the brain that inhibit acting out, inappropriate behavior,
etc..

222. How does alcohol affect the CNS?
•Alcohol inhibits the release of glutamate(the
most prevalent excitatory neurotransmitter).
–Glutamate ANTAGONIST
–Glutamate reduction produces a sedating effect
•Chronic use results in a compensatory
increase in the number of glutamate
receptors,
•This increase probably accounts for the

223. How does alcohol affect the CNS?
•Alcohol also increases the release of gamma-
aminobutyric acid (GABA)
–GABA agonist
–the most prevalent inhibitory neurotransmitter).
–Alcohol specifically affects the A subtype of
GABA receptor.
•The combined effect GABA and Glutamate
receptors is:
–sedation
–anxiety reduction,

225. Alcohol abuse effects
•Cirrhosis of the liver,
–Common side effect of chronic alcoholism
–in its severest form is fatal.
–
•Vitamin B1 deficiency
–associated with chronic alcoholism
–can produce brain damage and Korsakoff’ssyndrome
•Delirium tremors
–more severe reactions
–hallucinations, delusions, confusion, and in extreme cases, seizures
–possible death.
•Alcohol withdrawal symptoms
–involves tremors, anxiety, and mood and sleep disturbances;

226. Alcohol abuse effects
•Korsakoff’s syndrome
–Neurological syndrome due to alcohol damage, B1
deficiency
–involves severe memory loss along with sensory
and motor impairment.
–eye movement disorders
–ataxia (poor motor coordination)
–Individuals show severe anterograde amnesia
•Unable to make new memories
•Unable to learn new things

228. Psychoactive Agents
Stimulants
Psychodelics

229. Psychoactive Drugs
•Addiction:
–preoccupation with obtaining a drug
–compulsive use of the drug in spite of adverse consequences
–high tendency to relapse after quitting
–Typically defined as an individual showing both withdrawal and
tolerance.
•Withdrawal:
–negative reaction that occurs when drug use is stopped
–Body’s compensatory reaction.
•Tolerance:
–individual becomes less responsive to the drug
–requires increasing amounts of the drug to produce the same results.

230. Psychoactive stimulants
•Stimulants:
–activate the central nervous system to produce
•arousal,
•increased alertness,
•elevated mood
•Typically affect dopamine, norepinephrineand
serotonin
•Several drugs in this category
–Cocaine
–Amphetamine
–Methamphetamine
–Ritalin, Adderal, and most ADHD medications
–Ephedrine

231. Psychoactive stimulants
•Cocaine,
–extracted from the South American coca plant,
–produces
•Euphoria
•decreases appetite,
•increases alertness
•relieves fatigue.
•Cocaine blocks the reuptake of dopamine and serotonin at synapses,
–Potentiating effect of these neurotransmitters
–Makes neurotransmitter remain longer in synapse.
•Presumably, cocaine produces euphoria and excitement because
dopamine removes the inhibition the cortex usually exerts on lower
structures.

232. Cocaine
user
Normal

233. Psychoactive Drugs
•Amphetamines
–group of synthetic drugs
–Again produce euphoria
–increase confidence
–In low doses: increases concentration.
•increase the release of norepinephrine and
dopamine: DA Agonists

234. Psychoactive Drugs
•Common examples:
–Amphetamine (Adderal®); Dextroamphetamine
(Dexedrine®, Dextrostat®)
–Methamphetamine (Desoxyn®)
•Highly related:Ritalin:
–Ritalina, Rilatine, Attenta, Methylin, Penid,
Rubifen); and the sustained release tablets
Concerta, Metadate CD, Methylin ER, Ritalin
LA, and Ritalin-SR. Focalin

235. Amphetamine Action
•DA neurons release DA into the synapse:
From there 1 of 3 things can happen:
1.DA can then attach to the post-synaptic
membrane
2.DA can be degraded by enzymes
3.DA can be taken back up by the pre-synaptic
membrane.

236. Amphetamine Action
•Amphetamine appears to affect all three mechanisms:
1.Promotes release of DA into the synapse
2.Inhibits the DA degredativeenzyme, monoamine
oxidase(MAO),
3.Blocks the uptake proteins in the pre-synaptic
membrane
•The result : Amphetamine effectively promotes a
flood of DA into the brain reward center:
–Nucleus Accumbens or Nac
–This area is highly involved in both learning and reward.

237. Amphetamine Action
•Amphetamine and related compounds elicit a
variety of dose-dependent deleterious effects.
•Low doses of AMPH may
–improve attention
–improve vigilance
•At high doses:
–over-stimulation of the motor and cognitive systems
–behavioral stereotypy, repetitive thoughts and even
hallucinations.

238. Amphetamine Action
•In rodents, a high AMPH dose elicits behavioral
stereotypy:
–continuous digging
–Searching
–Licking
–Gnawing
–Circling
•In humans, high doses of AMPH may elicit:
–psychotic state,
–High rates of locomotion and repetitive behavior
–high potential for self-injury or injury to others

239. A normally moving rat

240. A rat given 8.0 mg/kg amphetamine

242. Psychoactive Drugs: Nicotine
•Nicotine:
–primary psychoactive and addictive agent in tobacco
–Also in chewing tobacco, nicotine gum, etc.
•It stimulates nicotinicacetylcholine receptors. AChagonist
–In the periphery,
•it activates muscles
•may cause twitching.
–In CNS:
•produces increased alertness
•Also faster response to stimulation.
•Given peripheral effects, why might individuals on
antipsychotics or those with Parkinson’s like to smoke?

243. Psychoactive Drugs: Caffeine
•Active ingredient in coffee, many soda pops; teas;
energy drinks, etc.
•Produces arousal, increased alertness, and
decreased sleepiness.
•Cardiovascular response: direct stimulation of the
heart
–mitigated to some extent by concurrent vagal
stimulation.
–CNS + PNS effects sometimes result in ventricular
irritability

244. Psychoactive Drugs: Caffeine
•Also get direct vasodilationwith concurrent
vasoconstrictionfrom stimulation of the medulla
–Result: either increases or decreases in blood pressure.
–Smooth muscle is relaxed by caffeine, while skeletal
muscle is stimulated.
•Action: blocks receptors for the neuromodulator
adenosine: Adenosine antagonist
–Because adenosine has sedative and depressive effects, blocking its
receptors contributes to arousal
–This increases the release of dopamine and acetylcholine.
–Acts like a back door amphetamine in releasing DA.

245. PsychodelicDrugs
•Psychedelic drugs:
–compounds that cause perceptual distortions in the user.
–May be referred to as hallucinogenic
•Not really inducing hallucinations, but distortions in perception:
–Light and color details are intensified,
–objects may change shape,
–sounds may evoke visual experiences,
–light may produce auditory sensations.
•Synesthesia: stimulation of one sensory or cognitive pathway leading
to automatic, involuntary experiences in a second sensory or cognitive
pathway

246. Psychoactive Drugs
•Lysergic acid diethylamide (LSD)
–best-known psychedelic
–is structurally similar to serotonin
–stimulates serotonin receptors
–Appears to disrupt the brain stem’s ability to screen out irrelevant
stimuli.
•Psilocybinand psilocin
–Another serotonin-like psychedelics
–both derived from the mushroom,Psilocybemexicana
•Mescaline
–the active ingredient in peyote(the crown or button on the top of the
peyote cactus),
–psychedelic properties result from stimulation of serotonin receptors.

247. Ecstasy or Molly
•Ecstasy or Molly: street name for a drug developed as a weigh-
loss compound methlenedioxymethamphetamine(MDMA).
•At low doses:
–psychomotor stimulant
–Increases energy, sociability, and sexual arousal.
•At higher doses:
–produces hallucinatory effects like LSD.
–Also can overstimulate muscles resulting in “locked” or frozen
muscles
–May permanently bind to MDMA receptors
•Affects learning and memory
•Affects emotions
•Affects motor movement

248. Ecstasy or Molly
•MDMA stimulates
–the release of dopaminewhich accounts for muscle
and arousal effects
–the release of serotonin, which probably accounts for
the hallucinatory effects.
•Damage to neurons much more immediate and
severe than with typical amphetamines
–Destroys autoreceptorson DA, 5HT neuron
–Overstimulates post-synaptic receptors
–Much greater and faster cell death

249. These brain sections
have been stained
with a chemical
that makes neurons
containing
serotonin turn
white. Photos in
the top row are
from a normal
monkey; those
below are from a
monkey given
MDMA a year
earlier.

250. Psychoactive Drugs:
Phencyclidine or PCP
•Developed as an anesthetic typically used by
veterinarians
•was abandoned for human use because it produces
schizophrenia-like disorientation and
hallucinations.
•PCP increases activity in the dopamine pathways
–This stimulates motivation system
–Also, drug’s motivating properties apparently are partly
due to its inhibition of a subtype of glutamate receptors.

251. Marijuana
•is the dried and crushed leaves and flowers of the Indian hemp plant,
Cannabis sativa.
•The major psychoactiveingredient is delta-9-tetrahydrocannabinol (THC)
–Acts on the anterior cingulate cortex and frontal cortex
•Other important active ingredient is Cannabidiol(CBD)
–at least 60 active cannabinoids identified in cannabis
–a major constituent of the plant, accounting for up to 40% of the
plant's extract
–is a non-psychotropicphytocannabinoid.
–considered to have a wider scope of medical applications than THC
.

252. Marijuana
•THC actions:
–THC binds with cannabinoid receptors, which ordinarily
respond to endogenous cannabinoids.
–Particularly in frontal lobe and cingulate cortex
–Two known cannabinoids receptors:
•anadamide
•2-arachidonyl glycerol, or 2-AG.
•These receptors are found on axon terminals;

253. Marijuana
•Cannabinoids (CBD))
–released by postsynaptic neurons
–act as retrograde messengers, regulating the presynaptic
neuron’s release of neurotransmitter.
–CBD is also a 5-HT1A receptor agonist,
–CBD's antagonistic effects at the cannabinoid receptors,
compared to THC's partial agonist effect.

254. Marijuana: multiple forms
•Cannabis sativa: typically more likely to be used
“recreationally”
•Lower CBD: THC ratio (much more THC)
•Well known for producing a “cerebral high”-likely due
to partial AGONIST effect on cannabinoid receptors
•When used for medical purposes: often used during
daytime treatments as does not produce drowsiness

255. Marijuana: multiple forms
•CBD:THC ratio: ratio of cannabinoid (CBD) to THC
•Cannabis indica: “Medical marijuana”
•4–5 times the amount of CBD to THC as found in Cannabis
sativa.
•Cannabis strains with relatively high CBD:THC ratios are less
likely to induce anxiety
•known for its sedative effects:
•more calming, soothing, and numbing experience
•can be used to relax or relieve pain.
•Also seems to reduce the frequency of seizures: probably due to
antagonist effects at cannabinoid receptor
•Also appears to serve as partial agonist for serotonin receptors

256. Addiction
•Rewardrefers to the positive effect an object or condition
–such as a drug, food, sexual contact, and warmth –has on
the user.
•Drug researchers have traditionally identified the
mesolimbicorticaldopamine system as the location of the
major drug reward system.
–It takes its name from the fact that it begins in the midbrain
(mesencephalon) and projects to the limbic system and prefrontal
cortex.
–The most important structures in the system are the nucleus
accumbens, the medial forebrain bundle, and the ventral tegmental
area.

257. Virtually all the abused drugs increase dopamine levels in the nucleus accumbens

258. Why are Psychoactive Drugs “bad”?
•Do tell us a great deal about brain functioning!
•BUT: pattern of effect they produce is usually unlike normal
functioning.
•Drugs are wide acting:
–affect wide areas of the brain indiscriminately
–normal activation tends to be more discrete and localized
•Can’t control drug effects
–Not act only in ways you want them to.
–May over-stimulate, “burn out” neurons
–May result in long term damage to system

259. Addiction TREATMENT
•Agonist treatments replace an addicting drug with another drug that
has a similar effect.
–Opiate addiction is often treated with a synthetic opiate called methadone.
•Antagonist treatments involve drugs that block the effects of the
addicting drugs.
–Drugs that block opiate receptors are used to treat opiate addictions and
alcoholism because they reduce the pleasurable effects of the drug.
•Another experimental strategy is to interfere with the dopamine
reward system.
–Baclofen reduces dopamine activity in the ventral tegmental area by
activating GABA
Breceptors on dopaminergic neurons.

260. Antiparkinsonian Agents

261. Parkinson’s Disease
•Progressive, onset @ 45-65 y.o.
•d/t imbalance between
dopamine & acetylcholine
•Symptoms:
•Slowed movement
•Rigidity = cogwheel
•Tremors –includes pillrolling
•Postural instability

262. Drug Effects
•Increases body’s supply of
Dopamine
•Interferes with Acetylcholine
levels
•Restores balance & stops
symptoms

263. Medications
•MAO Inhibitors
•Eldepryl = Selegiline
•Slows the breakdown of Dopamine
•Used with Levodopa
•Exogenous Dopamine
•Levodopa
•Levodopa-carbidopa
•Replaces low levels of dopamine

264. Meds, cont’d
•Amantadine
•Causes release of more dopamine
•Also keeps dopamine available
•Anticholinergics
•Block acetylcholine

265. Side Effects
•Dry mouth
•Palpitations
•Agitation/anxiety
•Severe Hypertension if taking
MAOI & eat cheese, red wine,
beer, yogurt

266. Psychotherapeutic
Agents
Ch 15

267. Mental Illness
•3 types
•Affective = mood disorders
•Psychoses = severe emotional
disorder
•Anxiety = sense of dread or fear

268. Anxiolytics
•Benzodiazepines
•Valium = diazepam
•Ativan = lorazepam
•Antihistamines
•Hydroxyzine = vistaril & atarax

269. Anxiolytics, cont’d
•Side Effects
•Drowsiness, blurred vision
•GI upset

270. Antimanic
•Treat manic-depressive disorder
= bipolar
•Lithium
•Valproic acid = depakene

271. Antimanics, cont’d
•Mechanism of action is unclear
•Increase amount of MAO
transmitters more
dopamine & serotonin

272. Antidpresssants
•Prozac
•Paxil
•Zoloft
•Desyrel
•Alter use of serotonin in body

273. Antidepressants, cont’d
•Side Effects
•Weight loss
•Sweating
•Sexual dysfunction

274. Antipsychotic Agents
•Treat
•Psychoses
•Schizophrenia
•Autism

275. Antipsychotics, cont’d
•Phenothiazines
•Largest group of antipsychotics
•Chlorpromazine (Thorazine) was
the 1
st
discovered
•Similar to antihistamines
•Block reception of Dopamine
•Do not cure, only control
symptoms

276. Antipsychotics, cont’d
•Side Effects
•Postural hypotension
•Sedation
•Blurred vision
•Parkinson-like symptoms

277. Precautions
•Do NOT take MAOI meds with
alcohol, yeast, yogurt products
•Do NOT abruptly stop
antidepressents –must wean off
•When starting, It may take up to 2 –
4 weeks to reach therapeutic level
•Caffeine limits effectiveness of meds

278. Central Nervous System
Stimulants
Ch 16

279. Effect
•Work on specific areas of brain
•Suppress appetite
•Treat ADD & ADHD
•Treat narcolepsy
•Treat migraine headache

280. amphetamines
•Treat narcolepsy & ADD
•Increase mental alertness
•Decrease fatigue
•Highly addictive

281. amphetamines, cont’d
•Examples
•Adderall
•Ritalin

282. analeptics
•Stimulate respiration
•High abuse potential
•Examples
•Caffeine
•Aminophylline
•Theophylline

283. anorexiants
•Suppress appetite
•Treat obesity
•Examples
•Didrex
•Tenuate

284. Serotonin agonists
•Treat migraines headaches
•Constrict brain blood vessels
•Decrease inflammatory
response
•Example
•Imitrex
•Zomig

285. Side Effects
•Insomnia
•Palpitations
•Nervousness
•Increased metabolism
•N-V-D, dry mouth
•Diuresis

287. Histamine and
Antihistaminics

288. Casestudy
•A 24 year old male patient John , suffers from allergic rhinitis.
Every winter, she develops a runny nose, itchy eyes, and
sneezing.
•To relieve hissymptoms, he takes an over-the-counter
antihistamine, diphenhydramine.
•John is annoyed by the unpleasant effects that accompany his
allergy medication. Every time he takes his antihistamine, he
feels drowsy and his mouth feels dry.
•He makes an appointment with his doctor who, advises him to
take loratadine. Upon taking new allergy medication, his
symptoms are relieved and he experiences no drowsiness or
other adverse effects.

289. Questions
•Why does Johndevelop seasonal rhinitis?
•Why does diphenhydramine relieve John`s
symptoms?
•Why does diphenhydramine cause
drowsiness?
•Why doesn't loratadine cause drowsiness?

290. Histamine
•Histos:Tissue
N
NH
2
H
1
2
3
N
54
Histamine
•Present mostly in mastcells:
skin, lungs, GITMucosa
•Non mast cellhistamine:
Brain, GastricMucosa
Histamine is a biogenic amine present in many animal and plant tissues.

291. Histamine
•Biogenic amine present in many animal and
plant tissues
•Also present in venoms and stinging
secretions
•One of the mediators involved in
inflammatory & hypersensitivity reactions.

292. Synthesis, storage &
metabolism of
histamine
•Synthesized by
decarboxylation of
amino acid histidine
•Histamine is present
in storage granules
of mast cells & also
found in skin, lungs,
liver, gastric mucosa
etc.

293. Mechanism of Action of
Histamine
Histamine
H
1Receptors H
2Receptors
H
3 Receptors
(presynaptic auto
receptors)
↑Ca2+
Smooth muscle contraction
Increased capillary
permeability
Vasodilation
Sensory nerve endings pain
& itching
↑cAMP
↑ Gastric acid secretion
Blood vessels:
vasodilation
Increased capillary
permeability
↓ histamine release
↓secretion
Vasodilation
↓cAMP

294. Pharmacological
actions
•CVS:
–Dilates arterioles, capillaries,venules,
•IV injection-decreasedBP
•Intradermal-Tripleresponse
Stimulating H1, H2, H3Receptors
Redspot
Wheal
Flare(Reflex
arteriolar dilatation)

295. Pharmacological actions
(Contd)
•Visceral smoothmuscles:
–Bronchospasm, abdominalcramps
•Secretions:
–Increased gastric secretion(H
2)
–Increased nasal secretions(H
1)
•Sensory Nerve Endings:Itching
•CNS:
–Wakefulness on intra CerebroventricularInjection

296. TherapeuticUses
•Betahistine
–To control vertigo in Meniere`s disease 8 mg tab ½
tablet QID
Histaminereleasers
•stings andvenom
•Ag-Abreaction
•Drugs
d-tubocurarine
Morphine

297. Adverse effects of
histamine release
•Itching,Urticaria
•Flushing
•Hypotension
•Tachycardia
•Bronchospasm
•Angioedema
•Wakefullness
•Increased acidity (Gastric acidsecretion)

298. Classification of H
1
Antagonists

299. Mechanism ofaction
Competitive antagonism
Histamine
General formula of H1Blocker

300. Pharmacological
actions
•CNS depression: (More with first generation)
–Sedation and drowsiness
–Some have antiemetic and antiparkinsonian
effects
•Antiallergic action
•Anticholinergic actions (More with first
generation)
–Dryness of mouth , Blurring of vision
–Constipation
–Urinary retention

301. Pharmacological
Actions
•Antimotion sickness effect: Dimenhydrinate,
Promethazine
•Antiemetic: Promethazine
•Antiparkinsonism: Diphenhydramine,
orphenadrine, promethazine(IV)
•Antivertigo: cinnarizine

302. Preparations & dosage
(Daily)
Drug Dose
1.Diphenhydramine25-50 mgoral
2.Dimenhydrinate 25-50 mgoral
3.Promethazine 25-50 mgoral/injection
4.Chlorpheniramine2-4 mgoral
5.Pheniramine 25-50 mgoral/im
6.Cinnarizine 25-150 mgoral
7.Cyprohepatidine4 mgoral

303. Therapeuticuses
1.Allergic rhinitis & commoncold
2.Allergic dermatitis, itching,urticaria
3.Wasp stings/ bite: pain and itchingdecreases
4.Mild blood transfusionreactions
5.Allergicconjunctivitis
6.Motion sickness: dimenhydrinate,promethazine
7.Morning sickness:promethazine

304. 8.Vertigo: cinnarizine
9.Chronic urticaria
10.Appetite stimulant: cyprohepatidine
11.Drug induced parkinsonism:
Diphenhydramine,
Therapeutic uses
(Contd..)

305. Adverseeffects
•Sedation
•Anticholinergiceffects
•Dermatitis on localuse
•Cyclizine, meclizine :teratogenicity

307. Second generation H
1Blockers
(Non Sedative:Less anticholinergicproperty)
•Fexofenadine
•Astemizole
•Loratidine
•Cetrizine
•Levocetrizine
•Azelastine
•Terfenadine
Uses:
•Allergicrhinitis
•AllergicDermatitis
•Allergicconjunctivitis
•Urticaria
•Commoncold

308. Advantages of second
generation
antihistaminics
•They have no anticholinergic side effects
•Do not cross blood brain barrier (BBB), hence
cause minimal or no drowsiness and sedation
•Do not impair Psychomotor performance

309. Druginteractions
•Increased effect of CNS depressants
•MAO inhibitors increase anticholinergic effect
of antihistaminics
•First generation antihistaminics can decrease
effectiveness of cholinesterase inhibitors used
in Alzheimer`s disease like donepezil and
rivastigmine

311. Answers
•The IgE-mediated hypersensitivity reaction is responsible for
initiation of certain inflammatory disorders, likeallergic
rhinitis .
•John suffered
from allergic rhinitis, with a runny nose, itchy eyes, and
sneezing.
•An environmental allergen, such as pollen, crosses the nasal
epithelium and enters the underlying tissue. There, the
allergen encounters previously sensitized mast cells and
crosslinks IgE/Fc receptor complexes on the mast cell surface.
•The mast cell degranulates and releases histamine, which
binds to H1 receptors in the nasal mucosa and local tissues.

312. Answers
•StimulationofH1 receptors causes blood vessel
dilation and ↑es vascular permeability, leading to
edema. This swelling in the nasal mucosa is
responsible for the nasal congestion experienced
in allergic rhinitis.
•The accompanying itching, sneezing, runny nose,
etc result from the combined action of histamine
and other inflammatory
mediators, including kinins, prostaglandins etc.
•These molecules initiate the hypersecretion and
irritation characteristic of allergic rhinitis.

315. NSAIDs have following group ofdrugs
Analgesic
Antipyretic
Antiinflammatory
31
5

316. Classifica
tion
31
6
A.Nonselective COX inhibitors (traditional NSAIDs)
1.Salicylates: Aspirin
2.Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen, Flurbiprofen.
3.Anthranilic acid derivative: Mephenamic acid
4.Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
5.Oxicam derivatives: Piroxicam, Tenoxicam.
6.Pyrrolo-pyrrole derivative: Ketorolac
7.Indole derivative: Indomethacin.
8.Pyrazolone derivative: phenylbutazone,
Oxyphenbutazone

317. B.Preferential COX-2 inhibitors Nimesulide, Meloxicam,
Nabumeton.
C.Selective COX-2 inhibitors Celecoxib, Etoricoxib,
Parecoxib.
D.Analgesic-antipyratics with poor antiinflammatory action
1.para aminophenol derivatives: Paracetamol
2.Pyrazolone derivative: Metamizol, Propiphenazone.
3.Benzoxazocine derivative: Nefopam
31
7

318. Mechanism of action of
NSAIDs
31
8
1.Antiinflammatory effect
due to the inhibition of the enzymes that produce
prostaglandin H synthase (cyclooxygenase, or COX),
which converts arachidonic acid to prostaglandins,
and to TXA2 and prostacyclin.

319. Aspirin irreversibly inactivates COX-1 and COX-2 by
acetylation of a specific serine residue.
This distinguishes it from other NSAIDs, which reversibly
inhibit COX-1 and COX-2.
31
9

320. 2.Analgesic effect
A.The analgesic effect of NSAIDs is thought to be
related to:
the peripheral inhibition of prostaglandin
production
may also be due to the inhibition of pain stimuli at
a subcortical site.
B.NSAIDs prevent the potentiating action of
prostaglandins on endogenous mediators of peripheral
nerve stimulation (e.g., bradykinin).
32
0

321. 3.Antipyretic effect
The antipyretic effect of NSAIDs is believed to be
related to:
inhibition of production of prostaglandins induced by
interleukin-1 (IL-1) and interleukin-6 (IL-6) in the
hypothalamus
the “resetting” of the thermoregulatory system,
leading to vasodilatation and increased heat loss.
32
1

322. NSAIDs and
Prostaglandin (PG)
synthesis inhibition
32
2
NSAIDs blocked PG generation.
Prostaglandins, prostacyclin (PGI2), and thromboxane
A2(TXA2) are produced from arachidonic acid by the enzyme
cyclooxygenase.
Cyclooxygenase (COX) exists in COX-1 and COX-2 isoforms.
COX -3 has recently been identified

323. Cyclooxygenase (COX) is found bound to the endoplasmatic
reticulum. It exists in 3 isoforms:
• COX-1 (constitutive) acts in physiological conditions.
• COX-2 (inducible) is induced in inflammatory cells by
pathological stimulus.
•COX-3 (in brain).
32
3

324. Nonselective COX
inhibitor
Salicylates Aspirin:
Aspirinis Acetylsalicylic acid converts to salicylic
acid in body, responsible for action.
32
4

325. PHARMACOLOGICAL
ACTIONS
32
5
•1.Analgesic, antipyretic, antiinflammatory actions:
Aspirin is a weaker analgesic than morphine type drugs.
Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine
it effectively relieves inflammation, tissue injury, connective tissue and
integumental pain, but is relatively ineffective in severe visceral and
ischaemic pain.
The analgesic action is mainly due to obtunding of peripheral pain
receptors
•and prevention of PG-mediated sensitization of nerve endings.
No sedation, subjective effects, tolerance or physical dependence is
produced.
Aspirin resets the hypothalamic thermostat and rapidly reduces fever by
•promoting heat loss, but does not decrease heat production.
Antiinflammatory action is exerted at high doses (3 -6 g/ day or 100 mg/kg/
day)

326. 2.Metabolic effects:
significant only at antiinflammatory doses
Cellular metabolism is increased, especially in skeletal
muscles, due to uncoupling of oxidative phosphorylation
increased heat production.
There is increased utilization of glucoseblood sugar may
decrease (especially in diabetics) and liver glycogen is
depleted.
Chronic use of large doses cause negative N2 balance by
increased conversion of protein to carbohydrate. Plasma free
fatty acid and cholesterol levels are reduced.
32
6

327. 3.Respiration:
Effects are dose dependent.
At antiinflammatory doses, respiration is stimulated by
peripheral (increased C02 production) and central (increased
sensitivity of respiratory centre to C02) actions.
Hyperventilation is prominent in salicylate poisoning. Further
rise in salicylate level causes respiratory depression; death is
due to respiratory failure.
32
7

328. 4.Acid-base and electrolytebalance:
32
8
Antiinflammatory doses produce significant changes in the
acid-base and electrolyte composition of body fluids.
Initially, respiratory stimulation predominates and tends to
wash out C02 despite increased production ….respiratory
alkalosis, which is compensated by increased renal
excretion of HCO3̄; (with accompanying Na+, K+ and
water).
Still higher doses cause respiratory depression with C02
retention, while excess C02 production continues….
respiratory acidosis .

329. 5.CVS:
Aspirin has no direct effect in therapeutic doses.
Larger doses increase cardiac output to meet increased
peripheral O2 demand and causes direct vasodilatation.
Toxic doses depress , vasomotor centre: BP may fall. Because
of increased cardiac work as well as Na+ and water retention,
CHF may be precipitated in patients with low cardiac reserve.
32
9

330. 6.GIT:
Aspirin and released salicylic acid irritate gastricmucosa,
cause epigastric distress, nausea andvomiting.
It also stimulatesCTZ.
7.Urateexcretion:
Aspirininhighdosereducesrenaltubularexcretionof
urate
33
0

331. 8.Blood:
Aspirin, even in small doses, irreversibly inhibits TXA2
synthesis by platelets. Thus, it interferes with platelet
aggregation and bleeding time is prolonged to nearly twice the
normal value.
long-termintakeoflargedosedecreasessynthesisofclotting
factorsinliverandpredisposestobleeding;canbeprevented
byprophylacticvitKtherapy.
33
1

332. Pharmacoki
netics
33
2
Aspirin is absorbed from the stomach and small intestines.
Its poor water solubility is the limiting factor in absorption:
microfining the drug particles and inclusion of an alkali
(solubility is more at higher pH) enhances absorption.
Aspirinisrapidlydeacetylatedinthegutwall,liver,plasma
andothertissuestoreleasesalicylicacidwhichisthemajor
circulatingandactiveform.
It slowly enters brain but freely crosses placenta.
The metabolites are excreted by glomerular filtration as well as
tubular secretion.

333. Uses of
Aspirin
33
3
As analgesic (300 to 600 mg during 6 to 8 h) for headache,
backache, pulled muscle, toothache, neuralgias.
Asantipyreticinfeverofanyorigininthesamedosesasfor
analglesia.However,paracetamolandmetamizolearesafer,
andgenerallypreferred.
Acute rheumatic fever. Aspirin is the first drug of choice. Other
drugs substitute Aspirin only when it fails or in severe cases.
Antirheumatic doses are 75 to 100 mg/kg/24 h (resp. 4–6 g
daily) in the first weeks.
Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h after meal
is effective in most cases. Since large doses of Aspirin are
poorly tolerated for a long time, the new NSAIDs (diclofenac,
ibuprofen, etc.) in depot form are preferred.

334. Aspirin therapy in children with rheumatoid arthritis has been
found to raise serum concentration transaminases, indicating
liver damage. Most cases are asymptomatic but it is potentially
dangerous.
An association between salicylate therapy and “Reye’s
syndrome”, a rare form of hepatic encephalopathy seen in
children, having viral infection (varicella, influenza), has been
noted.
Aspirin should not be given to children under 15years unless
specifically indicated, e.g. for juvenile arthritis (paracetamol is
preferred).
Postmyocardial infarction and poststroke patients: By
inhibiting platelet aggregation in low doses (100 mg daily)
Aspirin decreases the incidence of reinfarction.
33
4

335. 33
5

336. Adverse
effects
33
6
1.Gastrointestinal effects
most common adverse effects of high-dose aspirin use
(70% of patients):
nausea
vomiting
diarrhea or constipation
dyspepsia (impaired digestion)
epigastric pain
bleeding, and ulceration (primarily gastric).

337. These gastrointestinal effects are thought to be due to:
1.direct chemical effect on gastric cells or
2. decrease in the production and cytoprotective
activity of prostaglandins, which leads to gastric tissue
susceptibility to damage by hydrochloric acid.
33
7

338. The gastrointestinal effects may contraindicate aspirin use
in patients with an active ulcer.
Aspirin may be taken with prostaglandins to reduce gastric
damage.
Decrease gastric irritation by:
Substitution of enteric-coated or timed-release preparations, or
the use of nonacetylated salicylates, may decrease gastric
irritation.
33
8

339. 2.Hypersensitivity (intolerance)
Hypersensitivity is relatively uncommon with the use of aspirin
(0.3% of patients); hypersensitivity results in:
rash
bronchospasm
rhinitis
Edema, or
an anaphylactic reaction with shock, which may be life
threatening.
The incidence of intolerance is highest in patients with asthma,
nasal polyps, recurrent rhinitis, or urticaria.
Aspirin should be avoided in such patients.
33
9

340. Cross-hypersensitivity may exist:
to other NSAIDs
to the yellow dye tartrazine, which is used in many
pharmaceutical preparations.
Hypersensitivity is not associated with:
sodium salicylate or
magnesium salicylate.
34
0

341. The use of aspirin and other salicylates to control fever during
viral infections (influenza and chickenpox) in children and
adolescents is associated with an increased incidence of Reye's
syndrome, an illness characterized by vomiting, hepatic
disturbances, and encephalopathy that has a 35% mortality rate.
Acetaminophen is recommended as a substitute for children
with fever of unknown etiology.
34
1

342. Miscellaneous adverse effects and
contraindications
34
2
May decrease the glomerular filtration rate, particularly in
patients with renal insufficiency.
Occasionally produce mild hepatitis
Prolong bleeding time.
AspirinirreversiblyinhibitsplateletCOX-1andCOX-2and,
thereby,TXA2production,suppressingplateletadhesionand
aggregation.
The use of salicylates is contraindicated in patients with
bleeding disorders
Salicylates are not recommended during pregnancy; they may
induce:
postpartum hemorrhage
premature closure of the fetal ductus arteriosus.

343. Drug
interactions
34
3
Drugs Result
Diuretics Decreasediuresis
Beta-blockers Decrease antihypertensiveeffect
ACE inhibitorsDecrease antihypertensiveeffect
AnticoagulantsIncrease of GIbleeding
Sulfonylurea Increase hypoglycemicrisk
Cyclosporine Increasenephrotoxicity
GCS Increase of GIbleeding
Alcohol Increase of GIbleeding

344. PROPIONIC ACID
DERIVATIVES
34
4
Ibuprofen was the first member
The analgesic, antipyretic and antiinflammatory efficacy is
rated somewhat lower than high dose of aspirin.
 All inhibit PG synthesis, naproxen being the most potent;
but their in vitro potency tor this action does not closely
parallel in vitro antiinflammatory potency.
 Inhibition of platelet aggregation is short-lasting with
ibuprofen, but longer lasting with naproxen.

345. Ibuprofen:
In doses of 2.4 g daily it is equivalent to 4 g of Aspirin in anti-
inflammatory effect.
Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d), at
which it has analgesic but not antiinflammatory efficacy. It is
available in low dose forms under several trade names (e. g.
Nurofen
® –film-tabl. 400 mg).
A topical cream preparation is absorbed into fascia and muscle.
A liquid gel preparation of ibuprofen provides prompt relief in
postsurgical dental pain.
In comparison with indometacin, ibuprofen decreases urine
output less and also causes less fluid retention.
It is effective in closing ductus arteriosus in preterm infants,
with much the same efficacy as indometacin.
34
5

346. Flurbiprofen:
Its (S)(-) enantiomer inhibits COX nonselectively, but it has
been shown in rat tissue to also affect TNF-α and NO
synthesis.
 Hepatic metabolism is extensive. It does demonstrate
enterohepatic circulation.
The efficacy of flurbiprofen at dosages of 200–400 mg/d is
comparable to that of Aspirin and other NSAIDs for patients
with rheumatoid arthritis, gout, and osteoarthritis.
Flurbiprofen i.v. is effective for perioperative analgesia in
minor ear, neck, and nose surgery and in lozenge form for sore
throat.
34
6

347. Adverse
effect
34
7
Ibuprofen and all its congeners are better tolerated than aspirin.
Side effects are milder and their incidence is lower.
Gastric discomfort, nausea and vomiting, though less than
aspirin or indomethacin, are still the most common side effects.
Gastric erosion and occult blood loss are rare.
CNS side effects include headache, dizziness, blurring of
vision, tinnitus and depression.
Rashes, itching and other hypersensitivity phenomena are
infrequent.
They are not to be prescribed to pregnant woman and should be
avoided in peptic ulcer patient.

348. Pharmacokinetic and
interactions
34
8
Well absorbed orally.
Highly bounded to the plasma protein (90-99%).
Because they inhibit platelet function, use with anticoagulants
should, nevertheless, be avoided.
Similar to other NSAIDs, they are likely to decrease diuretic
and antihypertensive action of thiazides, furosemide and β
blockers.
All propionic acid derivatives enter brain, synovial fluid and
cross placenta. They are largely metabolized in liver by
hydroxylation and glucuronide conjugation and excreted in
urine as well as bile.

349. Us
es
34
9
Ibuprofen is used as a simple analgesic, and antipyretic in the
same way as low dose of aspirin. It is particularly effective in
dysmenorrhoea. In which the action is clearly due to PG
synthesis inhibition.
It is available as an over-the-court drug.
Ibuprofen and its congeners are widely used in rheumatoid
arthritis, osteoarthritis and other musculoskeletal disorders.
They are indicated in soft tissue injuries, vasectomy, tooth
extraction, postpartum and postoperatively: suppress swelling
and inflammation.

350. Anthranilic acid
derivative
35
0
Mephenamic acid:
Ananalgesic,antipyreticandweakerantiinflammatorydrug,
whichinhibitsCOXaswellasantagonisescertainactionsof
PGs.
Mephenamic acid exerts peripheral as well central analgesic
action.

351. Adverse effects:
Diarrhoea is the most important dose-related side effect. Epigastric distress
is complained, but gut bleeding is not significant.
Skin rashes, dizziness and other CNS manifestations have occurred.
Haemolytic anaemia is a rare but serious complication.
Pharmacokinetics:
 Oral absorption is slow but almost complete. It is highly bound to
plasma proteins-displacement interactions can occur; partly metabolized
and excreted in urine as well as bile. Plasma t1/2 is 2-4 hours.
Uses:
 Mephenamic acid is indicated primarily as analgesic in muscle, joint
and soft tissue pain where strong antiinflammatory action is not needed. It
is quite effective in dysmenorrhoea. It may be useful in some cases of
rheumatoid and osteoarthritis but has no distinct advantage.
35
1

352. Aryl-acetic acid
derivatives
35
2
Diclofenac:
An analgesic-antipyretic antiinflammatory drug, similar in efficacy to
naproxen. It inhibits PG synthesis and is somewhatCOX-2 selective. The
antiplatelet action is short lasting. Neutrophil chemotaxis and superoxide
production at the inflammatory site are reduced.
Adverse effects of diclofenac are generally mild epigastric pain, nausea,
headache, dizziness, rashes. Gastric ulceration and bleeding are less
common. Reversible elevation of serum aminotransferases has been
reported more commonly; kidney damage is rare.
 A preparation combining diclofenac and misoprostol (PGE
1)
decreases upper GI ulceration but may result in diarrhoea.
Diclofenac is among the most extensively used NSAID; employed in
rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis, toothache,
dysmenorrhoea, post-traumatic and postoperative inflammatory conditions-
affords quick relief of pain and wound edema.

353. Aceclofenac:
 A somewhat COX-2 selective congener of diclofenac
having similar properties. Enhancement of
glycosaminoglycan synthesis may confer chondroprotective
property.
35
3

354. Oxicam
derivatives
35
4
Piroxicam:
 It is a long-acting potent NSAID with antiinflammatory
potency similar to indomethacin and good analgesic-
antipyretic action.
It is a reversible inhibitor of COX; lowers PG concentration in
synovial fluid and inhibits platelet aggregation-prolonging
bleeding time.
In addition, it decreases the production of IgM rheumatoid
factor and leucocyte chemotaxis.

355. Pharmacokinetics:
It is rapidly and completely absorbed
99% plasma protein bound;
Largely metabolized in liver by hydroxylation and glucuronide
conjugation;
Excreted in urine and bile;
Plasma t1/2 is long nearly 2 days.
Adverse effects:
The g.i. side effects are more than ibuprofen, but it is better
tolerated and less ulcerogenic than indomethacin or
phenylbutazone; causes less faecal blood loss than aspirin.
Rashes and pruritus are seen in < 1% patients. Edema and
reversible azotaemia have been observed.
Tenoxicam:
A congener of piroxicam with similar properties and uses.
35
5

356. Pyrrolo-pyrrole
derivative
35
6
Ketorolac:
A novel NSAID with potent analgesic and modest antiinflammatory
activity.
In postoperative pain it has equalled the efficacy of morphine, but
does not interact with opioid receptors and is free of opioid side
effects.
it inhibits PG synthesis and relieves pain by a peripheral mechanism.
rapidly absorbed after oral and i.m. administration.
It is highly plasma protein bound and 60% excreted unchanged in
urine.
Major metabolic pathway is glucuronidation.
plasma t1/2 is 5-7 hours.

357. Adverse effects:
 Nausea, abdominal pain, dyspepsia, ulceration, loose
stools, drowsiness, headache, dizziness, nervousness, pruritus,
pain at injection site, rise in serum transaminase and fluid
retention have been noted.
Use:
 Ketorolac is frequently used in postoperative, dental and
acute musculoskeletal pain: 15-30 mg i.m. or i.v. every 4-6
hours (max. 90 mg/day).
It may also be used for renal colic, migraine and pain due to
bony metastasis.
Continuous use for more then 5 days is not recommended.
35
7

358. Indole
derivative
35
8
Indomethacin:
It is a potent antiinflammatory drug with prompt antipyretic action.
Indomethacin relieves only inflammatory or tissue injury related
pain.
It is a highly potent inhibitor of PG synthesis and suppresses
neutrophil motility.
In toxic doses it uncouples oxidative phosphorylation (like aspirin).
Pharmacokinetics:
Indomethacin is well absorbed orally
It is 90% bound to plasma proteins, partly metabolized in liver to
inactive products and excreted by kidney.
Plasma t1/2 is 2-5 hours.

359. Adverse effect:
Ahighincidence(upto50%)ofGIandCNSsideeffectsis
produced:GIbleeding,diarrhoea,frontalheadache,mental
confusion,etc.
It is contraindicated in machinery operators,
drivers, psychiatric patients, epileptics, kidney
disease, pregnant women and in children.
35
9

360. PREFERENTIAL COX -2
INHIBITORSNimesulide:
weak inhibitor of PG synthesis and COX-2 selectivity.
Antiinflammatory action may be exerted by other mechanisms
as well, e.g. reduced generation of superoxide by neutrophils,
inhibition of PAF synthesis and TNFa release, free radical
scavanging, inhibition of metalloproteinase activity in
cartilage.
The analgesic, antipyretic and antiinflammatory activity of
nimesulide has been rated comparable to other NSAIDs.
It has been used primarily for short-lasting painful
inflammatory conditions like sports injuries, sinusitis and other
ear-nose-throat disorders, dental surgery, bursitis, low
backache, dysmenorrhoea, postoperative pain, osteoarthritis
and for fever. 47

361. Nimesulideisalmostcompletelyabsorbedorally,99%plasma
proteinbound,extensivelymetabolizedandexcretedmainlyin
urinewithat1/2of2-5hours.
Adverse effects of nimesulide are gastrointestinal
(epigastralgia, heart burn, nausea, loose motions),
dermatological (rash, pruritus) and central (somnolence,
dizziness).
36
1

362. SELECTIVE COX -2
INHIBITORS
36
2
They cause little gastric mucosal damage; occurrence of peptic
ulcer and ulcer bleeds is clearly lower than with traditional
NSAIDs. They do not depress TXA2 Production by platelets
(COX-I dependent); do not inhibit platelet aggregation or
prolong bleeding time but reduce PGI2 production by vascular
endothelium.
It has been concluded that selective COX-2 inhibitors should
be used only in patients at high risk of peptic ulcer, perforation
or bleeds. If selected, they should be administered in the lowest
dose for the shortest period of time. Moreover, they should be
avoided in patients with history of ischaemic heart disease/
hypertension/ cardiac failure/ cerebrovascular disease, who are
predisposed to CV events.

363. Celecoxib:
It exerts antiinflammatory, analgesic and antipyretic actions
with low ulcerogenic potential. Comparative trials in
rheumatoid arthritis have found it to be as effective as
naproxen or diclofenac, without affecting COX-1 activity in
gastroduodenal mucosa . Platelet aggregation in response to
collagen exposure remained intact in celecoxib recipients and
serum TXB2 levels were not reduced. Though tolerability of
celecoxib is better than traditional NSAIDs, still abdominal
pain, dyspepsia and mild diarrhoea are the common side
effects. Rashes, edema and a small rise in BP have also been
noted.
Celecoxib is slowly absorbed, 97% plasma protein bound and
metabolized primarily by CYP2C9 with a t1/2 of 10 hours. It is
approved for use in osteo-and rheumatoid arthritis in a dose of
100-200 mg BD.
36
3

364. Etoricoxib:
This newer COX-2 inhibitor has the highest COX-2 selectivity.
It is suitable for once-a-day treatment of osteo /rheumatoid /
acute gouty arthritis, dysmenorrhoea, acute dental surgery pain
and similar conditions, without affecting platelet function or
damaging gastric mucosa. The t1/2 is 24 hours. Side effects are
dry mouth, aphthous ulcers, taste disturbance and paresthesias.
Parecoxib:
 It is a prodrug of valdecoxib suitable for injection, and to
be used in postoperative or similar short-term pain, with
efficacy similar to ketorolac.
36
4

366. AntiamoebicDrugs

367. •Amebiasisaffectsabout10%oftheworld's
population,causinginvasivediseaseinabout50
millionpeopleanddeathinabout100,000of
theseannually.
•Amoebiasisisanacuteorchronicinfectionwith
Entamoebahistolyticaproducedbyingestionof
cystsofthisorganism.
•The parasite exist in two form:
-Trophozoites or active form-does not persist
outside the body.
– Cyst or inactive form: can survive outside the
body, & labile.

369. •The outcomeinfection is variable.
•Asymptomaticbutexcretetheinfectiouscystform,
makingthemasourceforfurtherinfections.
• Amebicdysentery:Trophozoites
invadeintothecolonicmucosawithresultingcolitis
andbloodydiarrhea.
•Amebicliverabscess:Trophozoitesinvadethrough
thecolonicmucosa,reachtheportalcirculation,and
traveltotheliverandcauseliverabscess.

370. •Choice of drug depends upon:
–Clinical presentation
–Desired site of action
•Asymptomatic carriers generally are not
treated in endemic areas but in nonendemic
areas they are treated with a luminal
amebicide.
•Luminal agents used to treat asymptomatic
individuals found to be infected with E.
histolytica.
-Diloxanide furoate
-The nonabsorbed aminoglycoside
paromomycin&the8-hydroxyquinoline
compoundiodoquinol

371. •Metronidazole and Tinidazole are the only
nitroimidazolesare the drugs of choice for the
treatment of amebic colitis, amebic liver abscess,
and any other extraintestinal form of amebiasis.
•Metronidazoleissowellabsorbedinthegut,levels
maynotbetherapeuticinthecoloniclumen,andit
islesseffectiveagainstcysts.
•Patients with amebiasis (amebic colitis or amebic
liver abscess) also should receive a luminal agent to
eradicate any E. histolytica trophozoites residing
within the gut lumen.

372. •Nitatzoxanideanoralsyntheticbroad-spectrum
antiparasiticagent,effectiveagainstanumber
ofintestinalhelminthsandprotozoans.
•Other agents, dehydroemetine and chloroquine,
rarely used in Rx of amebic colitis or amebic liver
abscess and are reserved for only very unusual
cases where metronidazole is contraindicated.
•Tetracyclinesanderythromycinarealternative
drugsformoderatecolitisbutarenoteffective
againstextraintestinaldisease.

374. Con’d

375. Metronidazole
•Metronidazole is a
nitroimidazole antiprotozoal
drug, Kills the E. histolytica
trophozoites.
•Has antibacterial activity
against anaerobes, including
bacteroides & clostridium
species.
•Itisthedrug
pseudomembranous
of
colitis
choice
caused
forthe
bythe
anaerobic,gram-positivebacilluscldifficile&is
alsoeffectiveinthetreatmentofbrainabscess
causedbytheseorganisms

376. •Antiparasitic & antimicrobialspectrum
–Obligate anaerobicbacteria
–Helicobacterpylori
–Bacteroids
–Clostridia
–-Ehistolytica
–Giardialumblia
–-Trichomonavaginalis

377. •P/K:
–Well absorbed after oral & rectal administration
–Distributed in sufficient concentration in the liver,
gut, pelvic tissues, CNS, lungs & other tissues like
bone tissue. Reaches high concentration in body
fluids including CSF
–Metabolized by oxiadation & glucoronide conjugation
in the liver
–It is eliminated mainly by the kidney (urine) in
unchanged & some as metabolized from
–Plasma protein binding low (<20%)
–t½ 8 hours

378. Mechanism ofaction
–Metronidazole is aprodrug.
–Susceptiblemicroorganisms including
anaerobic bacteria & certainprotozoa reduce
ofmetronidazolebya
convertittoacytotoxic
thenitrogroup
nitroreductase&
derivative.
–Aerobicbacterialacksthisnitroreductase&
are therefore not susceptible to metronidazole

379. •Metronidazole diffused into anaerobic bacterial or
sensitive protozoal cells
↓
In electron transport chain, the nitro group of
metronidazole is reduced by ferridoxine (by
accepting electron from transport protein)
↓
The reduced product appear to be responsible for
killing the organism probably reacting with cellular
macromolecules such as DNA, protein & membrane .
↓
Inactivation of DNA
↓
Death of protozoa & susceptable bacteria.

380. Indication
s:
–All symptomatic forms of amoebiasis
–Giardiasis
–Trichomoniasis of urogenital tract in both sex
–Anaerobic infection (clostridial)
–Prophylaxis of post-surgical abdominal &
pelvic infection
–Helicobacter pylori

381. –Acute ulcerative gingivitis
–Acute dental infection
–Balantidiasis
–Osteomylitis
–Abscess of brain & lungs
–Pseudomembranous colitis
–Prophylaxis of endocarditis by bacillus fragilis
–Treatment of sepsis: post surgical infection,
intraabdominal infection & septicemia

382. •Toxicities:
–Common: headache, nausea, dry mouth,
metallic taste
–Occasional: vomiting, diarrhea, abdominal
distress
–Serious warrant discontinuation:
Dizziness, vertigo, Encephalopathy,
Convulsion, Incoordination, Ataxia

383. –Rare are: Urticaria, Flushing, Pruritus, Cystitis
–Disulfiram like reaction: Severe nausea &
vomiting,Due to inhibition of Acetyldehyde
dehydrogenase enzyme.
Disulfirum:
–In alcoholic patient
–Severe Hangover: Due to ↑Acetyldehyde
dehydrogenase.
–Symptom: Flushing of the skin, Accelerated HR,
shortness of breath, nausea,vomiting, throbbing
headache, visual disturbance,circulatory
collupse. Should not take 12 hours after alcohol
consume.

384. •Disulfiraum is used in cocaine dependence as it
inhibit Dopa decarboxylase → Prevent
breakdown of dopamine. ( A NT whose release
is stimulated by cocaine)
•The excess dopamine results in increase anxiety,
high BP, restlessness.

385. •Contraindication:
–Active disease ofCNS
–Evidence of blooddyscariasis
–1
st
trimester ofpregnancy
–Any type ofcarcinoma

386. Tinidazole
•A nitroimidazole,
appears to have similar
activity and a better
toxicity profile than
metronidazole
•Has a longer half-life of
13 hours.
•Excreted in urine in
unchanged (mainly) form
•Indication:
–Anaerobic and protozoal infections:
–Very effective in case of –Giardiasis,

387. Secnidazole
•Indication: It is used in the
treatment of amoebiasis, & has
also been tried in giardiasis, &
trichomoniasis
•Dose:
–Given in giardiasis by mouth, usually as a single
dose of 2 gm in adult; for child, the dose is 30
mg/kg
–In invasive hepatic amoebiasis a dose of1.5 g/
day is given single or in divided doses for 5 days
•Trade name: Secnid Susp. 500
mg, Tab. 1 gm; Secnidal, Sezol

388. •Emetine, an alkaloid derived from ipecac
•Dehydroemetine, a synthetic analog
•Both are effective against tissue trophozoites of E
histolytica, but because of major toxicity concerns
they have been almost completely replaced by
metronidazole.
•useislimitedtounusualcircumstancesinwhich
severeamebiasiswarrantseffectivetherapyand
metronidazolecannotbeused.
•Dehydroemetine is preferred because of its
somewhat better toxicity profile. Should be used for
the minimum period needed to relieve severe
symptoms (usually 3–5 days).
Emetin &
Dehydroemetine

389. •Routes of administration:
SCor IM in a supervised setting.
•Adverse effect:
Pain and tenderness in the area of injection are
frequent, and sterile abscesses may develop.
Diarrhea is common.
nausea, vomiting, muscle weakness and
discomfort
•Serious toxicities include cardiac arrhythmias,
heart failure, and hypotension

390. Iodoquino
l
•Effective luminal amoebicide that is commonly used
with metronidazole to treat amebic infections
•Pharmacokinetics:
–Poorly understood
–90% of the drug is retained in the intestine &
excreted in the feces. The remainder enters the
circulation, has a t½ of 11-14 hours, & is excreted
in the urine as glucoronides

391. •Mechanism of action:
–unknown. It is effective against organisms in the
bowel lumen but not against trophozoites in the
intestinal wall or extraintestinal tissue
•Adverse effects:
–anorexia, nausea, vomiting, abdominal pain,
headache, rash, & pruritus
•The drug may increase protein-bound serum iodine,
leading to a decrease in measured
131I uptake that
persist for months

392. •Should be taken with meal to limit GI toxicity
•Should be taken with caution in patient with
optic neuropathy, renal or thyroid disease. Di-
iodo chlorhydroxyquinoline causes subacute
myelo optic neuropathy, so it is not used now
•The drug should be discontinued if it produces
persistent diarrhea or signs of iodine toxicity
(dermatitis, urticaria, pruritus, fever)
•It is contraindicated in patients with intolerance
to iodine

393. Diloxanide
furoate
•A dichloroacetamide derivative.
•It is an effective luminal amebicide but is not active
against tissue trophozoites.
•In the gut, diloxanide furoate is split into diloxanide
and furoic acid
•About 90% of the diloxanide is rapidly absorbed and
then conjugated to form the glucuronide, which is
promptly excreted in the urine.The unabsorbed
diloxanide is the active antiamebic substance.

394. •The mechanism of action of diloxanide furoate is
unknown.
•Diloxanide furoate is the drug of choice for
asymptomatic luminal infections.
•It is used with a tissue amebicide, usually
metronidazole, to treat serious intestinal and
extraintestinal infections.
•Diloxanide furoate does not produce serious adverse
effects. Flatulence is common, but nausea and
abdominal cramps are infrequent and rashes are
rare.
•The drug is not recommended in pregnancy.

395. Paromomycin sulfate
•It is an aminoglycoside antibiotic that is not
significantly absorbed from the GIT
•It is used only as a luminal amebicide & has no
effect against extraintestinal amebic infections
•The drug may accumulate with renal insufficiency &
contribute to renal toxicity
•Have similar efficacy & probably less toxicity than
other agents; in a recent study, it was superior to
diloxanide furoate in clearing asymptomatic
infections
•Adverse effects:
–Occasional abdominal distress & diarrhea
•Should be avoided in patients with significant renal
disease & GI ulceration.

396. Nitazoxanid
e
•An oral synthetic broad-spectrum
antiprotozoal agent
•It was found initially to have activity against
a number of intestinal helminths &
protozoans

397. •Spectrum of activity:
–Cryptosporidium parvum; G.lumblia;
–E.histolytica
–A lumbricoides; Fasciola hepatica
–H. pylori
•Nitazoxanide appears to have activity against
metronidazole-resistant protozoal strains & is well
tolerated

398. •M/A:
Nitazoxanide is a nitrothiazolyl-salicylamide prodrug.
It is rapidly absorbed & converted to active metabolite
tizoxanide which inhibits the pyruvate:ferredoxin
oxidoreductase (PFOR) enzyme-dependent electron-
transfer reaction.
This reaction is essential in anaerobic glucose energy
metabolism.This results in cell swelling, mem. Damage
causing dysfunction of parasite.

399. •Therapeutic uses:
•Treatment of G. intestinalis infection & treatment of
diarrhea caused by cryptosporidia
•Dose:
–Children between 12 & 47 months
•100 mg 12 hourly for 3 days
–Children between 4-12 years
•200 mg 12 hourly for 3 days
–Children over 12 years & adults
•500 mg 12 hourly for 3 days

400. •Adverse effects:
–Rare. Abdominal pain, diarrhea, vomiting &
headache have been reported. A greenish tint to
the urine is seen in most individuals taking
nitazoxanide
•Nitazoxanide is considered a category B agent for
use in pregnancy based on animal teratogenicity &
fertility studies, but there is no clinical experience
with its use in pregnant women or nursing
mothers

401. Antifungal and Antiviral
Agents

402. Antifungal Agents
•Drugs categorized multiple
bases: (1) Type of infection: (a)
Systemic (Deep) Fungal
infections. (b) Topical
(Dermatophytic) Fungal
infections. (c) Mucous
membranes --Yeast infections.
(2) Route/Site of action. (3)
Mechanism of action. (4)
Chemical nature.

403. ANTIFUNGAL DRUGS
Drug
Infection
Type
Route/Site
Mechanis
m
Chemical
Group
Amphotericin
B
Deep/De
rm
IV for
Systemic/Topica
l
Cell
membran
e
Polyene
Nystatin
Derm/Ye
ast
PO for
GI/Topical/Vagi
nal
Cell
membran
e
Polyene
ItraconazoleDeep PO for Systemic
Cell
membran
e
Azole
FluconazoleDeep
IV,PO for
Systemic
Cell
membran
e
Azole
Ketoconazole
Deep/De
rm
PO for
Systemic/Topica
l
Cell
membran
e
Azole
Miconazole
Deep/De
rm
IV for
Systemic/Topica
l
Cell
membran
e
Azole
Sulconazole
硫康唑
Derm Topical
Cell
membran
e
Azole

404. ANTIFUNGAL DRUGS
Drug
Infection
Type
Route/Site
Mechani
sm
Chemical
Group
Clotrimazole
Derm/Yea
st
Topical/Vaginal
Cell
Membra
ne
Azole
Enilconazole
恩康唑
Derm Topical
Cell
Membra
ne
Azole
Econazole益
康唑
Derm/Yea
st
Topical/Vaginal
Cell
membran
e
Azole
Oxiconazole
奥昔康唑
Derm/Yea
st
Topical/Vaginal
Cell
membran
e
Azole
Tioconazole
噻康唑
Derm/Yea
st
Topical/Vaginal
Cell
membran
e
Azole
FlucytosineDeep PO for SystemicNuclear
Pyrimidin
e
GriseofulvinDerm PO for TopicalNuclearOther
TerbinafineDerm Topical
Cell
membran
e
Allylamin
e

405. •Basis for some selectivity:
•Bacteria:Prokaryotes, Have cell
wall, Key membrane lipid =
hydroxylated glycerols
•Fungi:Eukaryotes, Havecell
wall,Keymembrane lipid=
ergosterol
•Vertebrates: Eukaryotes, NO
cell wall, Key membrane lipid =
cholesterol

406. Amphotericin B
•Structure and chemical
characteristics:
•(1) Poorly water soluble.
•(2) Unstable in saline --must
use 5% dextrose.
•(3) Large, charged molecule,
polyene derivative.
•(4) Nystatin related and similar,
but more systemic toxicity

407. •Mechanism of Action:
•(1) Affinity for membranes with
ergosterol.
•(2) Forms channel through
membrane.
•(3) Small molecules leak.
•(4) Cell dies.
•(5) Resistance is rare and slow
to develop.

408. •Pharmacokinetics:
•Crosses membranes poorly by
diffusion and must inject where
need, e.g., intrathecal, IV.
•Clinical uses:Deep infection
of various fungal.
•Adverse Effects: Many
adverse effects, some serious.

409. Azole Derivatives
•Overview:Much lesstoxic
thanamphotericinB
•Mechanism of Action:
•Inhibit ergosterol synthesis:
Inhibits key cytochrome P450
step and Lanosterol(羊毛甾
醇)alpha-C
14
-demethylase

410. Ketoconaz
ole
Flucona
zole
Itraconaz
ole
Spectrum Narrow
Expande
d
Expande
d
Route(s) of Adm Oral Oral, IVOral
t1/2 (hr) 6-9 30 30-40
CSF penetration No Yes No
Renal excretion No Yes No
Interaction with other drugsFrequent
Occasio
nal
Occasion
al
Inhibition of mammalian sterol
synthesis
Dose-
dependent
inhibitory
effect
No
inhibitio
n
No
inhibition
Figure 34.5: Summary of azole fungistatic drugs. P342, Mycek, Harvey
& Champe [Pcol-Lipp2nd97]

411. Ketoconazole
•Broad spectrum antifungal
agent.
•Pharmacokinetics: Used PO
for systemic effect. Dose-
related kinetics, PO doses.
Hepatic biotransforming
enzymes approach saturation.
Half-life after stated oral dose:
6.5 hr --100 mg tablet, 8.1 hr --
200 mg tablet, 9.6 hr --300 mg
tablet

412. •Clinicaluses:variousfungal
infection.
•Adverse effects:
•(1) Most common --anorexia,
nausea, vomiting. divided doses
have been used to reduce GI
side effects.
•(2) Hepatocellular toxicity.
•(3) Adrenocortical suppression

413. Itraconazole
•Antifungalactivity:5-100
timesgreaterinvitropotency
andbroaderantifungalactivity
than ketoconazole. Good
activityagainstAspergillusspp.
Activity vs meningeal
cryptococcus.

414. •Clinical uses:
•Broad antifungal spectrum.
Drug of choice for
blastomycosis. May be effective
in aspergillosis, candidemia,
coccidioidomycosis, and
cryptococcosis.

415. •Adverse effects:
•Fewer adverse side effects than
ketoconazole. Nausea and
vomiting, Rash (especially in
immunocompromised patient),
Hypokalemia, Hypertension,
Edema, Headache.

416. Fluconazole
•In vivopotencies are 100-fold
ketoconazole. Similar with
itraconazole

417. Antiviral Agents
•Amantadine
•Mechanism:Inhibitearly viral
processes.
•Pharmacokinetics: PO, Well
absorbed,Eliminatedunchangedinurine.
•Uses:Highlyselective,InfluenzaA
viruses(H1N1,H2,N2,andH3N2),NOT
clinicallyactiveversusinfluenzaB
viruses.
•Adverse Effects: Dose related and
appear above 1-5 mcg/mL, CNS toxicity,
nervousness, confusion, hallucinations,

418. •Acyclovir
•Antiviralactivity:Effectiveagainst
herpessimplexvirus(HSV).
•Mechanism of action: Relatively
large margin of safety. It is a
Prodrug --must be activated.
•(1) Activated by herpesvirus
thymidine kinase (TK).
•(2) Binds to herpes virus thymidine
kinase 200 times more strongly than
to host TK.
•(3) Inhibits viral DNA polymerase.

419. •Pharmacokinetics:POandIV.
Widely distributed,including
CSF.
•Therapeutic application:
•(1) Essentially only for
herpesviruses (especially
H.simplex type 1).
•(2) Topical, Mucotaneous
herpesvirus infections, May be
useful for primary genital
herpes, less for recurrent (PO

420. •Adverse effects:
•Few side effects in humans,
Nausea with PO, Tissue
irritation if extravasation on IV.

421. •Ganciclovir:
•Conceptually similar to
acyclovir.Lower margin of
safetythanacyclovir.Highly
efficaciousandimportantdrug.
•Mechanism of action:
Prodrug, Activated drug
incorporated into both host and
viral DNA.

422. •Adverse effects:
•Predict toxicity by rapidly
dividing tissues, bone marrow,
GI mucosa, and gonads (at all
doses tested).

423. •Uses:
•Potent and broad spectrum vs
herpes viruses, especially
Cytomegalovirus (CMV ).

424. •Ribavarin:
•Effective against BOTH DNA and
RNA viruses. Prodrug that must
be phosphorylated.
Phosphorylated derivatives
inhibit viral nucleic acid
synthesis. Generally low toxicity.

425. •Zidovudine:
•The first and most important drug
for palliation of AIDS, Active against
HIV-1 and other mammalian
retroviruses.

426. •Mechanism ofaction:
•(1) Decreases reverse
transcriptase activity in
culturedcellsat0.013mcg/mL
•(2)InhibitsreplicationofHIV-1
virus
•(3) Prodrug that must be
phosphorylated: Phosphorylated
to triphosphate by cellular
enzymes, inhibits viral RNA-
directed DNA polymerase
(transcriptase), Triphosphate
binds more strongly to viral

427. •(4)DNA chaintermination:
azidothymidine triphosphate
canbeincorporatedintoDNA,
hencenucleotidescannotbe
addedtomodified3'-position.
•(5) Mammalian DNA
polymerases: Alpha-DNA
polymerase relatively resistant
to incorporating azido-TP,
Gamma DNA polymerase in
mitochondria does incorporate -
-source of toxicity?

428. •Resistantstrains:Isolatedfrom
AIDspatientstreated6monthsor
more, Still sensitive to
dideoxycytidine(双脱氧胞苷 )and
foscarnet(膦甲酸).
•Pharmacokinetics: PO, F=60 -65%.
Peak concentration 30 to 90
minutes. Wide distribution. Usual
dosage is 200 mg q4h!!
continuously!!

429. •Adverseeffects:
•(1) Hematologic:
Granulocytopenia and anemia in
up to 45% of patients. (2) Other
effects: occur sometimes,
Gastrointestinal disturbances,
paresthesia, skin rash, insomnia,
fever, headaches, abnormalities
of liver function, Myopathy,
Confusion, anxiety, depression,

430. •Clinical uses:
•(1) HIV positive patients before
onset of AIDS, Delays
progession of disease by 12-18
months. (2) Patients with AIDS –
can reduces opportunistic
infections, e.g., Pneumocystis
cariniipneumonia, stabilizes
weight, reduces HIV-associated
thrombocytopenia, stabilizes
HIV-associated dementia.
•

431. Antineoplastic Drugs

432. Categories:
•1)Antimetabolites:a)FolicAcid
Analogs (Methotrexate, MTX).b)
Pyrimidineanalogs(Fluorouracil,5-FU;
Fluorodeoxyuridine;Cytarabine).d)
Purineanalogs(6-Mercaptopurine, 6-
MP;6-Thioguanine,6-TG).
•2)Alkylatingagents:Nitrogen
mustards; Cyclophosphamide ;
Thiotepa.
•3) Natural products:Vinca
alkaloids (Vincristine; Vinblastine;
Vinorelbine); Paclitaxel (Taxol
®
)

433. •4) Antiumor antibiotics:
Anthracyclines (Doxorubicin
hydrochloride, Daunorubicin,
Bleomycin)
•5) Miscellaneous agents:
Cisplatin; Carboplatin;
Asparaginase; Hydroxyurea;
Corticosteroid

434. Mechanisms:
•Biologicalmechanism:
•(1) Cell cycle:
•a) Gap 1 (G
1
phase). b) DNA
synthesis (S phase). c) Gap 2
(G
2
phase). d) Mitosis (M phase).
G
0
is a resting phase in which
the cells are not prolifering.

436. •(2)Cellcyclenonspecific
agents(CCNSA):
•Kill proliferating cells
preferentially,actoncellsatall
phases.
•(3)Cellcyclespecificagents
(CCSA):
•Act at specific phase of the cell
cycle.

437. •Biochemicmechanism:
•1)Interferenucleotidesynthesis.
•2)Impactthestructureand
functionofDNA
•3)Interferetranscriptionand
blockRNAsynthesis.
•4)Interfereproteinsynthesis
andfunctions.
•5) Change hormone lever.

438. Resistance mechanism
•(1) Defective activation:
Cyclophosphamide requires
metabolicactivation,
Methotrexate conversion to
more active MTX-polyglutamate
in cells

439. •(2) Increased inactivation:
e.g., aldehyde dehydrogenase
converse cyclophosphamide to
inactive metabolite.
•(3) Altered nucleotide pools:
Can occur with antimetabolites.

440. •(4) Altered DNA repair:
Repair mechanisms increased,
i.e., ability to remove cross-links,
Affect the action of bleomycin
and other DNA-directed drugs
•(5) Altered target:Less
affinity for drug, Methotrexate
(Dihydrofolate reductase
changes ).

441. •(6) Decreased target:
decreased topoisomerase II,
e.g., etoposide
•(7) Gene amplification:
Methotrexate (MTX) increase
dihydrofolate reductase, hence
Requires more MTX to block
•(8) Decreased accumulation:
Decreased uptake
(Methotrexate --carrier protein
decreases). Increased Efflux
(Multidrug Resistance, P-
Glycoprotein (gP-170) in
membrane, pumps drug out)

442. Commonly used
antineoplastic drugs
•Antimetabolites
•Group Characteristics:
•(1) Resemble NORMAL
substrates.
•(2) Most inhibit DNA synthesis.
•(3) Some inhibit RNA synthesis
and/or function. (4) Bone
Marrow cell replication is
profoundly inhibited.
•(5) GI toxicity great with some
drugs.

443. Methotrexate (MTX)
•Structure:

444. •Mechanism ofaction:
•(1) Folic Acid Analogue, Carrier
transport into cell. (2) Binds
strongly to DHFR to deplete THF,
Decreases 1-carbon transfers in
Purine synthesis, Decreases [1-
C-THF] intracellular which
decreases dUMP dTMP,
Therefore, decreases NUCLEIC
ACID synthesis.

445. •Adverseeffects:
•(1) Dose limiting:a)
Myelosuppression
(Thrombocytopenia and
Leukopenia, Nadirs 7-10 days
after Rx, Recovery 14-21 days).
b) GI toxicity (Oral mucositis is
early sign of GI toxicity, Severe
mucositis, Small bowel
ulceration & bleeding, Diarrhea
--requires cessation to prevent

446. •(2)Nephrotoxicity:Conventional
doses,infrequenttoxicity;High
doses,toxicitycanbesevere
•(3)Immunosuppression .
•(4) Hepatotoxicity.

447. •ClinicalUses:
•Broad range. Well established:
(1) Acute Lymphoblastic
Leukemia of childhood. (2)
Choriocarcinoma. (3) Cancers of
breast, bladder, and head &
neck. (4) Useful in non-
Hodgkin's lymphomas

448. Flurouracil (5-FU)
•Structure:

449. •Mechanism ofaction:
•(1)Activatedbyconversionto
nucleotide
•(2)InhibitsDNA synthesis:
Inhibition of Thymidylate
synthase—themostimportant
mechanism ofaction(MOA)in
rapidlygrowingtumors(?)
•(3) 5-FU Incorporated into RNA:
Interfere with RNA processing -
All types, May be most
important MOA in slowly
growing tumors.

450. •Adverseeffects:
•(1) Dose limiting: a) Bone
marrow --esp. with bolus
administration. Leukopenia &
Thrombocytopenia (nadir 9-14
days after 5 days of Rx,
recovery by day 21). b) GI
Toxicity --esp. with infusion
administration. usually
Stomatitis & Diarrhea 4-7 days

451. •(2)Effectofrouteandschedule
onadverseeffects:
•IVbolus:myelosuppression is
dominant;ProlongedRx,may
causemegaloblasticanemia
•Continuous IV Infusion:
Frequently produce, stomatitis,
nausea, vomiting, and diarrhea;
Hepatotoxicity (elevated
transaminases);
myelosuppression less common

452. •(3)Effectofpeak 5-FU
concentration:
•Acute, reversible cerebellar
syndrome: somnolence, ataxia
of trunk or extremities,
unsteady gait, slurred speech,
nystagmus

453. •(4)Otheradverseeffects:
•Hyperpigmentation of skin is
frequent and may be
accompanied by
photosensitivity; Toxic effect of
radiation to skin may be
enhanced; Alopecia, acute and
chronic conjunctivitis, and nail
changes may be observed.

454. •ClinicalUseof5-FU:
•(1)Singleagent:Palliativein
advancedcolorectalcarcinoma
•(2) Combination: Breast cancer;
Carcinomas of ovary, stomach,
pancreas
•(3) Sequential MTX + 5-FU: Head
and neck cancer

455. Alkylating Agents
•Nitrogen mustard
•General view:
•(1) Developed from mustard war
gases of Word War I which were
highly reactive vesicants.
•(2) First chemicals used for
cancer Rx.
•(3) Not cell cycle specific, but
still more active in dividing
tissues.
•(4)"Radiomimetic" --action on
DNA resembles radiation.

457. •Mechanism ofaction:
•(1)Highly reactive:Form
covalentbondswithNDA,RNA
andprotein
•(2) Consequences: a) DNA -DNA
strand and DNA-Protein cross-
links. b) Misreading of genetic
code. c) DNA Chain breaks

458. •Adverseeffectsofalkylating
agents:
•(1)Moretoxictobonemarrow
andgutthantoliverandkidney,
etc.(2)Infertilitytobothmales
andfemales.(3)Mutagenic.(4)
Carcinogenic.
•Tumorresistance:
•Develops slowly & may require
several genetic / biochemical
changes

459. •ClinicalUses:
•Wide spectrum;
Lymphoreticular tissue tumors;
Limited activity against
sarcomas.

460. Cyclosphosphamide

461. •Mechanism ofaction:
•Hepatic cytochrome P -450 system,
enzymes phosphatase and
phosphamidase are primary
activators (hydrolyze P-N bond) to
intermediate, aldophosphamide,
which nonenzymatically breaks
down to --Phosphoramide mustard
(bifunctional) & Acrolein

462. •Pharmacokinetics:
•Oralbioavailability=90-100%,
IVinjectionnolocalirritation
•Half-life--cyclophosphamide --
3-10h;aldophosphamide --1.6h;
phosphoramide mustard--8.7h.
•Most metabolized--< 14%
unchanged in urine.

463. •ClinicalApplications:
•(1)Mostwidelyusedalkylating
agent,inpartduetoavailability
oforalroute
•(2) Active on
lymphoproliferative diseases,
e.g., Hodgkin's disease and
Chronic lymphocytic leukemia

464. •(3)Significant activityvs
multiplemyeloma &ovarian,
breast, small cell lung
carcinoma
•(4) Many combinations.

465. •Adverseeffects:
•(1)Bonemarrow suppression,
mostimportantleukopeniaand
thrombocytopenia
•(1)Nauseaandvomitingsaidto
berare
•(3) Sterile necrotizing
hemorrhagic cystitis. Acrolein
is probable cause. To minimize
cyctitis--high water intake and
take in AM

466. Natural Products
•VincaAlkaloids
•Vincristine sulfate and
Vinblastinesulfate

467. •Mechanism ofaction:
•(1)Uptakebyenergydependent
carrier
•(2)Bind to tubulin in
microtubules tocause their
dissolution.ContrasttoTaxol
whichstabilizestubules.
•(3) No cross resistance between
vincristine and vinblastine

468. •Uses:
•(1)Drugofchoiceforchildhood
leukemiasincombinationwith
prednisone
•(2) Used for lymphoreticular
neoplasms, carcinomas, and
sarcomas

469. •Adverseeffects:
•(1)Severevesicant.Mustbe
carefulofIVequipmenttoavoid
slough.
•(2) Neurotoxicity: a) Mild
sensory neuropathy with
sensory impairment and
paresthesia--Keep Rx. b) Severe
paresthesias, loss of reflexes,
ataxia, and muscle wasting--
stop Rx. c) Constipation and
abdominal pain -take laxatives.
e) Less hematologic effects
than many other cytotoxic

470. Antitumor Antibiotics
•Generalcharacteristics:
•(1) All interact with DNA and/or
RNA, but may also interact with
other cellular substituents.
•(2) Schedule dependence: LESS
"phase-specific" than
antimetabolites.
•(3) Tissue necrosis is only
generalizable toxicity.
•(4)All IV except bleomycin

471. •Doxorubicin(Adriamycin
R
)
•Mechanism ofaction:
•(1) DNA topoisomerase II
inhibitor:Crucial to DNA
replication and transcription.
•(2) Traditional explanations of
MOA:a) intercalates between
base pairs of DNA and inhibits
DNA-dependent RNA synthesis.
b) Generates free radicals that
cause membrane damage and
DNA strand breaks.

472. •Resistance:
•(1) Alterations in
Topoisomerase IIactivity.
•(2)Increased inactivationof
radicals:a) Increase in
glutathione-dependentenzymes,
e.g.,glutathione-peroxidase.b)
AlteredNADPHcontents.
•(3) Increase drug efflux: a)
Multi-drug resistance (MDR). b)
P-glycoprotein (gP-170) pump is
product of mdrgene

473. •Adverseeffects:
•Threecategoriesoftoxicity:a)
Local toxicities.b)Acute
toxicities.c)Chronictoxicity
•(1) Local Toxicity --
Extravasation
•Extravasation --DON'T! Severe
local tissue necrosis to point of
damaging underlying structures;
If occurs, treat immediately:
Remove blood from IV line;
Apply ice, steroid cream;
Locally adm. sodium

474. •(2)LocalToxicity--Radiation
Recall
•Interactionofdoxorubicinand
radiationinsometissuesto
produceenhancedreactions.
•Reactions include: a) Skin:
ulceration and necrosis. b)
Pulmonary: fibrosis and
sloughing of esophageal
mucosa. c) Heart, and intestinal
mucosa may also be affected

475. •(3) Acute Toxicities
•a) Hematologic: Leukopenia
with nadir 7-10 days; recovery
typically by 21 days;
Thrombocytopenia and anemia
less common
•b) If give too fast: "Histamine-
release" syndrome; Cardiac
arrest preceded by ECG
changes

476. •(4) Chronic Toxicities
•a) Cardiomyopathy and
congestive heart failure: require
cessation of Rx after
cumulative dose of 550 to 600
mg/m
2
; must maintain record of
total dose.

477. •ClinicalIndications:
•(1)Broadspectrumanti-cancer
activity.
•(2) Hodgkin's disease, non-
Hodgkin's lymphomas,
sarcomas, acute leukemia, and
breast, lung, and ovarian
carcinomas all responsive
•(3) Activity observed in bladder
tumors, and carcinomas of
prostate, thyroid, endometrium,
head and neck, and other solid
tumors
•

478. Antimicrobial
drugs
I. Antiseptics and disinfectants.
II. Sulfonamides.
III. Synthetic chemotherapeutics.

479. Control of Microbial Growth
•Sterilizing Agents--kill
everything (e.g. heat, radiation)
•Disinfectants--kill most things.
Too strong for living tissues (e.g.
lysol, NH3)
•Antiseptics--milder in action.
Can be used topically, but not
ingested. (e.g. alcohol, iodine)
•Chemotherapeutics --can be
ingested (e.g. penicillin, sulfa
drugs)

480. Medicines with an
antimicrobial activity are
divided into two groups:
1 –non-selective antimicrobial
agents, causes most
destructive effect on the
majority of microorganisms
(antiseptics and disinfectants).
2 -selective antimicrobial
drugs (chemotherapeutic
agents).

481. ORIGINS OF ANTISEPTICS
Joseph Lister (1827 -1912)
•Realised that deaths from operations mostly occurred
from infection contracted during the operation as a result
of unclean practices.
•He started using Carbolic acid (phenol) during operations
to maintain aseptic conditions with significant
improvements.
•Like Semmelweiss he initially encountered opposition,
but use of his methods by the Germans during the Franco-
Prussian war in 1870 provided his major breakthrough
and over the next 10 years, the practise of aseptic surgery
became accepted.

482. •narrow-spectrumand effective only
against a limited variety of pathogens
or broad-spectrum, affecting many
different types of pathogens
•bactericidalif they kill the susceptible
bacteria or bacteriostaticif they
inhibit the growth of bacteria
Antimicrobials could be

483. Antiseptics and
disinfectants
-a group of drugs that are able to inhibit the growth,
development or leads to death of microorganisms
in the environment surrounding the patient or on
the surface of the body.
Antiseptics -(anti-against;septicas-putrid). This is
a group of medicines that are used to eliminate
pathogens in the wound (skin, mucous membranes)
in the gastrointestinal tract and urinary tract.
Causes bacteriocidal or bacteriostatic effect
depending on the concentration.
Disinfectants-used for disinfection of medical
instruments, utensils, facilities, equipment, etc.
Disinfection -a complex of measures aimed at
prevention of infection in the wound (in the body as
a whole) or to prevent the spread of infection.
•Draw a sharp line between antiseptics and
disinfectants is not always possible, because many

484. Requirements for
antiseptics and
disinfectants.
•Must have a broad spectrum of action;
•Rapid onset of action;
•Should have a small latency period;
•Should have a high activity;
•Must be chemically resistant;
•High availability and low cost;
•Lack of local irritant or allergic effects on
tissues;
•Minimal absorption from the place of their
application;
•Low toxicity.

485. Sources of antiseptics
•Early antiseptics were
probably vegetable extracts
•Many spices contain
antibacterial agents
•Essential oils extracted from
plants often have antibacterial
properties
•Lister used carbolic acid
which chemically is a solution
of phenol
•Phenol was originally
extracted from coal tar.
•Coal tar preparations are still
used today in therapeutic
soaps and shampoos.
•To characterize the antimicrobial activity of the antiseptic
agents used phenol ratiowhich indicates action force of the
antimicrobial agent in comparison with the phenol.
•The difference between antiseptics and disinfectants -The
objectives of their application.

486. Classification of Antiseptics
and Disinfectants (according
chemical structure)
I. Inorganic
substances
1. Halogens:
•Iodine (2%, 3%, 5%
alcochol solution)
•Iodinolum
•Ioddicerinum
•Povidon-Iod
(Betadinum)
•Iodophorm
•Lugol’s solution
•Chloramine B
•Chlorhexidine
bigluconate
•Pantocidum (Halazone)
2.Oxidizing agents:
•Hydrogen peroxide
•Potassium
permanganate
3.Acids and alkalis:
•Boric acid
•Salicylic acid
•Solution of ammonia
4. Metallic salts:
•Hydrargyri dichloridum
•Hydrargyri
amidochloridum
•Silver nitrate
•Copper sulfate
•Zinc sulfate
•Zinc oxide

487. Classification continuation
II. Organic substances
1. Aldehydes:
•Formaldehyde (Formalinum)
•Glutaraldehide
•Hexamethylentetraminum
(Methenamine)
2. Alcochols:
•Spiritus aethylicus (Ethyl
alcohol)
3. Phenol derivatives:
•Phenol (Phenolum purum,
Carbolic acid)
•Cresol (Tricresolum)
•Resorcinol
•Thymol
•Benzylbenzoat
4. Dyes:
•Methylenum blue
•Brilliant green (Viride nitens)
•Etacridin lactate
5. Detergents:
•Aethonium
•Decamethoxin
•Roccal
•Dimexid
6. Tar, resins, products of
petroleum:
•Pix liquida Betulae (Birch tar)
•Ichthyolum
•Liniment by Vishnevsky
7. Nitrofuran derivatives:
•Nitrofurasone (Furacilinum)
8. Antiseptics from medicinal
plants:
•Chlorophyliptum
•Novoimaninum

488. Chlorine
•Discovered in 1774 by a Swede, C.W.
Scheele
•It is a pale green, toxic, reactive gas
•It is a powerful irritant and toxin
•Used as a gas warfare agent in WWI
•very nasty, inflicting lifelong damage on
those who survived
•The damaged lungs were possibly a factor
in the 1918 flu pandemic
•Solution of chlorine in water is both a
powerful bleach and disinfectant
•Semmelweis had used chloride of lime as
anantiseptic
Halogens

489. Halogens
The mechanism of antimicrobial
action
•Denaturation of proteins of the
protoplasm of microbial cells by
reacting with the amino group of
the proteins, displacing
hydrogen.
•Denatured protein loses its
activity.
•In the presence of organic
substanceshalogen’s
antimicrobial effectdecreases.

490. Iodines
•Iodine-active bactericidal element.
•At a dilution of 1: 20 000 -kill vegetative forms of
bacteria for 1 min,
•the dispute -15 min.
•Alcoholic solution of Iodine 5%(5 g of Iodine, KI -
2g, ethyl alcohol 95% 100ml)
•An irritant and a distraction action
•INDICATIONS: Disinfection of the surgical field,
disinfection of wounds, the surgeon's hands, in
myositis, neuralgia.
•Iodine is partially absorbed into the blood from the
skin and exhibits resorptive effects, especially in
children.

491. Halogens (Iodine)
•LUGOL'S SOLUTION (Iodine -1 part, 2 part -KI,
water-17 part)
•INDICATION:Mucos lubrication in pharynhitis and
larynhitis.
•IODDICERINE (Iodine, dimethyl sulfoxide, glycerol)
•Fungicidal, antimicrobial, antiviral, antinecrotic,
antioxidant effect.
•!!!The most active Iodine preparation!!!
•Doesn’t irritate tissue, does not cause pain
reaction, deeply penetrates into the tissue.
•INDICATION:Inflammatory infection (purulent
wounds, infectious ulcers, sore throats, tonsillitis,
pulpitis, otitis, pyoderma, erosion of the mucous
membranes, mastitis, candidiasis, inflammatory
diseases of the genital organs).
•Topically in the form of tampons, turundul,

492. Halogens (Chlorine
disinfectants)
CHLORINE -active bactericidal element is active in the
undissociated form of HOCl when Cl dissolved in water at
neutral and acidic pH.
•Bleach -not less than 32% of free Cl. Antimicrobial action -
fast, but not for long
•INDICATIONS: 0.2-0.5% sol. for the disinfection of
premises, infective patients discharge (pus, sputum, urine,
feces).
•Corrosive to metals.
CHLORAMINE B -25-29% active Cl.
•INDICATION: eye wash, hand disinfection, douching (0.25 -
0.5%), treatment of purulent wounds, burns, pustular skin
diseases (0.5-2%). Disinfection of premises, health
products and non-metallic tool, selection of patients
(1.5%).
•Deodorizing properties.
•4-8mg CHLORAMINE B is able to sterilize 1 liter of water
for 15-60 min. (Pantocid), if the water contains a lot of
organic substances.

493. Halogens
CHLORHEXIDINE BIGLUCONATE (Bisdiguanidine derivative).
•Has the properties of chlorine and detergent compounds.
•Capable of damaging the plasma membrane of
microorganisms.
•Strong antibacterial and fungicidal action.
•Bactericidal activity against GR+, Gr-bacterias, active
against Treponema, gonococci, trichomonas, Proteus.
INDICATIONS: disinfection of the surgical area, the surgeon's
hands, tools, burn surfaces, septic processes, prevention of
sexually transmitted diseases. In the form of a tabl. -in
infectious and inflammatory diseases of the mouth and
throat. 0.2% solution inhibits the formation of plaque and
effective in treating gingivitis.
SIDE EFFECTS: Dry hands, itchy skin, dermatitis.
•!!!Can not be used in conjunction with IODINE!!!
•CHLORHEXIDINE is often used as an active ingredient in
mouthwash pastes to reduce dental plaque and oral bacteria.
•It have an immediate bactericidal actionand a prolonged
bacteriostatic actiondue to adsorption onto the pellicle-

494. Oxidizing agents
•HYDROGEN PEROXIDE
•It is available as 30% and 3% solution.
More common 3% solutions is used.
•H2O2 = 2H+ O2
It is decomposed with release of
molecular form of oxygen that is
responsible for antimicrobial effect
•Releasing oxygen makes foam that
cleans and deodorizes putrid wounds
and ulcers.
•Catalases present in tissues speeds
decomposition and foaming of hydrogen
peroxide
•Hydrogen peroxide is used in treatment
of infected wounds and to stop small

495. Hydrogen
peroxide
Indications:
-rinsing the mouth and throat, for the
treatment of wounds that are infected
with anaerobic microflora.
Concentrated solutions (20-30%) is
indicated for the treatment of warts,
lichen planus.
Side effects:
-burn mucosa. Not used in deep
wounds, and not introduced into a
body cavity -may cause embolism.

496. Potassium
permanganate
•2KMnO4 + H2O= 2KOH+ 2MnO2 +
3O2
It liberates oxygen in atomic
form.
•Highly water soluble, used in
1:4000-1:10000 solution.
•Higher concentrations cause
burns and blistering.
•It promotes rusting.
Clinical uses:
•Gargling, douching, irrigating
cavities, urethra and wounds.
•Stomach wash in alkaloid
poisoning.
•In a 2-5% solution is used for
burns, bites of mosquitoes and
snakes, for quick healing of

497. Heavy metal compounds.
•Their mechanism of action is the blocking
of sulfhydryl, carboxyland amino groups
of proteins and enzymes of
microorganisms.
•Metal ions are formed by dissociation of
the salts, interaction with these active
biosubstrates functional groups cause
their denaturation.
•At a deeper penetration of the substance
in the tissue causes irritated cells and
nerve endings effect, and the extreme
manifestation of a cauterizingeffect of
metal salts.
•(Pb, ... Al, Zn, Cu, Ag, ... Hg)In such
sequence an increases antimicrobial
activity. As antiseptics most active are

498. Heavy metal compounds.
•With prolonged use of salts of heavy metals
can be cytotoxic effectdue to the inhibition of
thiol enzymes in the tissues.
•Symptoms of poisoning with salts of heavy
metals:a chemical burn of GIT mucosa, the
weakening of cardiac activity, collapse, kidney
and liver damage.
•In cases of poisoning:gastric lavage with
water, tea solution with activated carbon,
Unithiol.
Inside:milk, raw eggs, Unithiol or Tetacin
calcium, Sodium thiosulfate. Symptomatic
treatment:cardiac glycosides,
sympathomimetic, plasma expanders,
vasoconstrictors, narcotic analgesics.

499. Acids and alkalis
•Acids: boric acid, salicylic-Shift the pH to the acid
side → protein denaturation of microbial cell
protoplasm.Since proteins of the skin and mucous
membranes form ingdense, insoluble albuminates,
that is providing anti-microbial, anti-inflammatory,
antifungal effects.
•In high concentrations cauterize tissue(coagulative
necrosis )!
•Boric acid:used for washing and rinsing of the
mucous membranes of the mouth, diaper rash, acute
and chronic otitis media, colitis, pyoderma,
pediculosis.
•Side effect:It penetrates through the skin and
mucous membranes, especially in children,
cumulates. With long-term use in patients with
impairedrenal function develops acute and chronic
poisoning(nausea,vomiting, diarrhea, skin rashes,
confusionconsciousness, convulsions, oliguria,
sometimes shock.
•Salicylic acid:Weak antiseptic, irritant, low
concentrations (1-3%)–keratoplastic,in high (5% -

500. Alkalis
•Alkalines:NaHCO3, sodium tetraborate,
sol. of ammonia.
•NaHCO3, sodium tetraborate -melted
mucin, a softening effect. Inflammatory
exudate pH shiftsto the alkaline side
reduces the manifestations of
inflammation.
•10% ammonia solution exhibits antiseptic
effect,manifests cleaning properties,
dissolves fat. Given these properties, it is
suggested for washing hands before
surgery(25 ml solution of ammonia
diluted in 5 liters of water).
•

501. Group of (aromatic) phenol,
resorcinol, thymol, tar, ichthyol,
benzylbenzoate.
•Phenol (carbolic acid):3-5%
solution for disinfection of
furniture, household items,
hospital linen, patients discharge.
•0.25-1% -sometimes in skin
diseases accompanied by itching.
•0.1-0.5% -conservation of serum
and suppository.
•Readily absorbed through intact
skin and mucous membranes,
causing intoxication(short-term
stimulation of the CNS, respiratory
depression and cardiac activity,
decrease in body temperature,
Organic antiseptics

502. Organic compounds
Phenols
Resorcinol
•In small doses has keratoplasticproperty
in the more annoying -keratolytic.
•Used for the treatment of skin diseases
(eczema, seborrhea), fungal infections (2-
5% solutions, 5-20% ointment, paste).
Birch tar
•Has: antimicrobial, keratoplastic,
keratolytic and irritant effect.
•Is used to treat a number of skin diseases
and scabies.
•Is one of the components of balsamic
liniment of Vishnevskiy

503. Group of aldehydes and
alcohols
•PREPARATIONS: FORMALDEHYDE
SOLUTION,LIZOFORM, ETHYL ALCOHOL,
HEXAMETHYLENETETRAMINE
(METHENAMINE)
Formaldehyde solution (Formalin)
•Has antimicrobial (vegetative forms and
spores) and deodorizing effects.
•MECHANISM OF ACTION : dehydration of
microbial cells protoplasm proteins causing
its destruction.
•Is used as a disinfectant and deodorant,
skin treatment with sweating (0.5-1%),
disinfection tools (0.5%). For the

504. Aldehydes and alcohols
(Formaldehyde)
•If inhaled formaldehyde-tearing, coughing,
shortness of breath, agitation.
•Inoral poisoning-pain in the mouth, behind
the sternum, inepigastric region,
hematemesis, thirst, loss of consciousness,
cyanosis, coma.
•Emergency inpoisoning:Inhalation of water
vapor, oxygen saturation,gastric lavage
2.3% sol. of Ammonium chloride.
•Inward enter:2-3 tbsp.of activated carbon,
100 ml of 30% solution of magnesium
sulfate.
•In severe poisoning-forced diuresis, s/c1
ml 0.1% solution of Atropine sulfate,
Promedol, inward -Codeine in tabl.

505. Ethyl alcohol
•Bactericidal activity starts with alcohol 20% and
increases with concentration. On the spore form
does not affect.
•High concentrations of alcohol in the protein
environment form dense protein aggregates.
•70% -it is more deeply penetrates into the deeper
layers of the epidermis of the skin, sebaceous and
sweat glands, provides a high antiseptic effect
(antimicrobial strength of 70% is equal to 3%
phenol sol.).
•Application: disinfection of hands and operating
field (70%).
•Sterilization of surgical instruments (90-96%).
•Disinfection of the skin before injection (70%).
•Alcohol compresses for children (20%), adults
(40%).
•For the preparation of medicaments.

506. Group of dyes
Ethacridine lactate (rivanol),
Brilliant green,
Methylene blue
•Antimicrobial activity of this
group falls In the protein
environment
•The most sensitive Gr +
bacteria, cocci.

507. Ethacridine lactate (rivanol):
-used in surgery, gynecology, urology,
ophthalmology, dermatology. For washing of fresh
and infected wounds, cavities (pleura, peritoneum),
bladder, uterus.
Brilliant green
(1-2% water and alcohol sol.):
-for the treatment of skin with scratches, pyoderma,
blepharitis, and others.
Methylene blue:
-used internally for urinary tract infections (cystitis,
urethritis).
-I/V1% sol.50-100 ml in case of poisoning with
hydrocyanic acid or salts(in large doses translates
hemoglobin to methemoglobin which comes into
contact with a non-toxic form of cyanide complex
cyanmethemoglobin) .
-When administered I/Vin small doses (0.1-0.15

508. Nitrofuran derivatives
(furacillin, furazolidone)
•Spectrum of action:Gr-, Gr + bacteria
(staphylococci, streptococci, dysentery bacillus,
intestinal coli, Salmonella paratyphi, the causative
agent of gas gangrene, etc.) and protozoa
(Trichomonas, Giardia).
•Pharmacodynamic: influenced microbes reductase,
there is a restoration of the nitro group and their
transformation into toxic products for cells
(inhibition of the respiratory chain, the destruction
of the microbial wall).
•In the presence of pus does not lose effectiveness.
•Applyfor external treatment of wounds, skin,
mucous membranes, wash serous and joint
cavities, otitis media, conjunctivitis and others.
Eye diseases and orally for the treatment of
bacterial dysentery.

509. Detergents
•Detergents -a substances with a high surface
activity.
•Show antiseptic and cleansing action.
•Distinguish anionic and cationic detergents.
•Anionic detergentsinclude ordinary soaps
(sodium or potassium salts of fatty acids).
•As antiseptics mainly used cationic surfactants:
benzalkonium chloride, cetylpyridinium chloride,
miramistim.
•Benzalkonium chloride has antibacterial,
antiprotozoal and spermicidal action (spermicidal
effect develops in two stages: first -the
destruction of the flagellum, and then -the gap of
the sperm head, which makes it impossible to
fertilization).
•Used for treatment of skin, mucous membranes,
wounds, rinsing the bladder, urethra, and for

510. Miramistim:
•Antiseptic, antiviral, antibacterial agent
•Gr-, Gr +, anaerobes, fungi.
•Reduces the resistance of bacteria and
fungi to antibiotics.
Application:used as a 0.01% solution as an
antiseptic in dental practice for the
treatment of infected wounds, burns,
infections of upper respiratory tract,
urogenital system, stimulates local non -
specific immunity, accelerates
regeneration.
Cetylpyridinium chloride
in the composition of the drug "Tserigel"is
used for hand washing before surgery.

511. II. Synthetic
chemotherapeutic agents
•Sulfonamides
•Quinolones and
Fluroquinolones
•Nitrofuran derivatives

512. Sulfonamides
•Sulfa drugs (SA) -synthetic chemotherapeutic
agents, which are derivatives of sulfanilamide, or
amides of sulfonic acid.
The first preparation of SA: Red Streptocid (1935).
Common properties
of SA:
-Sulfa nucleus;
-Mechanism of
action;
-Spectrum of
antibacterial action.

513. Classification of SA
1. Preparations with the resorptive (system)
actions which are well absorbed in the
intestine, creating high concentrations in
the blood and other tissues:
•short-actingdrugs (period of half of
absorption less than 10 hours are applied
3-4 times per day, sometimes even 4 -6
times a day in an amount of 4-6 g/day):
•-Sulfadimezin;
•-Etazol;
•-Norsulfazol;
•-Urosulfan.

514. Classification of SA
•drugs with intermediate action(t1/2 = 10 -
24 hours):
•-Sulfazin;
•-Sulfamethoxazole.
• long-acting(t 1/2 = 24-28 hours):
•-Sulfadimetoxin;
•-Sulfapiridazin;
•-Sulfamonomethoxine.
•extremely long-acting(t 1/2 of 48 hours):
•-Sulfalen.

515. 2. Preparations of the intestinal action,
which are slowly and incompletely
absorbed from the GIT, they are use for the
treatment of intestinal infections (t 1/2 <10
hours).
•-Ftalazol;
•-Sulgin;
•-Ftazin;
3. SA for topical application (readily soluble
in water and is used topically in the eye
drops for the prevention and treatment of
gonococcal eye disease in newborns, as
well as for the treatment of conjunctivitis,
blepharitis, corneal ulcers and other
pathologies of the eye).
•
Classification of SA

516. Mechanism of action
•Certain microbes require
paraaminobenzoic acid (PABA) to
synthesize dihydrofolicacid which is
required to produce purines and
ultimately nucleic acids.
•Sulfonamides, chemical analogs of
PABA, are competitive inhibitors of
dihydropteroate synthetase .
•Sulfonamides therefore are reversible
inhibitors of folic acid synthesis and
bacteriostaticnot bacteriocidal.

517. Mechanism of action

518. Conditions necessary for the manifestation
of the antibacterial action of the SA:
•-microorganisms can use SA instead of PABA in
the case when the concentration of the drug in
tissues in 2000-5000 times higherthan the
concentration of PABA;
•-SA efficiency sharply decreases in the presence
of pus, blood and tissue breakdown products due
to the PABA high concentration in these products;
•-SA have antimicrobial action only against those
microorganisms which are themselves synthesized
DHFA;
•-In SA resistant microorganisms observed
increased synthesis of PABA;
•-The use of the SA in low concentrations
contributes to the formation of resistant strains of
microorganisms and leads to inefficiency of the
SA.

519. SA antimicrobial
spectrum
•Currently used SA have broad
spectrum, they inhibit gram-positive
and gram-negative
bacteria:Streptococcus pneumoniae,
beta-haemolytic streptococci,E. coli,
klebciella, shigella, salmonella,
enterobacter, gonococci,
meningococci, and pneumococci;
•Nocardia,
•Chlamidia,
•Protozoa (toxoplasmaand malarial

520. SA pharmacokinetics
• Absorption.Slightly in the stomach and
mainly in the small intestine. Within 30
minutes after the administration of the SA
are found in urine. The bioavailability is 70-
90%.
• Biotransport.Reversibly bind to serum
albumin, an agent which is directly
proportional to the degree of
hydrophobicity of the molecule of the drug.
SA can displace from its association
another protein drugs, particularly NSAIDs
and endogenous substances (bilirubin).
• Distribution.Pass through the blood-
tissue, placenta and blood-brain barriers.
Also passes into breast milk.

521. •Biotransformation.
Phase I reactions-acetylation, hydrogen
substitution in the group NH2-acetic acid
residue, thereby forming acetylated
derivatives which do not have antimicrobial
activity in an acidic medium and form
crystals that disrupts the function of the
kidney (crystalluria).
Reaction Phase II–formation of double
binding with glucuronic acid.
•Excretion.Advantageously, urine, saliva, to a
lesser extent and intestinal contents, but also
breast milk.
Are displayed in the form of metabolites and
unchanged.
SA pharmacokinetics

522. Clinical uses of SA
•Infections of urinary tract
•GIT infections
•Respiratory tract infection
•Pharingitis, gingivitis
•Chlamidial infections
•Wounds, burns
•Toxoplasmosis
•Malaria
•For systemic treatment cotrimoxazoleis
more often used nowadays
•Sufonamides are used for prevention of
infections.

523. Side effects of
sulfonamides
-occur in 3 -5% of patients and more frequently in children and the
elderly. Complications due to overdose, and patients with
hypersensitivity to the SA.
1.The central nervous system: nausea, vomiting, dizziness, headache
(central genesis), depression, increased fatigue.
2.Blood:leukopenia, thrombocytopenia, agranulocytosis,
methemoglobinemia, hemolytic anemia.
3. Kidneys:oliguria, proteinuria, hematuria, crystalluria.
4. Allergic reactions:fever, itching, rash, pain in the joints.
Prevention of crystalluria:
•-Drink plenty of liquids (3-5 liters per day);
•-drink alkaline mineral water or milk during SA using.
Contraindications: Toxic and allergic reactions to drugs.

524. 1 -Combination with 5-aminosalicylic acid:
•SALAZOSULFOPIRIDIN
•SALAZOPIRIDAZIN
2 -combined with Trimethoprim:
•Biseptol (trimethoprim +
sulfamethoxazole)
•Sulfaton (trimethoprim + sulfadimezin)
Combined sulfa drugs

525. Combined sulfa drugs
(BISEPTOLUM) .
•The mechanism of
action of the
combined drug on
the principle of
combined
violations of
nucleic acid
synthesis in two
points:
1. at the level of
DHFA inclusion in
PABA synthesis;
2. at the level of

526. Combined sulfa drugs
(BISEPTOLUM) .
•The second (additional) mechanism is
achieved by use of Trimethoprim (TMP) -
antimalarial drug.
•TMP has a similar antimicrobial activity
with the SA and is superior in activity in the
20-100 times. The most justifiable is a
combination of TMP with sulfamethoxazole
in the ratio of 1: 5.
•Thus, the combined preparation ‘Biseptol -
480’ created, which is a combination of
TMP with sulfamethoxazole 1: 5 (80 mg +
400 mg).
•

527. Features of combined
SA drugs
•-Effective even in the case of
resistance to SA;
•-Resistance to the combined drugs
develops slowly;
Side effects:
•1. Dispepsia;
•2. Skin rash;
•3. Sometimes superinfection;
•4. The reduction in reproductive
function (rare).

528. Antimicrobials with
different chemical
structure.
FLUOROQUINOLONES:
•mono fluorine
substitute
1.ciprofloxacin
2.ofloxacin
3.pefloxacin
4.norfloxacin
5.enoxacin
•bifluorine substitute
1.lomefloxacin
2.ofloxacin
3.sparfloxacin
•trifluorine substitute
1.traufloxacin
2.gatifloxacin
3.gemifloxacin
4.moxifloxacin

529. FLUOROQUINOLONES:
The spectrum of action:
•wide, including Pseudomonas aeruginosa,
Chlamydia, Giardia, Trichomonas, Yersinia,
anaerobes, anthrax.
Mechanism of action:
•block the enzyme DNA -gyrase, responsible for
supercoiling of the DNA molecule, as well as block
the enzyme topoisomerase type 4, is responsible
for the compact folding of the DNA molecule. This
leads to an uncoiling of DNA and the
microorganism death.
Type of antimicrobial action:
•bactericidal

530. Indications:trichomoniasis, giardiasis, plague,
anthrax, gonorrhea, anaerobic infections,
Legionnaires' disease.
Side effects:
•Excitation of the central nervous system,
anxiety, in large doses -convulsions (disrupt
the synthesis of GABA in the CNS) .
•Dyspepsia, drug-induced hepatitis, swelling of
the tongue
•Tachycardia, shortness of breath
•Anemia, leukopenia
•Photodermatitis, itching
•Disturbances of cartilage in children, so
containdicated for children under 12 years.
•Hypothyroidism
•
FLUOROQUINOLONES:

531. Naphthalidine Derivatives
•nalidixic acid
•oxolinic acid
•pipenamicacid

532. Naphthalidine Derivatives
The spectrum of action:
•narrow (only Gr-microorganisms)
Mechanism of action:
•blocks the enzyme DNA gyrase, as a
consequence despiralization DNA and death
of microorganisms.
Indication:
•when introduced into the body does not leave
the bloodstream, excrited with the urine in
unchanged form, so usedin infectious
diseases of the kidneys and urinary tract
infection (pyelonephritis, cystitis, urethritis,
prostatitis).
Type antimicrobial action:
•Bactericidal
(Side effects see FLUOROQUINOLONES)

533. Nitrofurans
(classification)
1.The drug is used topically for treatment of wounds and hands, with
anaerobic infections:
•FURACILLIN
•FURAZOLIDONE
2. The drug is used in infectious diseases of the GIT:
•FURAZOLIDONE
3. The drug is used in infectious diseases caused by protozoa:
•FURAZOLIDONE
4. The drug is used in infectious diseases of the kidneys and urinary
tract:
•FURAGIN
•FURADONIN
•SOLOFUR

534. The spectrum of action:
•Gr +, protozoa
•and anaerobic.
Mechanism of action:
•are acceptors of H+ ions and enter into
competition with the natural acceptors in
the chain of tissue respiration, as a
consequence of violating the microbial cell
respiration and death.
Type of antimicrobial action:
•bactericidal
Nitrofurans

535. Side effects:
•Peripheral paresthesia and
paresis
•Hypotension (donors are NO)
•Nausea, diarrhea, vomiting,
epigastric pain, anorexia
•Anemia and leukopenia
•Allergic reactions
Indications: see classification.
Nitrofurans

536. Derivatives of 8-oxyquinoline
(classification)
1.The drug is used topically for treatment of wounds
and hands:
•SAPROSAN
•HLORHINALDON
2. The drug is used in infectious diseases of the
gastrointestinal tract:
•ENTEROSEPTOL
•MEXAZA
•INTESTOPAN
3. The drug is used in infectious diseases caused by
protozoa:
•ENTEROSEPTOL
•QUINIOFON
•DIYODOHIN
4. The drug is used in infectious diseases of the
kidneys and urinary tract:
•NITROXOLIN (5-NOC)

537. The spectrum of action:
•Gr+,fungi, protozoa and anaerobic
Mechanism of action:
•Disrupt the synthesis of NAin the microbial cell;
•Uncouple oxidative phosphorylation processes ;
•Communicating with iron enzymes and break
breathing activity of microbial cells;
•All this leads to the death of microorganisms .
Type of antimicrobial action:
•bactericidal
Indication:
•see. classification
Derivatives of 8-
oxyquinoline

538. Side effects:
•Peripheral paresthesia and paresis,
polyneuritis, headache, optic nerve damage
(irreversible blindness).
•Dyspepsia, anorexia, itching in the anal
area.
•Hyperthyroidism, iodinephenomenon
(iodine poisoning: a runny nose, nasal
congestion, cough, conjunctivitis, acne-like
skin rash, treatment -the NaCl solution).
•Allergic reactions
Derivatives of 8-
oxyquinoline

539. Imidazole derivatives
•Metronidazole
•Tinidazole

540. The spectrum of action:
•anaerobes, Giardia, amoeba, balantidiums,
some protozoa, Helicobacter pilory
Mechanism of action:
•penetrate into the cells, where the enzymatic
actionofmetalloproteases separates nitro
fromthem, which causes the death of the
microorganism.
Nature of antimicrobial action:
•bactericidal
Indication:
•generalized anaerobic infection, amoebiasis,
amoebic dysentery, giardiasis,
trichomoniasis, balantidiazis, peptic ulcer and
duodenal ulcer.
Imidazole derivatives

541. Thyroid and Anti-Thyroid
Drugs
An overview of the thyroid,
thyroid drugs, and the
mechanisms through which
they affect thyroid
function.

542. Anatomy and Physiology
of the Thyroid Gland
•Member of the Endocrine System
•Secretes thyroid hormones, thyroxine
and calcitonin, which regulate
metabolism and growth.
•Located in neck adjacent to the 5
th
cervical vertebra (C5).
•Composed of epithelial cells which
specialize in the absorption of iodine
and, of course, secretion of thyroid
hormones.
•Follicles surround a protein core, the
colloid, where thyroglobulin, a substrate
in thyroid hormone synthesis, and
thyroid hormones are stored.

543. Synthesis of Thyroid
Hormones
•Regulation:
•The hypothalamus in the brain secretes thyroid releasing
hormone, TRH, that target the pituitary gland which, in turn,
secretes thyroid stimulating hormone, TSH. The pituitary
gland’s sensitivity toward TRH varies with the body’s need
for thyroid hormones.
•TSH is absorbed into the thyroid, stimulating the thyroid to
absorb iodine and synthesize hormones.
•Thyroid hormones provide negative feedback for TSH
production via a “homeostatic feedback loop.”
•TH Synthesis:
•Thyroid peroxidase (TPO) catalyzes the conversion of iodide
(I
2) to iodine (I
-
) using H
2O
2as a cofactor.
•TPO then catalyzes the addition of iodine to the C -3 and C-5
position of a tyrosine residue of thyroglobulin.
•Two iodinated thyrosine rings condense to form thyroxine, or
T4, with four iodine substituents.
•Triiodothyronine, or T3, with three iodine substituents,
accounts for about 10% of thyroid hormone production.

544. Mechanism of TH
Activation in Body
•Hydrophobic molecule transported in the
bloodstream with a requisite carrier protein, TBG.
Albumin also serves as a TH carrier protein.
•Transported across the cell membrane using a
transporter complex. TH enters nucleus.
•The iodine at position 5 on the outer ring serves to
sterically hinder the thyroid hormone binding
enzyme. T4 is converted to T3, the active form.
•Deiodinase, specifically IDI or IDII, cleaves the
iodine at position 5 to yield triiodithronine, T
3.

545. TH Effects on
Metabolism
•TH serves as a nuclear transcription factor,
regulating gene expression in targeted cells to
increase metabolism.
•Increase size and number of mitochondria in the cell.
•Synthesizes cytochromes which feed into the electron
transfer chain of cellular respiration, stimulating
metabolism through increasing ATP production.
•Increase ATPase concentration, the enzyme which
cleaves a phosphate group from ATP forming ADP and
inorganic phosphate.
•Increased K
+
and Na
+
concentrations in the cell.
•Increase the body’s basal metabolic rate, BMR, to
maintain electrochemical gradient in cell.
•Stimulate carbohydrate metabolism and lipolysis, or
the break down of fats.
•Affects protein synthesis.
•Increase the body’s sensitivity to cathecholamines,
i.e. adrenaline, which is also a derivative of TH.

546. Conditions that Impair
Thyroid Function:
Hypothyroidism
•Insufficient amount of thyroid hormone
synthesized causing lethargy and weight
gain, among other symptoms.
•Primary hypothyroidism is typically
caused by Hashimoto’s Disease, an auto -
immune disorder in which the thyroid is
destroyed by antibodies.
•Impaired hypothalamus and pituitary
function, typically due to a tumor, can
inhibit the secretion of THS, causing
secondary hypothyroidism.
•A diet insufficient in iodine causes
hypothyroidism as well.

547. Symptoms of Thyroid
Disfunction: Goiter
•Enlarged thyroid, symptom of
hypothyroidism.
•Goiters form for different reasons
depending on the cause of hypothyroidism
•Hashimoto’s disease, also known as chronic
lymphocytic thyroiditis, causes goiters due to
the accumulation of lymphocytes.
•The decreased amount of thyroid hormones in
the body, due to Hashimoto’s or other thyroid
disorders including infection, signals the
increased production of TSH which accumulates
in the thyroid causing a characteristic goiter.
•Goiters form due to an insufficient amount of
ingested iodine and serve to increase the
surface area of the thyroid and aid in its
absorption of iodine.

548. Treatment for
Hypothyroidism
•Hormone replacement therapy
•Administered orally with a bioavailability ranging from 48% -80%.
•Levothyroxine—Synthetic T4
•Liothyronine—Synthetic T3
•Liotrix—Combination of synthetic T4 and T3
•Natural Thyroid Hormones —Thyroid hormones derived from pigs,
contains T4 and T3
−Armour Thyroid
•Dosage specific to individual and is determined by their TSH
serum levels. Typically 1.5μg T4 per kg body weight.
•Because thyroid hormones serve to increase heart rate, T4, the
inactive form, is typically administered to older patients who have an
increased risk for heart attack on account of their age. Synthetic T3
is reserved for younger patients, who do not have a history of heart
problems and individuals non-responsive to T4 treatment.
•Some men are inefficient in the conversion of T4 to T3, making
combination drugs like Litrix and Armour Thyroid ideal treatment
options.
•Dosage for individuals suffering from secondary hypothyroidism
determined by the amount of free T4 and T3 circulating in their
system.
•Administering too high of a dosage leads to hyperthyroid
symptoms.

549. Conditions that Impair
Thyroid Function:
Hyperthyroidism
•The over production of thyroid hormones.
•Symptoms include fatigue, weight lose,
rapid heart beat, anxiety, swollen eyes,
and sensitivity to hot temperatures.
•Causes:
•Grave’s disease, and autoimmune disorder in
which antibodies serve as agonists to the THS
receptors on the thyroid’s surface, causing
thyroid growth and activation of hormone
synthesis and secretion.
•Thyroid tumors which cause the uncontrolled
synthesis and secretion of thyroid hormones.
•Thyroiditis, inflammation of the thyroid typically
caused by infection.

550. Treatment for
Hyperthyroidism
•Anti-thyroid drugs—Inhibits thyroid
hormone synthesis by irreversibly binding
to TPO inhibiting its ability to break down
iodine (I
2→I
-
) and covalently attach it to the
tyrosine residue of thyroglobulin.
•Propylthiouracil
•Methimazole
•Carbamizole─Degraded to methimazole in the
body.
•Radioactive Iodine
•Thyroidectomy
•β-Blockers used in the treatment of
thyroiditis to treat symptoms.

551. Anti-Thyroid Drugs
•Effective in the long-term treatment of
hyperthyroidism.
•6-8 weeks before maximum effect of the drug
achieved. Drug inhibits hormone synthesis, so
hormones synthesized prior to drug use will
continue to cause hyperthyroid condition.
•Typical side effects include headache, nausea,
vomiting, itchy skin and rash, and muscle aches
and pains.
•Serious liver damage, decreased red and white
blood cell synthesis, as well as decreased platelet
production have been reported in a few cases. The
drug’s interaction with other enzymes responsible
for clotting factor synthesis accounts for some of
these serious side effects.
•Administering too high a dosage of anti -thyroid
drugs can cause hypothyroidism.

552. Thyroid Treatment:
Potential Drug Interactions
•Drugs that reduce thyroid hormone production
•Lithium
•Iodine-containing medications
•Amiodarone (Cordarone)
•Drugs that reduce thyroid hormone absorption
•Sucralfate (Carafate)
•Ferrous sulfate (Slow Fe)
•Cholestyramine (Questran)
•Colestipol (Colestid)
•Aluminum-containing antacids
•Calcium products
•Drugs that increase metabolism of thyroxine
•Rifampin (Rifadin)
•Phenobarbital
•Carbamazepine (Tegretol)
•Warfarin (Coumadin)
•Oral hypoglycemic agents
•Drugs that displace thyroid hormone from protein binding
•Furosemide (Lasix)
•Mefenamic acid (Ponstel)
•Salicylates

553. TSH Replacement Drugs
•Thyrotropin alpha—A synthetic form of
TSH. Administered intravenously.
•Used in thyroid cancer treatment.
•Tumors of the hypothalamus or pituitary gland
can cause the uncontrolled release of TSH,
which accumulates in the thyroid and can cause
subsequent follicular or papillary cancer of the
thyroid. Partial or total thyroidectomy typical.
•Following thyroidectomy, the individual is
dependent on exogenous thyroid hormones to
regulate metabolism, but thyrotropin alpha is
also used to suppress the release of endogenous
TSH, which could trigger cancerous growth
again.
•Used as a diagnostic tool to determine the
reoccurrence of cancer.

554. Vitamins

555. •Polish biochemist Casimir Funk discovered
vitamin B1 in 1912 in rice bran.
•He proposed the complex be named
"Vitamin" (vital amines).
•By the time it was shown that not all
vitamins were amines, the word was
already ubiquitous.

556. Vitamin -definition
•An organic compound required as a
nutrient in tiny amounts by an organisms.
•It cannot be synthesized in sufficient
quantities by an organism, and must be
obtained from the diet.
•Vitamins have diverse biological function:
•hormone-like functions as regulators of mineral
metabolism (vit. D),
•regulators of cell and tissue growth and
differentiation (some forms of vit. A)
•antioxidants (vit. E, C)
•enzyme cofactors (tightly bound to enzyme as a
part of prosthetic group, coenzymes)

557. Vitamin classification
Lipid-soluble vitamins(A, D, E and K)
•hydrophobic compounds, absorbed
efficiently with lipids,
•transport in the blood in lipoproteins or
attached to specific binding proteins,
•more likely to accumulate in the body,
•more likely to lead to hypervitaminosis

558. Vitamin classification
Water-soluble vitamins-8 B vitamins and
vitamin C
•Function:mainly as enzyme cofactors,
•hydrophilic compounds dissolve easily in
water,
•not readily stored, excreted from the body,
•their consistent daily intake is important.
Many types of water-soluble vitamins are
synthesized by bacteria.

559. Lipid-soluble vitamins
Vitamin A
Retinol
•Biologically active forms
-retinoids: retinol,
retinal, retinoid acid.
•Major vit. A precursors
(provitamins) →plants
carotenoids.
•Foodstaf of animals
origin contain most of
vit. A in the form of
esters (retinylpalmi-
tates) –retinol andlong
fatty acid
Cyklohexanring and isoprenoid
chain

560. Retonol esters → hydrolysis by
pancreatic enzymes to retinol.
b-caroten is cleaved to retinal by b-
carotene 15,15´dioxygenase
(cofactors iron and bile salts).
Intestinal cells → esterification of
retinol → transported in
chylomicrons.
Remnants of chylomicrons →
liver→ esterification (if the
concentration exceeds 100 mg,
esters are stored).
Transport of retinol to target
organs tightly bound to retinol-
binding protein, RBP.
Vit. A transport and metabolism

561. Vitamin A and vision
•Vit. A is necessary to form
rhodopsin (in rodes, night vision)
and iodopsins (photopsins, in
cones–color vision) -visual
pigment.
•Retinaldehyd is a prosthetic
group of light-sensitive opsin
protein.
•In the retina, all-trans-retinol is
isomerized to 11-cis-retinol →
oxidized to 11-cis-retinaldehyd,
this reacts with opsin (Lys) →to
form the holoprotein rhodopsin.
•Absorption of light →
conformation changes of opsin
→ photorhodopsin.

562. Vitamin A and vision
•The following is a series
of izomerisation→
initiation of nerve
impulse.
•The final step is
hydrolysis to release all-
trans-retinaldehyde and
opsin.
•Deficiency of vit. A leads
to night blindness.
•Vitamin A is an important
antioxidant.

563. Vitamin A and other
functions
Transcription and cell differentiation
•Retinoic acid regulates the transcription of genes -acts
through nuclear receptors (steroid-like receptors).
•By binding to various nuclear receptors, vit. A stimulates
(RAR –retinoid acid receptor) or inhibits (RXR-retinoid „X“
receptor) transcription of genestranscription. All-trans-
retinoic acid binds to RAR and 9-cis-retinoic acid binds to
RXR.
•Retinoic acid is necessary for the function and
maintenance of epithelial tissues.
Retinol retinal retinoic acid
Retinol dehydrogease Retinaldehyde dehydrogenasa

564. Vitamin A -deficiency
•The early sign → a loss of sensitivity to green light,
•prolonged deficiency → impairment to adapt to dim
light
•more prolonged deficiency leads to night blindness
•Ever escalated deficiency leads to squamous
metaplasia-columnar epithelia are transformed
into heavily keratinized squamous epithelia .
•The conjunctiva loses mucus -secreting cells →
glykoprotein content of the tears is reduced →
xeroftalmia( „dry eyes“)
•Often complication -bacterial or chlamidial infection
which results in perforation of the cornea and
blindness

565. Vitamin A -deficiency
•Transformation of respiratory epithelium –loss of
protective airway function(antibacterial
properties) → bronchitis.
•Conversion of the urinary tract epithelium → higher
frequency of urinary stone formation
•Immunosuppression
•Impairment of reproductive function (both in men
and women).
•Worldwide deficiencyof vit. A
•3 –10 mil. children become xerophtalmic every
year
•250 000 to 500 000 go to blindness
•1 million die from infections

566. Vitamin A -toxicity
•Toxic dose:
•single dose of more than 200 mg
•more than 40 mg per day
•Acute symptoms -headache, vomiting, impaired
consciousness.
•Chronic intoxication –weight loss, vomiting, pain in
joints, muscles, blurred vision, hair loss, excessive
bone growth.
•Both vit. A excess and deficiency in pregnancy are
teratogenic–retinoic acid is gene regulator during
early fetal development
•Carotenoids are nontoxic-accumulation in
tissues rich in lipids (the skin of babies overdosed
with carrot juice may be orange).

567. Metabolic functions of
vitamin A
•Vision
•Gene transcription
•Immune function
•Embryonic development and reproduction
•Bone metabolism
•Haematopoieis
•Skin health
•Antioxidant activity

568. Sources of vitamin A
•cod liver
oil
•meat
•egg
•milk
•dairy
products
carrot
broccoli
spinach
papaya
apricots
http://health.allrefer.com/health/nutrition.html

569. Vitamin D
•Calciol, vitamin D
2(cholecalciferol) →
precursor of calcitriol, D
3(1,25-
dihydroxycalciferol).
•Regulates with PTH calcium and
phosphate level (absorption, reabsorption,
excretion).
•Synthesis in the skin (7-
dehydrocholesterol) UV → further
transformation in the liver and kidneys .

570. Synthesis
Non-enzymatic reaction in the skin Transport to the liver
UV irradiation 270 –300 nm
Photolysis

571. Liver Kidneys
Inactive form

572. Effects of vitamin D
•Transported in the blood on a carrier (vitamin-D
binding protein, VDBP).
•1,25(OH)
2D binds to intracellular receptors
(intestine, bone, kidney).
•The main function is to maintain plasma levels of
calcium (essential for neuromuscular activity) and
phosphate levels:
•increase Ca absorption in the intestine,
•reduce the excretion of calcium (stimulates
parathyroid hormone-dependent Ca reabsorption in
the distal tubule),
•mobilizing bone mineral, together with parathyroid
hormone

573. Vitamin D -deficincy
•Failure of absorption in the intestine.
•The lack of the liver and the renal
hydroxylation of vit. D (congenital
deficiency of 1-hydroxylase).
•The lack of UV irradiation.
•The main manifestation -impaired
ossification of the newly created osteiod,
abundance of non mineralized matrix.
•Vit. D is necessary for the prevention of
skeletal changes (rickets in growing
individuals, osteomalacia in adults).

574. Vitamin D and imunity
•It increases the activity of natural killer
cells (cytotoxic lymphocytes).
•Increases the phagocytic ability of
macrophages .
•Reduces the risk of virus diseases (colds,
flu).
•Reduces the risk of many cancers (colon,
breast and ovarian cancer).
•Reduces the risk of cardiovascular disease
→ have a positive impact on the
composition of plasma lipids.

575. Sources of vitamin D
•In addition to
sunbathing:
•various fish species
(salmon, sardines and
mackerel, tuna, catfish,
eel), fish oil, cod liver
•eggs, beef liver,
mushrooms

576. Vitamin E
•Vitamin E is a famil of a-, b-, g-, d-
tocopherols and corresponding
tocotrienols izomers.
•They are formed from chroman ring and
hydrofobic fytyl side chain.
•The highest biological activity has a-
tokoferol.

577. Vitamin E
•Adsorbtionfrom the small intestine.
•Its absorption is dependent on the
presence of lipids in the diet.
•Associated with plasma lipoproteins →
liver uptake through receptors for
apolipoprotein E.
a-tocopherol is bind to a-tocopherol
transport protein(a-TTP) →transported to
the target organs (the excess is stored in
adipocytes, in muscle, liver).
b-, g-a d-tocopherols are transferred into
the bile and degraded.

578. Vitamin E as antioxidant
•Stops free radical reactions (peroxyl radicals ROO

,
oxygen radicals HO

, lipoperoxid radicals LOO

).Chroman
ring with OH group → uptake radicals.

579. PUFA-H = polyunsaturated fatty acid
PUFA-OO= peroxyl radical of polyunsaturated
fatty acid
PUFA-OOH = hydroxyperoxy polyunsaturated
fatty acid
PUFA-OH = hydroxy polyunsaturated fatty acid
Free radical
chain reaction
Interaction and synergism
between antioxidant
systems operating in the
lipid phase (membranes)
and the aqueous phase
(cytosol)

580. Vitamin E as enzyme
cofactor
a-tocopherolquinongenerated by oxidation
of a-tocopherolcan actsas a cofactor of
mitochondrial unsaturated fatty acids .
a-tocopherolquinon + cytochrom B
5+
NADH+H
+
initiate formation of double
bonds in FA –temporarily changes to a-
tocopherol-hydroquinon (in the presence of
O
2changes back to a-tocopherolquinon).

581. Vitamin E –deficiency and
toxicity
•The lack of a-tocopherol in plasma is often
associated with impaired fat absorption or
distribution (in patients with cystic
fibrosis, in patients with intestine
resection)
•deficit of vit. D exhibit -neurological
problems, impaired vision, eye muscle
paralysis, platelet aggregation, impairment
of fertility in men, impaired immunity.
•Toxicity is relatively small.

582. Sources of vitamin E
•fortified cereals
•seeds and seed oils, like sunflower
•nuts and nut oils, like almonds and
hazelnuts
•green leafy vegetables,
•broccoli
•cabbage
•celery
http://health.allrefer.com/health/nutrition.html

583. Vitamin K
•Vitamin Kis a group of lipophilic,
hydrophobic vitamins.
•They are needed for the postranslation
modification of proteins required for blood
coagulation,
•They are involved in metabolism pathways,
in bone mineralisation, cell growth,
metabolism of blood vessel wall.

584. Vitamin K
1
Vitamin K
2
Vitamin K
•Vitamin K
1 (phylloquinon) –
plant origin
•Vitamin K
2(menaquinon) –
normally produced by
bacteria in the large
intestine
•K
1a K
2are used differently
in the body
•K
1–used mainly for blood
clothing
•K
2
–important in non-
coagulation actions -as in
metabolism and bone
mineralization, in cell
growth, metabolism of
blood vessel walls cells.
Synthetic derivatives of Vit.K

585. Vitamin K -function
•Cofactor of liver microsomal carboxylase
which carboxylatesglutamate residues to
g-carboxyglutamate during synthesis of
prothrombin and coagulation factors VII, IX
a X(posttranslation reaction).
•Carboxylated glutamate chelates Ca
2+
ions, permitting the binding of blood
clotting proteins to membranes.
•Forms the binding site for Ca
2+
also in
other proteins –osteocalcin.

586. Vitamin K -deficiency
•Deficiency is caused by fat malabsorption
or by the liver failure.
•Blood clotting disorders –dangerous in
newborns, life-threatening bleeding
(hemorrhagic disease of the newborn).
•Osteoporosis due to failed carboxylation of
osteokalcin and decreased activity of
osteoblasts.
•Under normal circumstances there is not a
shortage, vit. K is abundant in the diet.

587. Sources of vitamin K
•Green leafy vegetables
•vegetable oil
•broccoli
•cereals
http://health.allrefer.com/health/nutrition.html

588. Vitamin B
1(thiamine)
Vitamin B
2(riboflavin)
Vitamin B
3or Vitamin P or Vitamin PP (niacin)
Vitamin B
5(panthotenic acid)
Vitamin B
6(pyridoxineand pyridoxamine)
Vitamin B
7or Vitamin H (biotin)
Vitamin B
9or Vitamin M and Vitamin B-c (folic acid)
Vitamin B
12(cobalamin)
Water soluble vitamins

589. Vitamin B
1 (thiamine)
•Thiamin has a central role in energy-
yielding metabolism.
•Composed of a substituted pyridine and
thiazole ring.
•Active form is thiamine diphosphate
(thiamin pyrophosphate, TPP), a coenzyme
for three multi-enzyme complex →
•This complex catalyses oxidative
decarboxylation of a-ketoacids →
•pyruvate dehydrogenasein carbohydrate
metabolism,
a-ketoglutarate dehydrogenase→ cytric acid cycle,
•Branched-chain keto-acid dehydrogenase.
•TPP is coenzyme for transketolase –pentose phosphate
pathway.

590. Vitamin B
1-deficiency
1.Mild deficiency –leads to gastrointestinal
complients, weakness
2.Moderate deficiency -peripheral
neuropathy, mental abnormalities, ataxia
3.Full-blown deficiency -beri-beri –
characterized with severe muscle
weakness, muscle wasting and delirium,
paresis of the eye muscles, memory loss.
•Degeneration of the cardiovascular
system. .
•Beri-beri causes long-term consumption of
foods rich in carbohydrates but poor in
thiamine -husked rice, white flour and
refined sugar.

591. Source of vitamin B
1
•paddy grains, cereals
meat
yeast
honey
nuts

592. Vitamin B
2(riboflavin)
•Yellow to orange-yellow natural dye
slightly soluble in water.
•Has a central role in energy-yielding
metabolism.
•Provides the reactive moieties of the
coenzymesflavin mononucleotide (FMN)
andflavin adenine dinucleotid (FAD).
•Flavin coenzymes are electron carries in
oxidoreduction reaction.

593. Vitamin B
2
FMN →ATP-dependent phosphorylation of riboflavin
FAD →further reaction with ATP in which its AMP
moiety is transferred to FMN.

594. FMN a FAD function
FMN and FAD act as prosthetic groups of many
oxidoreduction enzymes, flavoprotein:
•oxydase of a-amino acids–degradation of amino
acids
•xantinoxidase–degradation of purines
•aldehyde dehydrogenas
•mitochondrialglycerol-3-phosphate dehydrogenase
–transport of reducing unit (H
+
) from mitochondra
to cytosol
•succinate dehydrogenas–citric acid cycle
•succinyl CoA-dehydrogenase–b-oxidation of FA
•NADH-dehydrogenase–part of respiratory chain in
mitochondria
•coenzymes in hydrogen transfer –formation of
reducing forms -FMNH
2a FADH
2

595. Vitamin B
2 absorption
•Riboflavin is absorbed in the proximal
intestine.
•Riboflavin is stored mainly in the liver,
kidney and heart in the form of FAD (70-
90%) or FMN.

596. Causes of vitamin B
2
deficiency
•Lack of dietary vitamin B.
•A result of conditions that affect
absorption in the intestine.
•The body not being able to use the vitamin.
•An increase in the excretion of the vitamin
from the body.

597. Vitamin B
2 –symptoms of
deficiency
•Cracked and red lips.
•Inflammation of the lining of mouth and
tongue.
•Dry and scaling skin-keratitis, dermatitis
and iron-deficiency anemia

598. Sources of vitamin B
2
•foods of animal
origin (liver, pork and
beef, milk, dairy
products, fish eggs)
•cocoa,
•nuts,
•yeast,
•of smaller quantities
in cereals.
http://health.allrefer.com/health/nutrition.html

599. Vitamin B
3 -niacin
•Active form –nikotinic acid and nikotinamid.
•NAD a NADP → key components of the metabolic
pathways of carbohydrates, lipids, amino acids.
•Nicotinic acid prevents the release of fatty acids
from adipose tissue, decreases lipoproteins VLDL,
IDL a LDL.
•High dose of niacin dilates blood vessels .

600. Vitamin B
3 -niacin
•Absorption:
•Atlowconcentrationbyactivetransport.
•Athighconcentrationbypassivediffusion.
•Transportation:
•Bothnicotinicacid(NA)andnicotinamide(NAm)
bindtoplasmaproteinsfortransportation.
•Biosynthesis:
•The liver can synthesize Niacinfrom the
essential amino acid tryptophan, but the
synthesis is extremely slow and requires vitamin
B
6(60 mg of Tryptophan= 1mg of niacin).
Bacteria in the gut may also perform the
conversion but are inefficient.

601. Vitamin B
3 -deficiency
•Pellagra:A serious deficiency of niacin.
•Themain results of pellagra can easily be
remembered as "the four D's": diarrhea,
dermatitis, dementia, and death.
•Pelagra is very rare now, except in
alcoholics, strict vegetarians, and people
in areas of the world with very poor
nutrition.
•Milder deficiencies of niacin can cause
dermatitis around the mouth and rashes,
fatigue, irritability, poor appetite,
indigestion, diarrhea, headache.

602. Sources of vitamin B
3
•foods of animal origin
•yeast
•sunflower seeds, beans, peas
•green leafy vegetable
•broccoli, carrots
http://health.allrefer.com/health/nutrition.html

603. Vitamin B
5–panthotenic
acid
•Part of acetyl-CoA –consists of pantoic
acid and b-alaninem.

604. Vitamin B
5–panthotenic
acid
•Co-enzyme A assists the following
reactions:
•formation of sterols (cholesterol and 7-
dehydrocholesterol).
•formation of fatty acids.
•formation of keto acids such as pyruvic
acid.
Other reactions are acylation, acetylation,
signal transduction deamination

605. Vitamin B
5-deficiency
Rare to occur.
•When occur it leads to paresthesias.
•Disorders of the synthesis of acetylcholine
–neurological symptoms (parestesie).

606. Sources of vitamin B
5
•meat, foods of animal origin,
•yeast,
•wholemeal bread,
•broccoli, avocado
•royal gelly

607. Vitamin B
6
•Prekursor of active coenzyme
pyridoxalphosphate –PPL.

608. Vitamin B
6
•Vitamin B
6is needed for more than 100 enzymes
involved in protein metabolism.
•It is also essential for red blood cell metabolism
and hemoglobin formation.
•The nervous and immune systems need vitamin
B
6to function efficiently.
•It is also needed for the conversion of tryptophan
to niacin (vitamin B
3).
•Vitamin B
6also helps maintain blood glucose
within a normal range. When caloric intake is
low,vitamin B
6helpsto convert stored
carbohydrate or other nutrients to glucose to
maintain normal blood sugar levels.

609. Transamination reaction

610. Vitamin B
6deficiency
Signs of vitamin B
6deficiency include:
•Skin:dermatitis(skin inflammation),
stomatitis(inflammationof the mucous
liningof any of the structures in the
mouth), glossitis(inflammationor infection
of the tongue).
•Neurological abnormalities: Depression,
confusion, and convulsions.
•Vitamin B
6deficiency also can cause
anemia.

611. Vitamin B
6 –narural
sources
•cereals,
•beans,
•meat,
•liver,
•fish,
•yeast,
•nuts and some fruits as
banana
•potatoes.
•It is also produced by
bacterial flora in the
colon.

612. Vitamin B
7-biotin
•Prosthetic group of pyruvate
carboxylase, acetyl-CoA carboxylase
and other ATP-dependent
carboxylases.

613. Biotin –natural source
•liver
•meat
•kidney
•yeast
•egg yolk
•mushrooms
•milk and diary products.

614. Vitamin B
9–folic acid
•Consist of pteroic acid -pteridine +
paraaminobenzoic acid (PABA) + glutamic
acid

615. Vitamin B
9–folic acid
•Active metabolit of folic acid is tetrahydrofolate
(THF) .
•THFis coenzym of transferases carrying one carbon
units.
•This reaction participate in nucleotide and nucleic
acid synthesis
•N
5
,N
10
-THFcarries one carbon units (methylen or
methenyl).

616. Folic acid deficiency
Deficiency results in elevated levels of
homocystein.
Deficiency in pregnant women can lead to
birth defects.

617. Sources of vitamin B
9
•sources of animal origin
•milk and milk products
•yeast
•greens

618. Vitamin B
12-cobalamin
•Chemically most
complex vitamin
•Complex of organic
compounds atom within
the molecule is Co,
similar to the heme.
•In man there are two
metabolically active
forms: methylkobalamin
a adenosylkobalamin.

619. Vitamin B
12-cobalamin
•Cobalamin catalyses two reactions
•Cytoplasmicmethylation of
homocystein tomethionin.
•Mitochondrial methylmalonyl-CoA
mutase(methylmalonyl-CoA → sukcynyl-
CoA) needs deoxy adenosylkobalamin.

620. Vitamin B
12–cobalamin
•Essential for the maturation of
erythrocytes.
•Protects against pernicious anemia.
•Essential for cell growth and reproduction.
•Essential for the formation of myelin and
nucleoproteins.

621. Vitamin B
12–cobalamin
•Vitamin B
12in food is bound to the protein.
•Hydrochloric acid in the stomach releases
free vitamin B
12.
•Once released vitamin B
12combines with a
substance called intrinsic factor (IF). This
complex can then be absorbed by the
intestinal tract.

622. Sources of vitamin B
12
•fish and shellfish,
•meat (especially liver),
•poultry,
•eggs,
•milk, and
•milk products
while lacto-ovo vegetarians usually get
enough B
12through consuming diary
products, vegan will lack B
12

623. Vitamin C
•Vitamin C is a water-soluble vitamin.
•Almost all animals and plants synthesize
their own vitamin C, not man.
•Vitamin C was first isolated in 1928 and in
1932 it was proved to be the agent which
prevents scurvy.

624. Vitamin C
•Vitamin C is a weak acid, called ascorbic
acid or its salts “ascorbates”.
•It is the L-enantiomer of ascorbic acid.
•The D-enantiomer shows no biological
activity.

625. The role of vitaminC
•Cofactor in the synthesis of norepinephrine
from dopamine.
•Involved in a variety of metabolic
processes (oxidation-reduction reactions
and cellular respiration, carbohydrate
metabolism, synthesis of lipids and
proteins).
•antioxidant and free radical scavenger →
maintain proper immune system.

626. The role of vitaminC
•T-lymphocyte activity, phagocyte function,
leukocyte mobility, and possibly antibody
and interferon production seem to be
increased by vitamin C.
•Involved in the synthesis of collagen,the
major component of ligaments, tendons,
cartilages and skin.
•Involved in tyrosine metabolism.

627. Deficiency of vitaminC
•Fatigue, personality changes, decline in
psychomotor performance and motivation.
•Vitamin C deficiency over 3-5 months
results in symptomatic scurvy.
•Scurvy leads to the formation of liver spots
on the skin, spongy gums, and bleeding
from all mucous membranes.
•In advanced scurvy there are open,
suppurating wounds and loss of teeth.
Severe scurvy may progress to neuritis,
jaundice, fever, dyspnea, and death.

628. Vitamin C as antioxidant

629. Vitamin C as antioxidant

630. Vitamin C as pro-oxidant
•Ascorbic acid reduces transition metals -
Cu
2+
, to Cu
+
, and Fe
3+
to Fe
2+
during
conversion from ascorbate to
dehydroascorbate. This reaction can
generate superoxide and other ROS :
•Fenton´s reaction:
•(1) Fe
2+
+ H
2O
2→ Fe
3+
+ OH·+ OH
−
•(2) Fe
3+
+ H
2O
2→ Fe
2+
+ OOH·+ H
+
2 Fe
2+
+ 2 H
2O
2→ 2 Fe
3+
+ 2 OH·+ 2 OH
−
2 Fe
3+
+ ascorbate → 2 Fe
2+
+
dehydroascorbate

631. welcome

632. Key points:

633. Antibiotics:
Substance (such as penicillin) that
destroys or inhibits the growth of other
pathogenicmicroorganisms and is
used in the treatment of external or
internal infections.
While some antibiotics are produced
by microorganisms, most are now
manufactured synthetically

634. Classification of antibiotics:
Antibiotics are classified severalways.
On the basis of mechanism ofaction
On the basis of spectrum ofactivity
On the basis of mode ofaction

635. On the basis of mechanism ofaction:
Cell Wall Synthesis inhibitors:
Penicillins Cephalosporins
Vancomycin
Beta-lactamase Inhibitors
Polymycin Bacitracin
Clindamycin
Streptogramins
DNA SynthesisInhibitors
Fluoroquinolones (ciprofloxacil
lin)
Metronidazole
RNA synthesisInhibitors
Rifampin
Protein Synthesis Inhibitors
Inhibit 30s Subunit
Aminoglycosides (gentamycin)

Tetracyclines
Inhibit 50s Subunit Macrolides
Chloramphenicol
Mycolic Acid synthesis
inhibitors
Isoniazid
Folic Acid synthesisinhibitors
Sulfonamides
Trimethoprim

636. On the basis of mechanism ofaction:

637. On the basis of spectrum activity:
Broad spectrum antibiotics:
Amoxicillin
Tetracycline
cephalosporin
Chlorampenicol
Erythromycin
Short spectrumantibiotics:
Penicillin–G
Cloxacillin
vancomycin
Bacitracin
Fluxacillin

638. On the basis of mode ofaction:
Bacteriostaticantibiotics
Tetracycline
Chlorampenicol
Erythromycin
Lincomycin
Bacteriocidalantibiotics
Cephalosporin
Penicillin
Erythromycin
Aminoglycosides
Cotrimoxazole

639. Antibioticsindications:
Pneumonia
Sepsis
Meningitis
Osteomyelitis
Urinogenital
Infections
Gall Infections
Quinsy
Skin Infections
Mucous
Diphtheria
SiberianUlcer
GynecologicInfections
Syphilis
RespiratoryInfections
ENTInfections
FungousInfections

640. Misuse of antibiotics:
Antibiotic misuse, sometimes called antibiotic
abuse or antibiotic overuse.
The misuse or overuse of antibiotics, may
produce serious effects on health.
It is a contributing factor to the creation of
multidrug-resistant bacteria, informally called
"super bugs" relatively harmless bacteria can
develop resistance to multiple antibiotics and
cause life-threatening infections.

641. Antibioticsresistance
If the concentration of drug requires
to inhibit or kill the microorganism is
greater than normal use then the
microorganism is considered to be
resistant to the drug.
OR
The ability of a microorganism to produce a
protein that disables an antibiotic or prevents
transport of the antibiotic into the cell.

642. Cross-resistance
Cross-resistance to a particular
antibiotic that often results in resistance
to other antibiotics, usually from a
similar chemical class, to which the
bacteria may not have been exposed.
Cross-resistance can occur, for
example, to both colistin and polymyxin
B or to both clindamycin and lincomycin.

643. Mistreatment ofDoctor

644. Inappropriate prescription:
In an analysis of prescribing
practices in teaching
hospitals worldwide, more
than 40 %
•of all antimicrobials
prescribed were considered
inappropriate
Antibiotic resistance comes mainly because of inappropriate
or improper use of antibiotics by physicians.Some 150
million prescriptions are written annually in the
USAAndOf those, 50 million are absolutely
unnecessary or inappropriate”.

645. Doctor’s are bound to prescribe the
antibiotics
Mr: Don’t forget to take
one
ofourantibiotics
samplebeforeyou
free
leave
thehospital

646. You get a fever. You have diarrhoea.
You catch a cold. Take a couple of
antibiotics (Amoxicillin ,Azithromycin)
You should avoid it ,don’t take
antibiotics without prescription.

648. But manydoctors/quacks
prescribed antibiotics in viral
diseases without test.
Viral illness needs time
to heal, antibiotic can not
help to cure this illness.

649. Antibioticssideeffects:
The most common side effects of
antibiotics :
Diarrhoea
Bloating and indigestion
Abdominal pain
Loss of appetite Being sick
Feeling sick Itchy skin rash
Coughing
life-threatening allergic reaction

650. Unconsciousness ofPatient
•Without proper direction the
patient take thedrug.
•They do not maintain the
dosage intervals and
complete the dose.
•Patient stop the drug when
feel better.

651. What Is The Rules OfPharmacist
The pharmacist should review the previous diseases
history of the patient
Hypersensitivity reaction of Drug
Drug-drug interaction
Exact dose and frequency of the drug
When the drug should be taken before or after meal
Suggest not to stop the antibiotics without complete the
course even feel better

652. MyOpinion
The doctor must be concern about the disease whether
it viral or bacterial.
They should not prescribed the drug without test or
over sure .
The pharmacist should also more conscious about the
dose ,drug interaction, resistant and hypersensitivity of
the drug .
The patient should strictly maintain the suggestion of
the pharmacist.

653. Thankyou

654. Sulfonamides
•Analogues of PABA
•Broad spectrum
•Competitive inhibitors
of dihydropteroate
synthase –needed for
folic acid synthesis
•Cidal in urine
•Mechanisms of
resistance
•Altered affinity of enzyme
for drug
•Decreased permeability or
active efflux
•New pathway of folic acid
synthesis
Gerhard Domagk gets a
Nobel for Medicine,
1939.

655. Sulfonamides
•Mostly absorbed from
GI tract
•Binds variably to
serum albumin
•Wide tissue
distribution, including
transplacentally
•Variably inactivated in
liver by acetylation and
then excreted in urine
•Some agents can
precipitate in acid
urine

656. Rapidly Absorbed and
Eliminated Sulfonamides
•Sulfisoxazole,
sulfamethoxazole,
sulfadiazine
•Bind extensively to
plasma proteins
•Highly
concentrated in
urine (cidal)
•Sulfamethoxazole
combined with
trimethoprim (Bactrim)
is widely used to treat
a variety of infections
(esp. UTI)

657. Poorly Absorbed
Sulfonamides
•Sulfasalazine
•Poorly absorbed in GI
tract
•Used to treat
ulcerative colitis and
irritable bowel
syndrome
•Gut flora metabolize
drug into 2
compounds, 1 toxic, 1
therapeutic (5-
aminosalicylate)
Ulcerative
Colitis

658. Sulfonamides for Topical
Use
•Sulfacetamide
•Good
penetration in
eye
•Non-irritating
•Silver
sulfadiazine
•Prevention and
treatment of
burn wound
infections
Bacterial corneal
infection

659. Long Acting Sulfonamide
•Sulfadoxine
•Serum half-life is
measured in days
rather than
minutes or hours
•Combined with
pyirethamine to
treat malaria
Plasmodium
vivax

660. Therapeutic Uses
of Sulfonamides
•Urinary tract
infections
•Nocardiosis
•Toxoplasmosi
s (avoid using
in pregnant
women)
Nocardia asteroides

661. Toxicity/Contraindications
of Sulfonamides -UT
•Crystallization
in acid urine
•Common to
uncommon
depending on
drug
•Alkalize urine or
increase
hydration

662. Toxicity/Contraindications
of Sulfonamides -blood
•Acute hemolytic anemia
•Rare to extremely rare
•Associated with glucose-6-
phosphate dehydrogenase activity
in RBC
•Agranulocytosis (extremely
rare)
•Aplastic anemia (extremely
rare)

663. Toxicity/Contraindications
of Sulfonamides -immune
•Hypersensitivity reactions
(common to uncommon )
•Skin and mucous membrane
manifestations (rashes)
•Serum sickness
•Focal or diffuse necrosis of the
liver (rare)

664. Toxic Epidermal Necrolysis
(TEN)

665. Toxicity/Contraindications
of Sulfonamides -
miscellaneous
•Nausea, anorexia,
vomiting (common)
•Kernicterus
•Displacement of
bilirubin from plasma
albumin to brain
resulting in
encephalopathy
•Never give sulfa drugs
to a pregnant or
lactating woman
•Potentiation of oral
coagulants,
sulfonylurea
hypoglycemic drugs,
and hydrantoin
anticonvulsants
Bilirubin deposits in
neonatal brain

666. The Quinolones
•Naladixic acid was a
byproduct of
chloroquine synthesis
•Current drugs are
fluoridated 4-
quinolones
•Broad coverage (some
broader than others)
•Targets DNA gyrase (G-
) and topoisomerase IV
(G+)
•Resistance due to
efflux and mutations in
targets

667. Quinolones
•Favorable
pharmacological
attributes
•Orally administered, quickly
absorbed, even with a full
stomach
•Excellent bioavailability in a
wide range of tissues and body
fluids (including inside cells)
•Mostly cleared by the
kidneys
•Exceptions are pefloxacin and
moxifloxacin which are
metabolized by liver
•Ciprofloxacin, ofloxacin,
and pefloxacin are
excreted in breast milk
“Got
Cipro?”

668. Therapeutic Uses
of Quinolones
•Urinary tract
infections
•Prostatitis
•STD’s
•Chlamydia
•Chancroid
•Notsyphilis or
gonorrhea (due to
increased
resistance)

669. Therapeutic Uses
of Quinolones
•GI and
abdominal
•Travelers
diarrhea
•Shigellosis
•Typhoid fever
•Respiratory
tract
•All work well
against atypicals
•New agents for
strep.
pneumonia

670. Therapeutic Uses
of Quinolones
•Bone, joint, soft
tissue
•Ideal for chronic
osteomylitis
•Resistance developing
in S. aureus, P.
aeruginosa, and S.
marcesens
•Good against
polymicrobial
infections like
diabetic foot ulcers

671. Therapeutic Uses
of Quinolones
•Ciprofloxacin for
anthrax and
tuleremia
•Combined with
other drugs,
useful for
atypical
Mycobacterium
sp. or for
prophylaxis in
neutropenic
patients
Pulmonary
Anthrax

672. Toxicity/Contraindications
of Quinolones
•Nausea, vomiting, abdominal discomfort
(common)
•Diarrhea and antibiotic-associated colitis
(uncommon to rare)
•CNS side effects
•Mild headache and dizziness (commonto rare)
•Hallucinations, delirium, and seizures (rare)
•Arthropy in immature animals (common)
•Quinolones not given to children unless benefits
outweigh the risks
•Leukopenia, eosinophila, heart arythmias
(rare)

673. The Beta-Lactams

674. Penicillins
•Penicillium notatum
produces the only
naturally occuring
agent –penicillin G or
benzylpenicillin
•Dosage and potency
based on IU (1 IU =
0.6 micrograms pure
penicillin G)
•P. chrysogenum
produces 6-
aminopenicillanic
acid, raw material for
semi-synthetics
•Dosage and potency
based on weight

675. Penicillins
•Spectrum of activity based on R
groups added to 6-aminopenicillanic
acid core
•All are bactericidal and inhibit
transpeptidases
•Mechanisms of resistance
•Alter affinity of transpeptidase
•Enzymatically cleave the beta-lactam
ring
•Efflux pumps
•Poor penetration into cell

676. Penicillins
•Administered orally, intramuscularly,
or intravenously depending on agent
•After oral dose, widely distributed in
tissues and secretions (except CNS,
prostatic fluid, and the eye)
•Do not kill intracellular pathogens
•Food interferes with adsorption
•Rapid elimination through kidney,
secreted in breast milk

677. Penicillins G and V
•Effective against aerobic G+ organisms except
Staphylococcus, Pen G active against Neisseria
and anaerobes
•2/3 of oral Pen G destroyed by stomach acid, Pen V
is more resistant so more is delivered to serum
•Rapid elimination through kidney so probenecid,
procaine, of benzathine added to slow excretion
•Most drug is bound to serum albumin but
significant amounts show up in liver, bile, kidney,
semen, joint fluid, lymph, etc.
•Cautious use in neonates and infants because renal
function is not fully established
•Patients with renal failure clear the drugs through
liver although at a slow pace

678. Penicillins G and V
Therapeutic Uses
•Streptococcus
pneumoniaeinfections
•S. pyogenesinfections
•Viridans strep
endocarditis (also
given prophylactically)
•Anaerobes except
Bacteroides fragilis
group
•Meningococcal
infections
•Syphilis and other
diseases caused by
spirochetes

679. Isoxazolyl Penicillins
•Oxacillin, cloxacillin, dicloxacillin,
nafcillin
•Designed to resist staphylococcal beta -
lactamases
•Like Pen V, stable in stomach acid but
usually given parentally for serious
staph infections
•MRSA not covered
•Absorption and fate of drugs after
absorption, excretion similar to Pen G
and Pen V

680. Aminopenicillins
•Ampicillin and amoxicillin
•Broad spectrum
•Not effective against beta-lactamase
producers
•Beta-lactamase inhibitors extend
spectrum
•Both are acid resistant but
amoxicillin is better absorbed, even
with food
•Don’t bind plasma proteins as much
as predecessors
•Secreted through the kidney

681. Aminopenicillins
Therapeutic Uses
•Upper
respiratory tract
infections
•Otitis media
•Uncomplicated
UTI
•Acute bacterial
meningitis in
kids
•Typhoid fever

682. A Carboxypenicillin and
a Ureidopenicillin
•Ticarcillin and
piperacillin
•Ticarcillin is anti-
Pseudomonasdrug
•Piperacillin +
tazobactam has the
broadest spectrum
•Give parentally
•Used for serious
infections

683. Toxicity/Contraindications
of Penicillins
•Hypersensitivity reactions
(uncommon)
•Rash, fever, bronchospasm, vasculitis,
serum sickness, exfoliative dermatitis,
SJS, anaphylaxis
•Drugs act as haptens when bound to
serum proteins
•Rashes will disappear when drug is
withdrawn or can treat with
antihistamines
•For patients with allergies, switch to a
different class of antibiotics or try to
desensitize

684. Toxicity/Contraindications
of Penicillins
•Pain and sterile
inflammatory reaction at
injection site (dose-
related)
•Large doses given to
patients with renal failure
can cause lethargy,
confusion twitching and
seizures
•Sudden release of
procaine can cause
dizziness, tinnitus,
headache and
hallucinations
•Pseudomembranous
colitis

685. Cephalosporins
•Base molecule is 7-
aminocephalosporanic
acid produced by a
Sardinian sewer mold
•R groups determine
spectrum of activity and
pharmacological
properties
•Mechanism of
action/resistance and
class pharmacology
essentially the same as
penicillins

686. First Generation
Cephalosporins
•Cefazolin, cephalexin,
cephadroxil
•Excellent against
susceptible staph and
strep
•Modest activity against
G-
•Cefazolin given
parentally, others
orally
•More than half of the
drug is bound to
plasma proteins
•Excreted by kidneys
unmetabolized
•Good for staph and
strep skin and soft
tissue infections

687. Second Generation
Cephalosporins
•Cefaclor, cefuroxime, cefprozil
•Modest activity against G+,
increased activity against G-, works
against anaerobes
•Cefaclor and cefprozil given orally
•Absorption and excretion same as
first gen.
•Good for treating respiratory tract
infections, intra-abdominal
infections, pelvic inflammatory
disease, diabetic foot ulcers

688. Third Generation
Cephalosporins
•Ceftaxime, ceftriaxzone,
cefoperazone,
cefpodoxime
•Broad spectrum killers
•Drugs of choice for
serious infections
•No effect against Listeria
and beta-lactamase
producing pneumococci
•Cefpodoxime given orally,
others parentally
•Most excreted by kidney
•Therapeutic uses
•Bacterial meningitis (2
exceptions)
•Lyme disease
•Life-threatening G-sepsis

689. Fourth Generation
Cephalosporin
•Cefepime
•Same antimicrobial spectrum
as third generation but resists
more beta-lactamases
•Given parentally, excellent
penetration into CSF
•Good for nosocomial
infections

690. Toxicity/Contraindications
of Cephalosporins
•Hypersensitivity reactions
(uncommon) essentially same as for
penicillins
•Cross-reaction between 2 classes

691. Carbapenems
•Beta-lactam ring is fused
to a 5 member ring
system
•Effect on microbes and
pharmacology of
carbapenems similar to
penicillins

692. Select Carbapenems
•Imipenem
•Broad spectrum including anaerobes
and Pseudomonas aeruginosa
•Parentally administered
•Must be combined with cilastatin to be
absorbed
•Excreted by kidneys
•Meropenem, ertapenem, and
doripenem are similar to imipenem
but don’t need co-administration
with cilastatin

693. Aztrenam –a
monobactam
•Works only on G-, including
Pseudomonas aeruginosa
•Useful for treating G-infections
that require a beta-lactam
because it does not elicit
hypersensitivity reactions

694. Toxicity/Contraindications
of Carbapenems
•Nausea and vomiting (common)
•Hypersensitivity reactions
(uncommon)
•Essentially the same as for
penicillins, exception is the
monobactam
•Cross-reactivity is possible,
exception is the monobactam