Pharmacokinetics and Pharmacodynamics.pdf

It explains about pharmacokinetics and pharmacodynamics

1. PHARMACOKINETICS
“What the body does to the drug”
DR IM Omwenga, PhD

2. Pharmacokinetics (PK)
The study of the dispositionof a drug
The disposition of a drug includes
the processes of ADME
Absorption
Distribution
Metabolism
Excretion
Elimination

3. ADME

5. DRUG R&D
Drug discovery and development
•10-15 years to develop a new medicine
•Likelihood of success: 10%
•Cost $800 million –1 billion dollars (US)

6. Why drugs fail

7. Importance of PK studies
Patients may suffer:
Toxic drugs may accumulate
Useful drugs may have no benefit
because doses are too small to
establish therapy
A drug can be rapidly metabolized.

8. Routes Of
Administration
Routes Of Drug
Administration
EnteralParenteral
OralInjection RectalRespiratoryTopical
Swallowing/
sublingual

9. Absorption
The process by which drug proceeds from the
site of administration to the site of
measurement (blood stream) within the
body.
Necessary for the production of a therapeutic
effect.
Most drugs undergo gastrointestinal
absorption. This is extent to which drug is
absorbed from gut lumen into portal
circulation
Exception: IV drug administration

10. IV vs Oral
I.V Drug Oral Drug
Immediately Delayed
completely incomplete

11. Is the passage of drug through cell
membranes to reach its site of action.
Mechanisms of drug absorption
1.Simple diffusion = passive diffusion.
2.Active transport.
3.Facilitated diffusion.
4.Pinocytosis(Endocytosis).

16. Characters
common.
Occurs along concentration gradient
Non selective
Not saturable
Requires no energy
No carrier is needed
Depends on lipid solubility
Depends on pka of drug -pH of medium

19. Factors Affecting
Diffusion
Thesecanbeviewedasthefactorswhichaffecttherateoftransfer
ofdrugmoleculesacrossmembranes.
Theseinclude:
1.Concentration
Drugstendtomovealongaconcentrationgradient.Thehigherthe
concentrationononeside,therefore,thehigherthediffusionrate.
2.Bloodflow
Thehighertherateofperfusion,thefastertherateofdiffusion.

20. Sublingualareasandthelungsarewellperfusedhencerateofdrug
absorptionisfaster.Thebloodisconstantlymoppingawaythe
absorbeddrughencemaintainingalowerconcentrationonthe
insidemembrane.
3.Thephysico-chemicalpropertiesofthedrug
Theseincludefactorssuchassolubility,molecularsize,
disintegration,polarity…
4.Surfaceareaforabsorption
Thebiggerthesurfacearea,thefastertheabsorption.

21. Thesmallintestinesprovidealargesurfacearea.Thisisduetoitslength
andtheavailablenumerousvilliandmicro-villi.
5.Motility
ThisbasicallyinvolvestheGIT.IncreaseinGITmotilitymeansdecreased
timeforabsorption.Converseistrue.
6.Thevehicle
Thisistheinertsubstancethatthedrugisformulatedin.Oilypreparations
leadtopoorabsorptionandviceversafordrugsadministered
intramuscularly.Aqueouspreparationsarebetterabsorbedtopically–
creamsVsointments.

22. Occurs against concentration gradient.
Requires carrier and energy.
Specific
Saturable.
Iron absorption.
Uptake of levodopa by brain.

26. Occurs along concentration gradient.
Requires carriers
Selective.
Saturable.
No energy is required.

30. Endocytosis: uptake of membrane-bound
particles.
Exocytosis: expulsion of membrane-bound
particles.
High molecular weight drugs or
Highly lipid insoluble drugs

32. Absorption relies on
Passage through membranes to reach the
blood
passive diffusion of lipid soluble species.
The Process

33. Absorption & Ionization
Non-ionised
drug
More lipid soluble drug
Diffuse across
cell
membranes more
easily

34. First Pass Metabolism
Bioavailability: the fraction of the administered dose
reaching the systemic circulation
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation

37. Factors Affecting
Bioavailability
Molecular weight of drug.
Drug Formulation (ease of dissolution).
(solution > suspension > capsule > tablet)
Solubility of the drug
Chemical instability in gastric pH
(Penicillin & insulin )
First pass metabolism reduces bioavailability

39. Factors Affecting Bioavailability
(BAV)
Intestinal motility (Transit Time)
Diarrhea reduce absorption
Drug interactions
Food
slow gastric emptying
generally slow absorption
Tetracycline, aspirin, penicillin V

40. Determination of
bioavailability
A drug given by the
intravenous route will have
an absolute bioavailability
of 1 (F=1 or 100%
bioavavailable)
While drugs given by other
routes usually have an
absolute bioavailability of
less than one.
The absolute bioavailability
is the area under curve (AUC)
non-intravenous divided by
AUC intravenous
.

41. Toxicity
The therapeutic
index is the degree
of separation
between toxic and
therapeutic doses.
Relationship
Between Dose,
Therapeutic Effect
and Toxic Effect.
The Therapeutic
Index is Narrow for
Most Cancer Drugs
100× 10×

42. DRUG DISTRIBUTION
Followingabsorption,thedrugisthetransportedthroughbloodandgets
distributedtomanyareasofthebody.
Theseincludetissues,cellularcompartments,metabolicareasand
excretoryorgans.
Inplasma.Thedrugexistsintwoforms:
Freedrug
Drugboundtoplasmaproteins
Thereisalwaysanequilibriumachievedbetweenfreeandbounddrug.

43. Schematically:
Cellular
compartments
Liver
Administere
d drug
Cellular
tissues
Blood Plasma
Free
Bound
Kidneys
Urine
Intestines
Feces

44. Distribution
The movement of drug from the blood
to and from the tissues

45. DISTRIBUTION
Determined by:
• partitioning across various membranes
•binding to tissue components
•binding to blood components (RBC,
plasma protein)
•physiological volumes

46. DISTRIBUTION
All of the fluid in the body (referred to as the total
body water), in which a drug can be dissolved, can be
roughly divided into three compartments:
intravascular (blood plasma found within blood
vessels)
interstitial/tissue (fluid surrounding cells)
intracellular (fluid within cells, i.e. cytosol)
The distribution of a drug into these compartments
is dictated by it's physical and chemical properties

47. TOTAL BODY WATER
Vascular
3 L
4% BW
Extravascular
9 L
13% BW
Intracellular
28 L
41% BW

48. Distribution
Apparent volume of distribution (Vd) =
Amt of drug in body/plasma drug conc
VOLUME OF DISTRIBUTION FOR SOME DRUGS
DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~ 5000

49. Factors affecting drugs Vd
Blood flow: rate varies widely as function of tissue
Muscle = slow
Organs = fast
Capillary structure:
•Most capillaries are “leaky” and do not impede diffusion
of drugs
•Blood-brain barrier formed by high level of tight
junctions between cells
•BBB is impermeable to most water -soluble drugs

50. Factors influencing drug
distribution
1.pHofthecompartments(acrossthemembranes)
Non-ionizedmoleculeseasilycrossthemembranesand
movefromonecompartmenttotheother.Drugswilltendto
accumulateinthecompartmentswheretheyareionized.
Asageneralrule,weakorganicacidstendtoaccumulatein
compartmentswithahigherpHwhilebaseswillaccumulate
incompartmentswithalowpH.

51. Examples:
ThepHofmilkis6.3(mildlyacidic)hencebasicdrugstendto
accumulateinmilk.
Acidificationoralkalanizationofurinecandeterminehowmuch
ofagivendrugiseliminatedorre-absorbedfromthekidneys.
Thisisimportantincasesofpoisoningoroverdosewithweakly
acidicdrugsuchasabarbiturate.Theurinecanbemade
alkalinewithsodiumbicarbonate,thedrugwillionizeinurine,
hencewillnotbere-absorbedandwilltherefore

52. bepassedoutinurine.
Toeliminateaweaklybasicdrug,theurinecanbeacidified
withascorbicacidtoeliminatethedrugfromthesystem.
2.Polarityofthedrug
Thepolarityofadrugdeterminesitslipid/waterpartition
coefficient.Verypolardrugsorionizeddrugstendtopartition
inaqueouslayerwhilethenon-polarornon-ionizeddrugs
tendtopartitioninnon-aqueouslayers(lipidlayers).

53. 3.Electricalpotentialacrosscellularmembranes
Thisbasicallyaffectsionizeddrugswhichaccumulateonthe
sideofthemembranewiththeoppositechargewiththatofthe
drug.
4.Proteinbinding
Plasmacontainsseveraltypesofproteinswhichinclude
globulins,albumins,transferins,celloplasmins,alphaandbeta
lipoproteins.Theseproteinsandespeciallythealbuminsbind
mostdrugsreversibly.

54. 5.TissueBinding
Sometissueshavetheaffinityforcertaindrugssuchthat
suchdrugsarenoteasilydistributedintoallthetissues..
Theconcentrationofsuchdrugswillbemuchhigherin
othertissuesandmuchlowerinsomeothertissues.
Examples:
Thekidneyscontainaproteinwhichhasahigheraffinity
formetals.Theheavymetals,therefore,tendtoaccumulate
inthekidneyleadingtodamage.

55. Theeyes;somedrugshaveahighaffinitytoretinalpigment
melaninhencethesedrugstendtoaccumulateintheretina
(chlorpromazineandotherphenothiazines)–bindtomelanine
andaccumulateintheuvealtractcausingretinotoxicity.
TheFat(Adipose)tissue;Highlylipidsolubledrugstendto
accumulateintheadiposetissue.Thismayhaveanyofthetwo
consequencesi.e.decreasedtherapeuticeffectsduetoremoval
fromcirculationorprolongedactivity–depotmechanism.

56. SodiumthiopentoneisshortactingasaGAbecauseitis
quicklychanneledintotheadiposetissue.Itis,therefore,
bestforinductionofGAthenotheranestheticsmustbe
giventopotentiate/maintainGA.Obesepeopletendto
recoverfaster.
PoisonoussubstancessuchasDDTtendtoaccumulate
inadiposetissue.OtherdrugsincludeGluthetimide,
Diazepam,Phenoxybenzamine…

57. Thelungs;Somedrugsareretainedwithinthelungsastheyare
boundtopulmonaryphospholipidse.gImipramine,Methadoneand
Chlorpromazine.
Bones;Thoughrelativelyinert,theboneaccumulatessuch
compoundsasleadandtetracyclines.Tetracyclinesform
complexeswithcalciuminboneandothercalciumcontaining
tissuessuchasteeth.Theconsequencesaremuchmoreserious
infastgrowingbones.Thisleadstoformationofbrittlebonesand
teethtendtobepermanentlyyellow.

58. ThisisprincipallywhytetracyclineisC/Iin
expectantmothers,breastfeedingmothers
andchildrenbelow12years.
Glands;Thyroidglandconcentratesiodine
andreducesthetotalavailableiodinein
circulation.Thyroidhormonesynthesisis
dependentoniodineavailability.

59. 6.Barrierstodrugdistribution
Severalphysiologicalbarriersinterferewithdistributiontoallthe
bodycompartments..Thesebarriersinclude;
a)TheBloodBrainBarrier(BBB)–transferofdrugsintothebrainis
regulatedbytheBBB,whichconsistsofasinglelayerofspecial
braincellsknownastheastrocytes.Theseastrocytesarevery
selectiveastothetypeofmoleculeswhichcanpassthroughtothe
restofthebrain.Onlydrugswithahighenoughlipid/waterpartition
coefficientareabletopenetrate.

60. Blood Brain Barrier
•Disruption by osmotic
means
•Use of endogenous
transport systems
•Blocking of active
efflux transporters
•Intracerebral
implantation
•Etc

61. Lipidinsolubledrugsorhighlyionizeddrugswillnotenterthe
brain.
b)Theplacentalbarrier–Theplacentaisderivedfromboththefetal
andmaternaltissuesanditisperfusedbybothfetalandmaternal
blood.Thebloodvesselsofthefetusandthoseofthemother
withintheplacentaareseparatedbyanumberoftissuelayers
whichcollectivelyconstitutetheplacentalbarrier.Thisplacental
membraneselectivelyallowspassageofdrugsandother
substancesfromthemothertothefetus.

62. FactorssuchaspKa,lipidsolubility,protein
bindingetcwhichregulatepassageacross
othermembranesalsoapply.
c)TheBloodTesticularBarrier;Thisisabarrier
betweenthebloodandsometesticularcellsand
onlycertaindrugswhicharelipidsolubleare
abletocrossthisbarrierandpenetrateinto
thesecells.

63. Plasma Protein Binding
Many drugs bind to plasma
proteins in the blood steam
Plasma protein binding limits
distribution.
A drug that binds plasma protein
diffuses less efficiently, than a drug
that doesn’t.

64. Physiochemical properties -
Po/w
The Partition coefficient (Po/w) and can be
used to determine where a drug likes to go
in the body
Any drug with a Po/w greater than 1(diffuse
through cell membranes easily) is likely be
found throughout all three fluid
compartments
Drugs with low Po/w values (meaning that
they are fairly water-soluble) are often
unable to cross and require more time to
distribute throughout the rest of the body

65. Physiochemical Properties -
Size of drug
•The size of a drug also dictates where it can go in the body.
•Most drugs : 250 and 450 Da MW
•Tiny drugs (150-200 Da) with low Po/w values like caffeine can
passively diffuse through cell membranes
•Antibodies and other drugs range into the thousands of daltons
•Drugs >200 Da with low Po/w values cannot passively cross
membranes -require specialized protein -based transmembrane
transport systems -slower distribution
•Drugs < thousand daltons with high Po/w values -simply diffuse
between the lipid molecules that make up membranes, while
anything larger requires specialized transport .

66. Elimination
The irreversible removal of the
parent drugs from the body
Elimination
Drug Metabolism
(Biotransformation)
Excretion

67. Drug Metabolism
The chemical modification of drugs with
the overall goal of getting rid of the drug
Enzymes are typically involved in
metabolism
Drug
Metabolism
More polar
(water soluble)
Drug
Excretion

68. •From 1898 through to 1910 heroin was marketed as a non -
addictive morphine substitute and cough medicine for
children. Bayer marketed heroin as a cure for morphine
addiction
•Heroin is converted to morphine when metabolized in the
liver
METABOLISM

69. Phases of Drug Metabolism
Phase I Reactions
Convert parent compound into a more polar
(=hydrophilic) metabolite by adding or
unmasking functional groups (-OH, -SH, -NH2, -
COOH, etc.) eg. oxidation
Often these metabolites are inactive
May be sufficiently polar to be excreted readily

70. Phases of metabolism
Phase II Reactions
Conjugation with endogenous substrate to
further increase aqueous solubility
Conjugation with glucoronide, sulfate,
acetate, amino acid

71. Mostly occurs
in the liver
because all of
the blood in the
body passes
through the
liver

72. The Most Important
Enzymes
Microsomal cytochrome P 450
monooxygenase family of enzymes, which
oxidize drugs
Act on structurally unrelated drugs
Metabolize the widestrange of drugs.

73. • Found in liver, small intestine, lungs, kidneys,
placenta
• Consists of > 50 isoforms
• Major source of catalytic activity for drug oxidation
• It’s been estimated that 90% or more of human drug
oxidation can be attributed to 6 main enzymes:
• CYP1A2 • CYP2D6
• CYP2C9 • CYP2E1
• CYP2C19 • CYP3A4
In different people and different populations,
activity of CYP oxidases differs.
CYP family of enzymes

75. Inhibitors and inducers of
microsomal enzymes
Inhibitors: cimetidine prolongs action of
drugs or inhibits action of those
biotransformed to active agents (pro -drugs)
Inducers: barbiturates, carbamazepine
shorten action of drugs or increase effects of
those biotransformed to active agents
Blockers: acting on non -microsomal
enzymes (MAOI, anticholinesterase drugs)

76. Phase II
Main function of phase I reactions is to
prepare chemicals for phase II
metabolism and subsequent excretion
Phase II is the true “detoxification”
step in the metabolism process .

77. Phase II reactions
Conjugation reactions
Glucuronidation (on -OH, -COOH, -NH2, -SH groups)
Sulfation (on -NH2, -SO2NH2, -OH groups)
Acetylation (on -NH2, -SO2NH2, -OH groups)
Amino acid conjugation (on -COOH groups)
Glutathione conjugation (to epoxides or organic
halides)
Fatty acid conjugation (on -OH groups)
Condensation reactions

78. Glucuronidation
Conjugation to a-d-glucuronic acid
Quantitatively the most important phase II pathway for
drugs and endogenous compounds
Products are often excreted in the bile

79. Phase I and II -Summary
Products are generally more water soluble
These reactions products are ready for (renal) excretion
There are many complementary, sequential and
competing pathways
Phase I and Phase II metabolism are a coupled
interactive system interfacing with endogenous
metabolic pathways

80. Excretion
The main process that body eliminates
"unwanted" substances.
Most common route -biliary or renal
Other routes -lung (through exhalation),
skin (through perspiration) etc.
Lipophilic drugs may require several
metabolism steps before they are
excreted

81. ADME -Summary

82. PHARMACODYNAMICS
DR IM Omwenga, PhD

83. Pharmacodynamicsis the study of the
biochemical and physiological effects of drugs and
their mechanisms of action.
Simply stated, pharmacodynamics refers to the
effects of a drug on the body.

84. Two state receptor model
A receptor may exist in two
interchangeable states, active (Ra) &
inactive (Ri) which are in equilibrium.
Binding of drug shift this equilibrium in
either direction.

85. •Ligand-any molecule which attaches selectively to
particular receptors.
•Affinity -The strength of the reversible interaction
between a drug and its receptor, as measured by the
dissociation constant, is defined as the affinity of one
for the other.
•Intrinsic activity –capacity to induce a functional
change in the receptor.
•Specificity -A drug that interacts with a single type of
receptor that is expressed on only a limited number of
differentiated cells will exhibit high specificity.

86. Agonists
•Drugs that bind to physiological receptors and mimic the
regulatory effects of the endogenous signaling compounds are
termed agonists.
•If the drug binds to the same recognition siteas the
endogenous agonist (the primary or orthosteric site on the
receptor) the drug is said to be a primary agonist.
•Allostericagonists bind to a different region on the receptor
referred to as an allosteric site.

88. Antagonist
•Drugs that block or reduce the action of an agonist are termed
antagonists.
•Antagonism most commonly results from competition with an
agonist for the same or overlapping site on the receptor (a syntopic
interaction)
•Physical antagonist binds to the drug and prevents its absorption like
charcoal binds to alkaloids and prevents their absorption.
•Chemical antagonist combines with a substance chemically like
chelating agents binds with the metals.
•Physiological antagonist produces an action opposite to a substance but
by binding to the different receptors e.g. adrenaline is a physiological
antagonist of histamine because adrenaline causes bronchodilatationby
binding to β2 receptors, which is opposite to bronchoconstrictioncaused
by histamine through H1 receptors.
•Pharmacological antagonistsproduce no effect , shows no intrinsic
activity.

89. •Partial agonists -Agents that are only partly as effective as
agonists regardless of the concentration employed.
•Inverse agonists -Many receptors exhibit some
constitutive activity in the absence of a regulatory ligand;
drugs that stabilize such receptors in an inactive
conformation are termed inverse agonists(produce effect
opposite to that of agonist).

92. Efficacy
A maximal effect (Emax) an agonist can
produce.
It can be measured with a graded dose-
response curve only.

93. POTENCY
The amount of the drug needed to produce a
given effect.
potency is determined by the affinity of the
receptor for the drug.
The dose causing 50% from the maximal
effect (EC50) can be obtained from graded
dose-response curve.
In quantal dose response curve, ED50, TD50
and LD50 are potency variables.

98. Repeated administration of a drug results in
diminished effect“Tolerance”.
Tachyphylaxis: is a type of tolerance which occurs
very rapidly.
Desensitization: decreased response to the agonist
after its repeated injection in small doses.
May be due to
1-Masking or internalization of the receptors.
2-Loss of receptors (down regulation)-decreased
synthesis or increased destruction.
3-Exhaustion of mediators (depletion of
catecholamine).

101. PHYSIOLOGICAL
RECEPTORS
GPCR
Ion channels
Transmembrane enzymes
Transmembrane, non-enzymes
Nuclear receptors
Intracellular enzymes

102. Therapeutic window
Therapeutic effect is seen only with in a narrow range of plasma
conc.
Both above & below this range, beneficial effect is suboptimal.
Drugs having low therapeutic window
Theophylline
Carbamazepine
Digoxin
Lithium
Phenytoin

105. Therapeutic Index
Is the ratio of the LD50 to ED50
Represent an estimate of the
safety of a drug.

106. Importance of graded dose-response
curves
1.Calculation of the ED50 (The dose that produces
50% of the maximum response in one animal
Comparing ED50 of different drugs on the same animal gives an
idea about the equieffectivedoses i.ethe doses that produce the
same effect.
Comparing ED50 of the same drug in different patients gives an
idea about the relative sensitivity of the patients to the same drug
i.ethe degree of biological variation inherent in a population.
2. Calculation of the maximum response
Comparing the maximum response obtained by different drugs on
the same organ gives an idea about the intrinsic activity.
3. Determination of the stepinessof the dose
response
Any small change in the drug concentration produces significant
increase in the tissue response. This means that maximum
response to the drug could be reached very fast and the toxicity
could be reached very fast too.

107. SYNERGISM
(Greek: Syn-together; ergon-work)
When the action of one drug is facilitated or
increased by the other, they are said to be
synergistic.
In a synergistic pair, both the drugs can have
action in the same direction or given alone one
may be inactive but still enhance the action of
the other when given together.

108. Additive
The effect of the two drugs is in the same direction and
simply adds up:
effect of drugs A + B = effect of drug A + effect of drug B

109. Supraadditive (potentiation)
The effect of combination is greater than the individual
effects
of the components:
effect of drug A+ B > effect of drug A+ effect of drug B
This is always the case when one component is inactive
as such.

110. Antagonism
Competitive antagonist
•Same binding site as of agonist
•resembles chemically with agonist
•Right shift of DRC
•Surmountable antagonism by increasing
agonist dose
•Inactivation of certain agonist molecules
•Response depends on concentration of
both
e.gAch –Atropine, Morphine -
Naloxone

111. Non-Competitive antagonist
•Different binding site as of agonist.
•Not resembles chemically with agonist.
•Flattening/downward shift of DRC.
•Unsurmountable antagonism (Maximum response
is suppressed).
•Inactivation of certain receptors.
•Maximum response depends on concentration of
antagonist
e.g. Diazepam -Bicuculline

113. Body size
It influences the concentration of the drug attained at the site of
action. The average adult dose refers to individuals of medium
built. For exceptionally obese or lean individuals and for
children dose may be calculated on body weight (BW) basis:

114. Age
The dose of a drug for children is often calculated from the
adult dose

116. Questions ?