4. Autacoids and therapy of Inflammation(0).pdf

signifi cantly. Th is implies that these receptors have
evolved over millions of years from an ancient common
ancestral protein. Comparing the amino acid sequences
of the receptors allows us to construct an evolutionary
tree and to group the receptors of this superfamily into
various sub-families, which are defi ned as class A (rhodopsin-like receptors), class B (secretin-like receptors),
and class C (metabotropic glutamate-like and pheromone receptors). Th e most important of these, as far as
medicinal chemistry is concerned, is the rhodopsin-like
family—so called because the fi rst receptor of this family
to be studied in detail was the rhodopsin receptor itself,
a receptor involved in the visual process. A study of the
evolutionary tree of rhodopsin-like receptors throws up
some interesting observations ( Fig. 4.16 ).
First of all, the evolutionary tree illustrates the similarity
between diff erent kinds of receptors based on their relative
positions on the tree. Th us, the muscarinic, α-adrenergic,
β-adrenergic, histamine, and dopamine receptors have
evolved from a common branch of the evolutionary tree
and have greater similarity to each other than to any
receptors arising from an earlier evolutionary branch (e.g.
the angiotensin receptor ). Such receptor similarity may
prove a problem in medicinal chemistry. Although the
receptors are distinguished by diff erent neurotransmitters or hormones in the body, a drug may not manage to
make that distinction. Th erefore, it is important to ensure
that any new drug aimed at one kind of receptor (e.g. the
dopamine receptor) does not interact with a similar kind
of receptor (e.g. the muscarinic receptor).
Receptors have further evolved to give receptor types
and subtypes which recognize the same chemical messenger, but are structurally diff erent. For example, there
are two types of adrenergic receptor (α and β), each of
which has various subtypes (α1 , α2A , α2B , α2C , β1 , β2 , β3 ).
Th ere are two types of cholinergic receptor—nicotinic
(an ion channel receptor) and muscarinic (a 7-TM receptor). Five subtypes of the muscarinic cholinergic receptor
have been identifi ed.
Th e existence of receptor subtypes allows the possibility of designing drugs that are selective for one receptor
subtype over another. Th is is important, because one
receptor subtype may be prevalent in one part of the body
(e.g. the gut), while a diff erent receptor subtype is prevalent in another part (e.g. the heart). Th erefore, a drug
that is designed to interact selectively with the receptor
subtype in the gut is less likely to have side eff ects on the
heart. Even if the diff erent receptor subtypes are present
in the same part of the body, it is still important to make
drugs as selective as possible because diff erent receptor
subtypes frequently activate diff erent signalling systems,
leading to diff erent biological results.
A closer study of the evolutionary tree reveals

1. 4. Autacoids Pharmacology
1
Seyoum Gizachew (PhD Candidate)

2. Autacoids
•Autacoids
–Autos= self,
–akos= remedy/healing.
•Autacoids are also called local hormones.
–Generally they act at the site of synthesis and release.
2

3. Autacoids, cont’d
Classification
-Biogenic amines: Histamine (Histidine), Serotonin (Tryptophan)
-Biogenic Peptides: Angiotensin and kinins
-Small Proteins: cytokines
-Membrane derived lipids: Leukotrienes (LTs), Prostaglandins
(PGs), thromboxane A2 (TxA
2) & Platelet Activating Factor (PAF)
-Endothelium-derived agents: NO (gas), Endothelin (ET) (peptide)
3

4. -is an endogenous substance synthesized, stored and
released in
(a) mast cells, which are abundant in the skin, GI, and the
respiratory tract,
(b) basophilsin the blood, and
(c) some neuronsin the CNS andperipheral NS
•Heterocyclic molecule composed of imidazole ring attached with
alkyl amino group.
What is Histamine?
4

5. Biosynthesis
Synthesized chiefly in
•Mast cells: stomach, liver, intestine, heart and lung
•Basophilicgranulocytes : blood
Other sites of synthesis include:
Neurons of the CNS and
Epidermis of the skin
5

6. Histamine Release
•Mast cells and basophils are the major source of histamine.
–store histamine in cytoplasmic granules along with other amines,
proteases, proteoglycans, some cytokines/chemokines,
•rapidly released upon triggering with a variety of stimuli.
Immunologic Release
•the most important pathophysiologic mechanism of mast cell and
basophil histamine release.
•These cells, if sensitized by IgE antibodies attached to their surface
membranes, degranulate explosively when exposed to the appropriate
antigen.
•Degranulation: simultaneous release of histamine, ATP, and other
mediators that are stored together in the granules.
•Histamine released by this mechanism is a mediator in immediate (type
I) allergic reactions, such as hay fever and acute urticaria.
6

7. Histamine
Release…
Fig. Immunologic Release
•Initial exposure to
allergen (sensitization
phase) leads to
production of IgE by
plasma cells differentiated
from allergen-specific B
cells (not shown).
•The secreted IgE binds
IgE-specific receptors
(FcεR).
•Re-exposure to allergen
leads to cross-linking of
membrane-bound IgE
(effector phase). This
cross-linking causes
degranulation of
cytoplasmic granules and
release of mediators.
7

8. Histamine Release…
Chemical and Mechanical Release
•Certain amines, including drugs such as morphine and
tubocurarine,
–can displacehistamine from its bound form within cells.
•Not associated with mast cell injury or explosive degranulation.
•Loss of granules from the mast cell also releases histamine,
because sodium ions in the extracellular fluid rapidly displace the
amine from the complex.
•Chemical and mechanical mast cell injury causes degranulation
and histamine release.
8

9. Termination of Histamine Action
•Cellular uptake
plasma membrane monoamine transporter and
organic cation transporters
•Metabolism (Major)
9

10. Receptors
Are sites where histamine, its agonists & antagonists act
4 types identified (H1-H4)
H1 & H2 well studied and clinically targeted
Belong to the GPCRs super family
Classified based on;
•Post receptor signaling mechanism
•Tissue distribution
•Sensitivity to ligand
10

11. 11

12. 12

13. Pharmacological Effects of Histamine
•Ranges from mild allergic symptomsto anaphylactic shock
•Involves both the H1 and H2 receptors
dilatation of small blood vessels flushing (H1)
decreased PVR and BP (H1 initial response, H2 sustained
reaction)
increased capillary permeability, edema (H1)
•H
1–in vascular endothelium NO and PG release 
vasodilation
•H
2–in vascular smooth muscle cells vasodilation mediated
by cAMP
13

14. Effects on Human Heart
•Histamine affects both cardiac contractility and electrical events
directly.
–It ↑es the force of contraction of both atrial and ventricular
muscle by promoting the influx of Ca
2+
•↑es HR by hastening diastolic depolarization in the SA node.
•↑es automaticity, and in high doses especially, elicit arrhythmia
•If histamine is given IV, direct cardiac effects are overshadowed
by baroreceptor reflexes elicited by the reduced BP.
14

15. H
1receptors
•Activates PLC
•found in periphery smooth muscle (bronchi, intestine, Blood
vessel), skin and CNS
•mediates the increase in vascular permeability induced
by Histamine
•Mediates Inflammation and allergic response
•Vasodilation BP Shock
»Increased blood flow, redness, itchy eyes, hives
•Smooth Muscle Contraction (bronchoconstriction)
•Implicated in neurotransmission, arousal and sexual
behavior.
15

16. H
2Receptor
Receptor is smaller
coupled to Gsand activates adenylyl cyclase
Increases cAMP production
Found in the stomach and heart
Mediates the release of gastric acid
» Stomach ulcers
16

17. H
3and H
4Receptors
H
3Receptor…
•GPCR
• May play role in CNS (autoreceptors)
• Possible regulation of synthesis and release of Histamine
• Signaling pathway not well known
H
4Receptor…
• GPCR
• Found in intestines, spleen, T-cells and neutrophils
• Suggests role in Immunity.
17

18. What are an antihistamines?
•Compete against the receptors’ natural substrate, histamine, in
binding to the receptors.
–Reduce or abolish effects of histamine.
•Histamine is released by our body during an allergic reaction and
acts on a specific histamine receptor.
Classes of antihistamines
•H
1 receptor antagonists (blockers)
•1
st
generation antihistamines
•2
nd
generation antihistamines
•3
rd
generation antihistamines
•H
2receptor antagonists (blockers)
18

19. Ethanolamines (First generation H
1receptor antagonists)
•This class has significantanticholinergicside effects and sedation,
however reduced the GI side effects.
Diphenhydramine
•Oldest and most effective antihistamine on the
market
•Available over the counter
•Because it induces sedation, it’s used in
nonprescription sleep aids.
•Removes secretion from respiratory tract
cough
•Has anti-nauseating effect
used in motion sickness 19

20. Dimenhydrinate
Clemastine
•Exhibits fewer side effects
than most antihistamines.
•Widely used as an
antipruritic (stops itching)
•Anti-emetic (anti nausea)
•Also causes strong sedation
•Readily crosses the BBB
20

21. Alkylamines (First generation H
1receptor antagonists)
Chlorpheniramine
Brompheniramine
•used to prevent allergic
conditions.
•Shown to have antidepressant
properties and inhibit the
reuptake of serotonin.
•Available over the counter
•Used to treat the common cold:
relieves runny nose, sneezing
relives itchy, watery eyes
*
*
21

22. Promethazine
•Has strong anti-cholinergic and sedative effects
•It was originally used as an antipsychotic drug
•Now it is most commonly used
sedative or anti-nausea drug
requires a prescription
Phenothiazine derivative
(First generation H
1receptor antagonists)
22

23. Piperazine derivatives
(First generation H
1receptor antagonists)
•Produce significant anti-cholinergic effects
•Used most often to treat motion sickness, vertigo, nausea,
vomiting and itching (skin rash)
Meclizine
23

24. Cyproheptadine
•both an antihistamine and an antiserotonergic agent.
•It is a 5-HT2 receptor antagonist and also blocks calcium channels.
•Used to
•treat hay fever
•S/E, drowsiness, Weight gain and increased growth in children
24
Miscellaneous

25. Second generation H
1-receptor antagonists
•These are relatively newer drugs
•much more selective for the peripheral H
1-receptors involved in
allergies as opposed to the H
1-receptors in the CNS.
provide the same relief with many fewer adverse side effects.
•Do not cross the BBB as readily as the 1
st
generations
Bulkier & less lipophilic
•Studies have also showed
anti-inflammatory activity
management of inflammation.
25

26. Second generation H
1-receptor antagonists
Acrivastine
•relieves itchy rashes and hives.
•non-sedating because it does not cross the BBB readily.
26

27. Second generation H
1-receptor antagonists, cont’d
Cetirizine
Used to treat allergies
27
Astemizole
•long duration of action
•It suppresses the formation of edema and pruritis.
•It doesn’t cross the BBB
•It has been taken off the market in most countries because of
adverse interactions with erythromycin and grapefruit juice
(CYP3A4 inhibitors, Arrhythmia).

28. Second generation H
1-receptor antagonists, cont’d
Loratadine
Terfenadine
•It is the only drug of its class
available over the counter
•It has long lasting effects and does
not cause drowsiness because it
does not cross the BBB readily
•It was formerly used to treat
allergic conditions
•In the 1990’s it was removed from
the market
cardiac arrhythmias
28

29. Third generation H
1-receptor antagonists
•These drugs are derived from second generation antihistamines.
–Active enantiomers or metabolites of 2
nd
generation drugs
•designed to have increased efficacy and fewer side effects.
Levocetrizine
•Active enantiomer of cetirizine
•more effective and fewer adverse effects.
•Also it is not metabolized and is likely to be safer than
other drugs due to a lack of possible drug interactions.
•does not cross the BBB and does not cause significant
drowsiness.
•Desloratadineand Fexofenadineare the other drugs.
29

30. Clinical Uses of H1-Antihistamines
•Allergic rhinitis (common cold)
•Allergic conjunctivitis (pink eye)
•Allergic dermatological conditions
•Urticaria (hives)
•Angioedema (swelling of the skin)
•Pruritus (atopic dermatitis, insect bites)
•Anaphylactic reactions (severe allergies)
•Nausea and vomiting (first generation H
1-
antihistamines).
30

31. Adverse side effects
•Associated mainly with the first generation H
1-antihistamines
–lack of selectivity for the H
1receptors( peripheral &CNS)
–Anti-cholinergic activity
–Side effects are due to CNS depression:
•Sedation
•Dizziness
•Tinnitus (ringing in the ear)
•Blurred vision
•Uncoordination
•Tremor
•Dry mouth/dry cough
•Newer second & 3
rd
generation H
1-antihistamines are more
selective for the peripheral histamine receptors and have far less
side effects (drowsiness, fatigue, headache, nausea and dry mouth)
31

32. H2-antagonists
•Inhibit gastric acid secretion
•(-) effect of gastric motility, emptying time, sphincter,
pancreatic & mucous secretion.
32

33. Anticholinergic drugs ╠►unwanted side effects
Gastrin receptor blocker ╠►unsuccessful
33
Peptic Acid Secretion

34. H2-antagonists
•Adverse effects
Cimetidine:
headache, dizziness, constipation, diarrhea
alterations of hepatic function
CNS disturbances (elderly & impaired RF)
Serum prolactin elevation
Sexual dysfunction (female) & gynecomastia (male)
34

35. H2-antagonists
Inhibits CYP-450 –accumulation of warfarin, phenytoin,
theophylline, propranolol, diazepam & phenobarbital
Ranitidine:
Serum prolactin elevation
weak inhibitor of CYP-450
Nizatidine & famotidine –do not inhibit CYP-450
•Therapeutic Uses: Peptic acid disorders
35

36. Serotonin(5-HT)
•Serotonin (5-HT) synthesis
36

37. Serotonin (5-HT), cont’d
•About 90% of 5-HT is stored in enterochromaffin cells of GIT.
•These cells contain tryptophan hydroxylase and can synthesize 5-
HT.
•The remaining 10% are stored mainly in platelets and very small
amount in CNS.
•The platelets do not contain tryptophan hydroxylase and cannot
synthesize 5-HT
–but obtain it by active uptake of 5-HT released from
enterochromaffin cells into the blood.
•Fate of 5-HT: The majority of secreted 5-HT undergoes active
reuptake into the serotoninergic neurons.
•The remaining part of 5-HT is metabolized by MAO to 5-
hydroxyindoleacetic acid (5-HIAA) which is excreted in urine.
37

38. Serotonin receptors
5-HT1e
5-HT1f
38

39. Serotonin Receptors, cont’d
Largest NT receptor family
About 7-subtypes are identified
5HT1-4, have well defined functions
All but 5HT3 are members of GPCRs
5HT3 is ligand gated ion channel (Na
+
& K
+
)
•5-HT1 family
-Share 40-60% overall sequence homology
-Coupled to inhibition of adenylcyclase via Go/Gi
-5-HT1C appellation is vacant as renamed as 5-HT2
39

40. Serotonin Receptors, cont’d
5-HT1A
-High density in cortical and limbic structures.
-Coupled to inhibition of adenylcyclase (AC) or opening of
K
+
channel (both in hippocampus but later in dorsal raphe)
-Implicated in
Affective disorder (anxiety and depression), impulsivity and
aggression: (partial agonist-buspirone-anxiolytic)
Modulation of body temperature, sexual behavior and feeding
40

41. Serotonin Receptors, cont’d
5-HT1B & 5-HT1D
-High density in the Basal ganglia (substantia nigra & globus
pallidus)
-Presynaptic (auto-receptor, modulate 5-HT release) and
postsynaptic (other NTs, ACh, DA)
-Located on cerebral arteries and vasculatures (tryptans used
for migraine, sumatriptan, zolmitryptan)
41

42. Serotonin Receptors, cont’d
•5HT2 receptors; 3 subtypes (5HT2A-2C)
–Coupled to Gq/11
–Broadly distributed in the CNS
5-HT2A: concentrated in frontal cortex (cognitive & integrative
function)
-Increase body T
0
and mediate contractile response in vasculature.
-Implicated in the hallucinogenic effects of agonists.
-Atypical antisychotics (clozapine, olanzapine) target this receptor
5-HT2B
-Mediate vasodilatation and antagonist are being developed for
migraine.
5-HT2C
-High density in the choroid plexus (regulate volume and
composition of CSF)
42

43. Serotonin Receptors, cont’d
5-HT3 receptors
-Ligand gated ion channel
-Regulate intestinal motility and secretion
-Participate in emetic response in both GIT & CNS
-Mediate nociceptive mechanisms in the spinal cord and medulla
(facilitates release of Substance P)
-High density in the area postrema (ondansetron, granisetron,
tropiseteron)
-Chemotherapeutic agents release 5-HT from enterochromaffin
cells, enhanced afferent input causes depolarization of the CTZ.
43

44. Serotonin Receptors, cont’d
•5HT4 receptors
–Coupled to Gs(stimulation of adenylate cyclase)
–Widely distributed throughout the body
–Evoke secretion in GIT
–Facilitate peristaltic movement
44

45. Sites of 5HT actions
•Enterochromaffin cells
Abundantly found in GIT mucosa
Most important sources of peripheral 5HT
Release 5HT augmented by mechanical stretching
Enhance GIT motility
•Platelets
Not synthesize 5HT
Uptake from circulation & store it
5HT binds to 5HT2A & promotes platelet aggregation
If injury is deep, 5HT exerts direct vasoconstriction.
45

46. Sites of 5HT actions cont….
•CVS
–Positive ionotropic & chronotropic actions on heart
–Amplifies local constrictive activity of NA, Angio. II
•GIT
–Released during mechanical or vagal stimulation
–Triggers peristaltic contraction
–Plays important role in emesis
•CNS
–Regulates multiple actions in the CNS
•Sleep, cognition, sensory perception, motor activities
•Temperature regulation, nociception
•Appetite, sexual behavior & hormone secretion.
46

47. 5HT receptor agonists
5HT1 receptor agonists
•Useful in treatment of acute migraine
•Includes: Sumatriptan, Zolmitriptan, Naratriptan &
Nizatriptan
•Pharmacological properties
–Effect limited to 5HT1 receptors only
–Much more selective than ergot alkaloids
–Interact potently with 5HT1B & 5HT1D receptors
–Are inactive at
•α1,α2, β-adrenergic, dopaminergic, muscarnic & BZD
receptors.
47

48. 5HT receptor agonists cont….
•Mechanism of antimigraineactivity
–Two hypotheses
•Cause constriction of intracranial blood vessels &
restore blood flow to the brain.
•Modulate NT release from axon terminals
–Both 5HT1B & 5HT1D are presynaptic
autoreceptors
oAgonists may block the release of
proinflammatory neuropeptides at the nerve
terminal.
oAccounts for their efficacy in acute treatment of
migraine.
48

49. Pharmacokinetics of Triptans
49

50. 5HT receptor agonists cont….
Adverse reactions
•Rare but serious cardiac events:
–Coronary artery vasospasm
–Atrial & ventricular arthymia
–Myocardial infarction
•Most commonly experienced side effects:
–Pain, stinging
–Burning sensation
–Asthenia
–Flushing, drowsiness, nausea
50

51. 5HT receptor agonists cont….
•Contraindications
–Generally, triptans are contraindicated to patients with:
•History of ischemic or coronary artery diseases
•Cerebrovascular or peripheral vascular diseases
•Uncontrolled hypertension
–Naratriptan: C/I in severe renal or hepatic failure
–Rizatriptan: taken cautiously during renal or hepatic failure
–Sumatriptan, Rizatriptan & Zolmitriptan are C/I in patients
taking MAO inhibitors.
51

52. 5HT receptor agonists cont….
•Clinical applications
–Effective in acute treatment of migraine
–Not used for prophylactic treatment of migraine
–Treat as soon as possible after onset of migraine
–Oral dosage forms are most convenient to use.
52

53. 5HT receptor antagonists
•5HT antagonists
–Have widely differing chemical structures.
–Mainly target 5HT2A/2C & 5HT3 receptors.
•Ketanserin
–Potently blocks 5HT2A and less potently 5HT2C receptors.
–No significant effect on other 5HT receptors
–Has affinity for α1 & H1 receptors
–Lowers BP in patients with hypertension
•Comparable to β-antagonists & diuretics effect
•Reducing tone of both venous & arteries
•Effect related to α1 blocking activity not of 5HT2A/2C
•F=50%, t
1/2= 12-25 hrs & eliminated by metabolism.
53

54. 5HT receptor antagonists cont….
•Ketanserin
–Inhibits 5HT induced platelet aggregation
–No severe side effects have been reported
–available in Europe for the treatment of HTNand vasospastic
conditions but has not been approved in the USA
•Clozapine
–5HT2A/2C receptor blocker
–Also acts on dopamine receptors selectively
–Atypical antipsychotic
•Reduce negative symptoms of schizophrenia
•Reduced extra pyramidal side effects.
54

55. 5HT receptor antagonists cont….
•Methysergide
–Potent 5HT2A/2C antagonist
–Non selectively blocks 5HT1 receptors
•Used in prophylactic treatment of migraine, diarrhea &
malabsorption.
•Not useful for acute treatment of migraine
•S/Es: GI disturbances, back pain, drowsiness, insomnia,
hallucinations, cardiac valvular damage.
55

56. 5HT receptor antagonists cont….
•5HT3 receptor antagonists
–Includes: Ondansetron, Granisetron& Dolasetron
–Used in treatment of chemotherapy induced emesis
–Cancer treatment
•Causes release of 5HT from enterochromaffin cells
•Act on 5HT3 receptors on vagal nerves & CTZ
–Leads to vomiting.
56

57. Lipid derived autacoids
57

58. Lipid derived autacoids
•Eicosanoids (Eicosa = 20 carbons)
–Arachidonate metabolites
–Not stored, rather synthesized & released up on need
–Synthesized & released by;
•Physical, chemical & hormonal stimuli
–Pivotal role:
•Inflammation
•Smooth muscle tone
•Haemostasis, thrombosis
•Parturition, GIT secretion
58

59. Lipid derived autacoids cont’d
•Biosynthesis
–Limited by availability of substrate
•Release of Arachidonic acid (AA) from membrane
phospholipids
–Diverse physical, chemical, inflammatory stimuli
•Activate PLA2
•Release AA from membrane phospholipids
–Once released, AA is metabolized to d/t products
•Cyclooxygenases (COXs) pathway …….prostanoids
•Lipoxygenases (LOXs) pathway…….leukotrines
•CYP450 epoxygenase pathways…epoxy & hydroxy
derivatives
•Non-enzymatically via the isoeicosanoid pathway.
59

60. Products of Prostaglandin Endoperoxide Synthases
(Cyclooxygenases)
•Two unique COX isozymes convert AA into prostaglandin
endoperoxides.
–PGH synthase-1 (COX-1): expressed constitutively in most cells.
–PGH synthase-2 (COX-2) is more readily inducible.
•COX-2− markedly up-regulated by shear stress, growth factors, tumor
promoters, and cytokines.
•COX-1 − generates prostanoids for “housekeeping” functions, such
as gastric epithelial cytoprotection.
•COX-2: major source of prostanoids in inflammation and cancer.
•This distinction is overly simplistic.
–For e.g., endothelial COX-2 is the primary source of vascular
prostacyclin (PGI2),
–Renal COX-2-derived prostanoids are important for normal renal
development and maintenance of function. 60

61. Products of Cyclooxygenases,cont’d
•NSAIDs: inhibitors of the COXs.
•Both COX-1 and COX-2 promote uptake of 2 O
2by cyclization of
AA to yield a C9–C11 endoperoxide C15 hydroperoxide (PGG2).
•PGG2, then rapidly modified by the peroxidase moiety of the COX
enzyme to add a 15-hydroxyl group that is essential for biologic
activity (PGH2).
•Prostaglandins, thromboxane, and prostacyclin, collectively termed
the prostanoids,
–generated from PGH2 through the action of downstream
isomerasesand synthases.
•These terminal enzymes are expressed in a relatively cell-specific
fashion, such that most cells make one or two dominant
prostanoids.
61

62. Products of Cyclooxygenases, cont’d
•Prostaglandins differ from each other in two ways:
–(1) in the substituents of the pentane ring (indicated by the
last letter, e.g., E and F in PGE and PGF) and
–(2) in the number of double bonds in the side chains
(indicated by the subscript, e.g., PGE1, PGE2).
•PGH2 is metabolized by prostacyclin, thromboxane, and PGF
synthases (PGIS, TXAS, and PGFS) to PGI2, TXA2, and
PGF2α, respectively.
62

63. FIGURE: Pathways of arachidonic acid (AA) release and metabolism63

64. Cyclooxygenase catalyzes two successive
reactions
+2 O
2COOH COOH
O OH
O
O
arachidonic acid (AA)
PGG
2COOH
OH
O
O PGH
2
H
2O
Diverse prostaglandins
cyclooxygenase
peroxidase
64

65. COOH
OH
O
O COOH
OH
OH
OH COOH
OH
OH
O COOH
OH
O
OH COOH
OH
O
OH PGD
2
PGE
2
PGF
2a
PGI
2 (prostacyclin)
Derivatives of prostaglandin H
2
65

66. Derivatives of prostaglandin H
2(2)COOH
OH
O
O
PGH
2
Thromboxane A
2COOH
OH
O
O COOH
OH
O
O
O
Thromboxane B
2
H
2O
Thromboxane A synthase
66

67. Prostanoid receptors
•As a result of their short half-lives, the eicosanoids act mainly in an
autocrine and a paracrine fashion,
–i.e., close to the site of their synthesis, and not as circulating
hormones.
•bind to receptors on the cell surface, and pharmacologic specificity
is determined by receptor density and type on different cells.
•A single gene product (receptor) identified for each of the PGI2
(IP), PGF2α (FP), and TXA2 (TP) receptors,
•While four distinct PGE2 receptors (EPs 1–4) and two PGD2
receptors (DP1 and DP2).
67

68. Prostanoid receptors, cont’d
•All of these receptors are G protein-coupled.
Classified into three clusters
Relaxant receptors: EP
2, EP
4, IP, and DP
1; activate AC, ↑ cAMP
Contractile receptors: EP
1, FP, & TP; activate phosphatidylinositol
metabolism; ↑ cytosolic Ca
2+
EP
3can couple to both elevation of intracellular calcium (Gq/11) and
a decrease in cAMP (Gi).
•Inhibition of gastric acid secretion
•Enhancement of platelet aggregation
•Contraction of smooth muscle
68

69. Roles of prostanoids
•Inflammation: PG E, I, Leukotrienes C
4, D
4
•Fever, pain: Prostaglandin E
•Regulation of BP: Vasoconstrictor (TXA
2, PGF
2α), Vasodilator
(PGI
2and PGE
2).
•Thrombocyte aggregation: stimulated by thromboxane A
2,
inhibited by PG E & I
•Uterine contraction: PGE, PGF
2a
•Integrity of gastric mucosa: Prostaglandins E, F, I
•Regulation of blood flow and urine secretion in the kidney:
PGE, prostacyclin, thromboxane A
69

70. Products of Lipoxygenase
•The metabolism of AA by the 5-, 12-, and 15-lipoxygenases
(LOX) results in production of hydroperoxyeicosatetraenoic acids
(HPETEs), which rapidly convert to hydroxy derivatives
(Hydroxyeicosatetraenoic acid, HETEs).
•5-LOX, the most actively investigated pathway, gives rise to
–Leukotrienes (LT)and is present in leukocytes (neutrophils,
basophils, mast cells).
–associated with asthma, anaphylactic shock, and CVD.
•Incorporation of O
2to AA by 5-LOX, in association with 5-LOX-
activating protein (FLAP),
–yields 5(S)-HPETE, which is then further converted by 5-LOX
to the unstableepoxide leukotriene A4 (LTA4).
70

71. Products of Lipoxygenase, cont’d
•LTA4 is either converted to;
–Dihydroxy LTB4, via the action of LTA4 hydrolase, or
–is conjugated with glutathione to yield LTC4, by LTC4
synthase.
•Degradation of GSH by peptidases yields LTD4 and LTE4.
•LTC4, D4, and E4, are called cysteinyl leukotrienes.
•LTC4 and LTD4 are potent bronchoconstrictors
–asthma and anaphylaxis.
71

72. FIGURE: LT biosynthesis. FLAP
,
5
-
LOX
-
activating protein
; GT,
glutamyl transpeptidase; GL, glutamyl leukotrienase. *Additional products include
5,6
-
;
8,9
-
; and
14,15
-
EET; and
19
-
,
18
-
,
17
-
,
and
16
-
HETE
.
72

73. Lipoxins
•An effective host defense mechanism involves inflammation
to eliminate pathogens from the site of infection,
–followed by the resolution of inflammation and the
restoration of tissue homeostasis.
•Lipoxins are endogenous anti-inflammatory, pro-resolving
molecules that play a vital role in reducing excessive tissue
injury and chronic inflammation.
•Three major lipoxygenases (LO) involved in lipoxin synthesis
from arachidonic acid (5-LO, 15-LO, and 12-LO).
–Lipoxin A4, Lipoxin B4
73

74. LT & LX (lipoxins) receptors
•Two receptors exist for LTB4 (BLT1 and BLT2) and for
LTC4/LTD4 (cysLT1 and cysLT2).
•LTE4 functions (orphan receptor GPR99 and the ADP
receptor P2Y12).
•BLT1 receptor
–High affinity receptor
–Mainly expressed in leukocytes, thymus & spleen
•BLT2 receptor
–Low affinity receptor
–Mainly expressed in leukocytes, liver, ovary & intestine
•Both BLT1 &2 are members of GPCRs
•One receptor for LXA4= ALX receptor
74

75. Epoxygenase (CYP450) Products
•CYP450 monooxygenases convert AA to hydroxy-or
epoxyeicosatrienoic acids (EETs).
•The products are 20-HETE, generated by the CYP hydroxylases
(CYP3A, 4A, 4F) and the 5,6-, 8,9-, 11,12-, and 14,15-EETs,
which arise from the CYP epoxygenase (2J, 2C).
•Their biosynthesis can be altered by
–pharmacologic, nutritional, and genetic factors that affect
P450 expression.
•EETs reduced to less active, dihydroxyeicosatrienoic acids
(DHETs) by soluble epoxide hydrolase (sEH).
75

76. Epoxygenase (CYP450) Products, cont’d
EETs
•Important modulators of CVS & renal function
•Synthesized in endothelial cells & cause vasodilatation
–Activate K+ channels (hyperpolarization)
–Act as endothelium derived hyperpolarizing factor (EDHF)
–Potential target for treatment of hypertension (inhibitors of sEH)
–Receptors exist but none has been cloned.
76

77. Inhibitors of eicosanoid biosynthesis
•Inhibition of PLA2
–Reduces release of the substrate, AA
•Reduces synthesis of all downstream metabolites
–Glucocorticoids
•Inhibit PLA2 indirectly by inducing synthesis of annexins
•Down regulate induced expression of COX-2
•NSAIDs
–Inhibit COXs
–Do not inhibit LOXs
•Increase formation of LTs by shunting substrate to LOXs.
77

78. Inhibitors of eicosanoid biosynthesis, cont’d
•Dual inhibitors of COXs & LOXs
–Are under investigation
•LOX inhibitors
–Zileuton
•Inhibits 5-LOX pathway
•Introduced to market for treatment of asthma
•Withdrawn from market
•LT receptor antagonists
–Zafirlukast, Pranlukast & Montelukast
–Antagonize LTRs & used for treatment of asthma
78

79. 79

80. Clinical uses of eicosanoids
•NSAIDs & selective COX-2 antagonists
–Analgesics, antipyretic & anti-inflammatory agents
–Low dose aspirin is used in cardioprotection
•LT antagonists
–Useful in treatment of asthma
•The use of eicosanoids or eicosanoid derivatives as therapeutic
agents is limited
–Systemic administration associated with ADRs
–Very short half life.
80

81. Clinical uses of eicosanoids cont’d
•Therapeutic abortion
–Systemic or intravaginal administration of PGE1 analog
(Misoprostol) plus mifepristone is very useful in
terminating early pregnancy.
•Gastric cytoprotection
–Several PG analogs suppress gastric ulceration
–Misoprostol (200 mcg QID with food, t
1/2<30min)
•Heals gastric ulcers as effective as H2 antagonists.
81

82. Clinical uses of eicosanoids cont’d
•Impotence
–PGE1 (alprostadil) may be used in the treatment of impotence, 1-3
hour erection (onset = 5-10 min).
–Causes complete or partial erection in impotent patients who don’t
have vascular system disorder.
–can be injected directly into the cavernosa or placed in the urethra
as a minisuppository.
•Pulmonary HTN
–Rare idiopathic disease affecting young adults
–Leads to right heart failure & is fatal
–Therapy with PGI
2delayed or precluded the need for lung or heart
transplant.
82

83. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
•Chemically heterogeneous group of compounds
•Most of them are organic acids
•Share certain therapeutic actions & side effects
•Unlike aspirin, all are competitive inhibitors of COXs
•Well absorbed orally & highly bound to Plasma Proteins
•All are analgesics, antipyretic & anti-inflammatory
•Excreted by either
–Glomerular filtration or
–Tubular secretion
83

84. NSAIDs cont’d
•MOA
–Principal therapeutic effects of NSAIDs derive from their
inhibition of PG synthesis
•Inhibiting COXs
–Aspirin differs from all other NSAIDs
•Irreversibly inhibit COXs
•So duration of aspirin effect depends on turn over rate
of the COXs
–Other NSAIDs are competitive inhibitors of COXs
–So duration of action depends on drug disposition
84

85. Therapeutic effects of NSAIDs
•Pain
–Effective against pain of low to moderate intensity
–Much less efficacy than opioids
•No respiratory depression
•No dev’t of physical dependence
•Fever
–Reduce fever but not temperature rise during exercise
–COX-2 PGs are responsible for rise in temperature.
85

86. Therapeutic effects of NSAIDs cont’d
•Inflammation
–Chief clinical application
•Rheumatoid arthritis
•Osteoarthritis
•Cancer chemoprevention
–Under active investigation
–Frequent use of aspirin showed 50% decrease in risk of
colon cancer.
86

87. Adverse effects of NSAIDs therapy
•GI disturbances
–Anorexia, nausea, dyspepsia, abdominal pain etc.
•Results of induction of gastric or intestinal ulcers
–Ulceration
•Superficial to perforations
•Single or multiple point
•May be accompanied with blood loss/hemorrhage
•Increase in association with
–H. pylori, heavy alcohol consumption.
–Selective COX-2 inhibitors have reduced GI SEs.
87

88. Adverse effects of NSAIDs therapy cont’d
•Antiplatelet aggregation
–Result of inhibition of TXA
2synthesis
•Renal & renovascular adverse effects
–Little effect on normal subjects
–Significant ADRs in patients with
•CHF
•Hepatic cirrhosis & chronic kidney disease
–Retention of salt & water causing edema.
88

89. Adverse effects of NSAIDs therapy cont’d
•Pregnancy
–Prolongation of gestation by NSAIDs
–Increased risk of postpartum hemorrhage
•Hypersensitivity
–Some individuals are allergic to aspirin & NSAIDs
•Drug interactions
NSAIDs
With ACEIs increase risk of hyperkalemia
•With Warfarin, increase risk of bleeding
–NSAIDs antiplatelet activity
–NSAIDs also interfere with plasma binding & metabolism of
warfarin.
89

90. Important considerations to use NSAIDs
•Rapid onset & short duration drugs are preferred for simple
fevers & pain
•Adverse effects are manifested in the 1
st
weeks of therapy
•If no benefit from one NSAID, switch to the others
•Avoid combination of NSAIDs
–No clinical benefits of combinations
–Synergistic adverse effects
•COX-2 inhibitors should be used at lowest possible dose for the
shortest possible period.
90

91. Salicylates
•Salicylic acid is so irritating
–Can only be used externally
–Various derivatives were synthesized for systemic use
Pharmacological effects of therapeutic doses
•Analgesia: Salicylates
–Relieve low intensity pain of integumental structures than
from visceral tissues
•Headache, myalgia & arthralgia
–Lower pain by virtue of their peripheral action.
91

92. Pharmacological properties…cont’d
•Antipyresis
–Lower elevated body temperature rapidly & effectively
–In toxic doses, they rather cause pyresis.
•Respiration
–Increase consumption of O
2& CO
2production
•Result of uncoupling of oxidative phosphorylation
–Increased CO
2production stimulates respiration
•Increase mainly depth rather than rate of respiration.
92

93. Pharmacological properties…cont’d
•Renal effects
–Cause salt, water retention & acute renal function reduction
in patients with
•CHF
•Renal disease & hypovolemia
•CVS effects
–Low doses of aspirin (100mg daily) is cardioprotective
–At higher doses (>3g daily) given in acute rheumatic fever
•Salt & water retention, ↑ed plasma volume (up to 20%)
•Decreased haematocrit value (dilution effect)
•Increased cardiac output & work.
93

94. Pharmacological properties…cont’d
•GI effects
–epigastric distress, N, N, gastric ulceration
–Exacerbate peptic ulcer symptoms
–Cause gastrointestinal hemorrhage
–These effects mainly occur with acetylated salicylates
•Aspirin irreversibly acetylates COXs
–Non acetylated salicylates fail to acetylate COXs
•So are weaker inhibitors & cause lower side effects.
94

95. Pharmacological properties…cont’d
Hepatic effects
•Higher doses can cause hepatic injury
–Onset of injury not acute & occurs several months later
–Usually no symptoms
•Increased levels of hepatic transaminases
–Reversible upon discontinuation of medications
–Use of salicylates is C/I in patients of chronic liver disease
95

96. Pharmacological properties…cont’d
Uricosuric effects
•Effects of salicylates on uric acid excretion is dose dependent.
–Low doses (1-2g daily) may ↓se urate excretion & ↑se plasma
urate level.
–Medium doses (2-4g daily) don’t alter urate levels.
–Higher doses (>5g daily) induce uricosuria & lowers plasma urate
level.
•Paradoxical effect: can be explained by two modes of
salicylate interaction with the urate monocarboxylate
exchanger (URAT1):
–acting as an exchange substrate to facilitate urate
reabsorption at low dose, and
–acting as an inhibitor for urate reabsorption at high dose.
96

97. Pharmacological properties…cont’d
•Effects on blood
–Aspirin prolongs bleeding time
•Irreversible inhibition of platelet COX & reduced
production of TXA2
–Patients with:
•Hypoprothrmbinemia
•Vitamin K deficiency or
•Hemophilia should avoid aspirin use
–Aspirin use should be stopped one week before surgery
–Avoid concurrent use of aspirin with anticoagulants.
97

98. Pharmacological properties…cont’d
•Metabolic effects
–Salicylates uncouple oxidative phosphorylation
•Inhibition of number of ATP dependent reactions
•Increase O
2consumption & CO
2production
•Depletion of hepatic glycogen
•Salicylates & pregnancy
–No evidence of teratogenecity in humans
–When administered during 3
rd
trimester
•Increase perinatal mortality risk
•Increased risk of ante partum & postpartum hemorrhage
•Prolong gestation & complicate delivery.
–Low-dose aspirin (81 mg/day) prophylaxis is recommended in
women at high risk of preeclampsiaand should be initiated b/n 12
wks and 28 wks of gestation and continued until delivery.
98

99. Pharmacokinetics
Absorption
•Orally ingested salicylates
–Are absorbed rapidly: partly from stomach & mainly from
upper small intestine
–C
maxreached in about 1 hour
–Absorption is usually affected by
•Disintegration & dissolution of tablets
•pH of GI mucosa
•Gastric emptying time
–Absorption mainly occurs by passive diffusion
–Presence of food delays absorption.
99

100. Pharmacokinetics cont’d
•Distribution: Salicylates
–Well distributed to most body tissues.
–Cross placental barrier
–80-90% bound to plasma proteins, mainly to albumin
–Compete with variety of compounds for plasma proteins
•T3, T4, penicillin, phenytoin, bilirubin, uric acid, warfarin
etc.
–Aspirin can be detected in plasma only for short time
•Result of hydrolysis in plasma, liver & erythrocytes.
100

101. Pharmacokinetics cont’d
•Biotransformation & excretion
–Takes place in many tissues
•Particularly in hepatic ER & mitochondria
•aspirin is hydrolyzed to salicylate and acetic acid by
esterases in tissues (liver) and blood
–Salicylic acid is glucuronidated, conjugated to glycine to form
salicyluric acid (the major metabolic pathway), oxidized to
gentisic acid(a minor metabolic pathway), or remains free as
salicylic acid, which is secreted in the proximal tubule of the
kidney.
–Metabolites are excreted in urine
–Excretion of free salicylates depends on urine pH.
101

102. Examples
•Aspirin (Acetyl salicylic acid) & Sodium salicylate are most
commonly used
•Salicyl salicylic acid
•Sodium thiosalicylate
•Magnesium Choline salicylate
•Diflunisal are some of the salicylates
102

103. Therapeutic uses
•Salicylates are clinically used for their:
–Antipyresis
–Analgesia
–Rheumatoid arthritis
–Inflammatory bowl disease
•Mesalamine(5-aminosalicylic acid, 5-ASA) is mainly used
–Orally inactive, because
»Poorly absorbed
»Inactivated in stomach
–So given as rectal suppository
103

104. Salicylate intoxication
•Often occurs in children & is sometimes fatal
•Fatal dose varies with the preparation of salicylates
–10-30g of aspirin leads to death
–4.7g of methyl salicylate may be fatal in children
•Salicylism: refers to mildchronic salicylic toxicity
–Syndromes includes: headache, dizziness, tinnitus, nausea
difficulty in hearing, blurred vision, sweating, thirst etc
–On high doses salicylates have toxic effects to CNS
–Uncoupling of oxidative phosphorylation leads to high heat
production causing hyperthermia.
104

105. Salicylate intoxication cont…
•Hypernatremia, dehydration, depletion of K
+
also occurs
during salicylate intoxication in children.
•When large doses of salicylate are administered, severe
salicylate intoxication may result.
–The symptoms listed above are followed by restlessness,
delirium, hallucinations, convulsions, coma, respiratory
and metabolic acidosis, and deathfrom respiratory failure.
105

106. Detoxification of intoxication
•Activated charcoal:
–Used to prevent further absorption of the drug from GIT
•NaHCO3:
–Used to make the urine more alkaline & increase excretion
•Hemodialysis:
–Used if the above methods are inadequate or if plasma
salicylate concentration is >1000μg/ml
•Plasma salicylate, glucose, pH & K
+
levels should be
monitored frequently during therapy.
106

107. Para-aminophenol derivatives
•Acetaminophen
–Is active metabolite of Phenacetin
•Due to analgesic nephropathy, hemolytic anemia & bladder
cancer phenacetin is no longer used clinically.
–Is effective alternative for its analgesic & antipyretic activity
but is weaker anti-inflammatory agent.
•Indicated for pain relief in patients with non-inflammatory
osteoarthritis.
•But not used for chronic inflammatory conditions
–E.g. Rheumatoid arthritis.
–Well tolerated & has reduced GI SEs than NSAIDs
–OTC drug, acute over dosage can cause hepatic injury.
107

108. Pharmacological properties
Analgesic & antipyretic activity comparable to NSAIDs
But very weak anti-inflammatory activity
Poor ability to inhibit COXs
Daily dose (1g) results in roughly 50% inhibition of COX
1 & 2
MOA
Suggested to COX inhibition might be disproportionately
pronounced in the brain.
108

109. Pharmacological properties cont’d
•Single or repeated therapeutic doses of acetaminophen
–No effect on CVS
–No effect on respiratory system
–No effect on platelets or coagulation process
–Not cause acid-base changes, no uricosuric effect
–No or very little GI effects.
109

110. Pharmacokinetics & metabolism
•Oral acetaminophen:
–Has excellent bioavailability
–C
maxreaches within 30-60 minutes, t
1/2is about 2 hours
–Uniformly distributed throughout most body fluids.
–Less binding to plasma proteins than NSAIDs
–Metabolized in the liver
•Gucuronidation (60 %)
•Sulfation (35 %)
•CYP mediated N-hydroxylation (small amount).
110

111. Therapeutic uses
•Acetaminophen:
–Is suitable substitute for aspirin for analgesic & antipyretic
uses in aspirin intolerable patients.
–Particularly suitable for patients in whom aspirin is C/I
•Peptic ulcer disease
•Aspirin hypersensitivity
•Children with febrile illness.
–Conventional oral dose is 325-1000mg/daily
–Total daily dose should not exceed 4g
–No more than 5 doses should be administered in 24 hours.
111

112. Toxicity & common side effects
•Acetaminophen:
–Is well tolerated at recommended therapeutic doses
–Rash & other allergic reactions occur occasionally
–Can rarely cause neutropenia, thrombocytopenia
–Most serious SE of over dosage is fatal hepatic necrosis.
–Renal tubular necrosis & hypoglycemic coma may also
occur.
112

113. Hepatotoxicity
•When overdosed the glucuronide & sulfate conjugation pathway
becomes saturated.
–Excess drug is metabolized by CYP & produce N-acetyl-P-
benzoquinoneimine(NAPQI)
–NAPQI
•Is highly reactive intermediate
•In normal doses, reduced by glutathione (GSH) & made
harmless
•In large doses, it depletes hepatic GSH & the remaining
metabolite is involved in damaging hepatic cells.
•Different conditions increase susceptibility to hepatotoxicity
–CYP induction (heavy alcohol consumption)
–GSH depletion (fasting or malnutrition)
113

114. Hepatotoxicity cont’d
•Early symptoms (2 days of
acute poisoning) of hepatic
damage include
–N,V, abdominal pain etc
•Plasma transaminase levels
increase 12-36 hrs after
ingestion.
•Hepatic damage symptoms are
manifested within 2-4 days
–Tender hepatomegally,
jaundice & coagulopathy
114

115. Management of toxicity
•Acetaminophen overdose
–Is a medical emergency
–Cause severe liver damage in 90% of the cases.
•Early diagnosis & treatment is essential
•Activated charcoal:
–If given within 4hrs of ingestion, it decreases acetaminophen
absorption by 50-90% & is preferred method.
•Gastric lavage:
–Is not recommended
115

116. Management of toxicity cont’d
•N-acetyl cysteine (NAC):
–Is the antidote for acetaminophen overdose
–Works by detoxifying NAPQI
•Repletes GSH stores
•Conjugates directly with NAPQI by serving as GSH
substitute.
–Can be administered with activated charcoal
•Since absorption of NAC is not affected
•Supportive care:
–Indicated when necessary
•Intubation, glucose provision etc
116

117. Acetic acid derivatives
•Include: Indomethacin, Sulindac & Etodolac
•Indomethacin
–Prominent antipyretic, analgesic & anti-inflammatory.
–More inhibitor of COXs than aspirin
•Patient intolerance limits its use to short term use.
–Evidence of both peripheral & central effects.
–Also has direct COX-independent vasoconstrictoreffect.
117

118. Indomethacin cont’d
Pharmacokinetics
•Oral indomethacin:
–Has excellent bioavailability
–C
maxreaches within 1-2hrs of dosing
–90% bound to plasma proteins & tissues
–10-20% excreted unchanged in urine.
–Majority converted to inactive metabolites.
•Glucuronidation, O-demethylation& N-deacylation
–Free drug & metabolites are eliminated in urine, bile & faces
–There is enterohepatic cycling of conjugates
•t
1/2is variable (averages about 2.5 hours)
118

119. Indomethacin cont’d
Drug interactions
–Does not interfere with uricosuric effect of Probenecid.
–Does not directly modify activity of warfarin
•Act by platelet inhibition
•Gastric ulceration increases risk of bleeding.
–Antagonizes natriuretic & antihypertensive effects of
furosemide & thiazide diuretics
–Blunts antihypertensive effects of β-blockers, ARBs,
ACEIs.
119

120. Indomethacin cont’d
•Therapeutic uses
–High rate of intolerance limits its long term use.
–used when the pain or fever is refractory to other NSAIDs
–Indomethacin is effective for
•Relieving joint pain, swelling & tenderness
•C/Is
–Renal failure, peptic ulcer, thrombocytopenia &
hyperbilirubinemia
•Adverse effects
–Are dose dependent, GI complications, neutropenia,
thrombocytopenia, CNS effects.
120

121. Phenyl acetic acid derivatives
•Diclofenacis the prototype drug & the most widely used NSAID.
•Exhibits approximately equal selectivity for both COX 1 & 2
•Pharmacological properties of Diclofenac:
–Has analgesic, antipyretic & anti-inflammatory activity
–Has rapid absorption, short t
1/2, high first pass effect
–Extensively bound to plasma proteins
–Accumulates in Synovial fluid after oral administration
•Explains why therapeutic effect is longer than plasma t
1/2
–Metabolized in the liver by CYP2C
•4-hydroxy diclofenac is major metabolite, excreted in
urine(65%) & bile (35%).
121

122. Phenyl acetic acid derivatives cont’d
•Diclofenac is approved for the long term treatment of
–Rheumatoid arthritis, osteoarthritis, Ankylosing spondylitis.
•also used for short term treatment of
–Acute musculoskeletal & post operative pain, dysmenorrhea
•It is also available in combination with Misoprostol
–Retains diclofenac efficacy with reduced GI adverse effects
•Adverse effects
–GI side effects (20%)
–Modest reversible elevation of hepatic transaminases (5-
15%)
–CNS side effects, rashes, fluid & salt retention, rare renal
impairment.
122

123. Phenyl acetic acid derivatives cont’d
•Transaminase levels should be measured during the 1
st
8 wks of
therapy with diclofenac.
–Drug should be discontinued if:
•Abnormal values of transaminases persist
•Other signs of hepatic symptoms develop
•Diclofenac is not recommended for
–Children
–Nursing mother
–Pregnant women
123

124. Propionic acid derivatives
•Include: Ibuprofen, naproxen, flurbiprofen, fenoprofen,
ketoprofen & oxaprozin
•Are comparable in efficacy with aspirin in the control of
rheumatoid & osteoarthritis.
•Are all non selective inhibitors of the COXs
•Have considerable variation in their potency of COX inhibition
•Interfere with the actions of antihypertensive & diuretic drugs
•Increase risk of bleeding when given with warfarin
•Also shown to cause bone marrow suppression when given with
methotrexate.
124

125. Propionic acid derivatives cont’d
Ibuprofen
•Available OTC as 200-800 dose tablets
•Orally well absorbed, avidly bind to plasma proteins
•Metabolized in liver & excreted in urine, t
1/2about 2 hours
•Better tolerated than aspirin & indomethacin
–Used in pts with history of GI intolerance to other NSAIDs
•Associated with less frequent adverse effects
–GI side effects (5-15%)
–Thrombocytopenia, rashes, fluid & salt retention, blurred vision
•Patients who develop ocular disturbances should discontinue.
•Can occasionally, be used by pregnant women
–But concerns apply regarding 3
rd
trimester effects
•Can be used with caution by breast feeding women
–Excretion into breast milk is thought to be minimal
125

126. Enolic acid derivatives (oxicams)
•Are derivatives of enolic acid w/h inhibit both COXs
•Include: piroxicam, meloxicam, ampiroxicam
•Have analgesic, antipyretic & anti-inflammatory effects
•Are non selective COX inhibitors
–Meloxicam shows modest selectivity to COX2
•Are comparable in efficacy to aspirin, indomethacin or
ibuprofen
–For long treatment of rheumatoid arthritis & osteoarthritis
•Main advantage of the group
–Their long t
1/2allows once daily dose.
126

127. Enolic acid derivatives (oxicams), cont’d
•Piroxicam
–Is effective as anti-inflammatory agent
–Can inhibit activation of neutrophills independent of COX
inhibition.
–Additional modes of anti-inflammatory activity
•Inhibition of proteoglycanase& collagenase
–Is absorbed completely after oral administration &
•Undergoes enterohepatic recirculation, t
1/2is about 50
hours.
•C
maxobtained 2-4 hours, extensive binding to plasma
proteins.
•Mainly metabolized in the liver by CYP2C9.
127

128. Enolic acid derivatives (oxicams), cont’d
•Piroxicam
–Used in the treatment of rheumatoid & osteoarthritis
–Is less suited for acute analgesia
•Due to slow onset of action
–Given with a daily dose of 20mg
–Caution should be taken with patients taking Lithium
•Piroxicam can reduce renal excretion of Lithium.
128

129. COX2 selective NSAIDs
•This group of drugs inhibit COX2 selectively
•Include: celecoxib, valdecoxib, rofecoxib, lumiracoxib.
Pharmacokinetics:
•Well absorbed & are extensively bound to plasma proteins
•Widely distributed throughout the body
•Achieve sufficient brain concentration & have central analgesic
effect.
•Do not pharmacodynamically affect warfarin activity
–But both rofecoxib & valdecoxib may influence disposition of
warfarin & amplify risk of bleeding.
•Coxibs can limit effectiveness of several antihypertensives.
129

130. COX2 selective NSAIDs cont’d
•Clinical uses of coxibs:
–Approved for clinical use based on lowered GI SE profile
–Useful to afford relief from pain:
•After dental extraction
•Inflammatory osteoarthritis
•Rheumatoid arthritis
–The use of coxibs should be avoided in pts with cardiovascular
or Cerebrovascular disorders.
–As a result of potential CVS hazards coxibs should be used in
the lowest possible dose for the shortest period.
130

131. COX2 selective NSAIDs cont’d
•Celecoxib
–Well absorbed, C
maxwith in 2-4 hours, t
1/2about 11 hours
–Extensively bound to plasma proteins
–Metabolites are excreted in urine & faces
–Given once or twice a day (100-200mg)
–Mainly metabolized by CYP2D6 & CYP2C9
–Inhibits metabolism of
•Metoprolol, SSRIs, TCAs, antiarrhythmic drugs
–Associated with reduction of the effects of antihypertensives &
diuretics.
–approved in the treatment of osteoarthritis & rheumatoid arthritis.
•Rofecoxib and Valdecoxib,
–higher incidence of cardiovascular thrombotic events
–withdrawn from the market.
131

132. Drugs used in Gout
132

133. Pathophysiology of gout
•The term gout describes the different pathological conditions
usually associated with elevated serum uric acid (≥6.8 mg/dL).
–Recurrent attacks of acute arthritis
–Deposition of monosodium urate crystals in tissues (tophi)
–Uric acid nephrolithiasis
•In humans
–UA is the end product of degradation of purines
–UA serves no known physiologic purpose (byproduct)
•Hyperuricemia may be result of
–Excessive UA production
–Lower rate of excretion
133

134. Pathophysiology, cont’d
•Acute attacks of gouty arthritis are characterized by;
–Rapid onset of excruciating pain
–Swelling & inflammatory pain
•The attack:
–Usually starts with the great toe
–And then affects insteps, ankles, heels, knees, wrists, fingers
& elbows.
•There is a predilection of acute gout for peripheral joints of
lower extremity.
–Lower temperature of these joints
–High intra-articular UA concentration.
134

135. Pathophysiology,cont’d
•Development of crystal induced inflammation involves a number
of chemical mediators causing,
–Vasodilatation
–Increased vascular permeability
–Increased chemotactic activity
•Leukocytes Phagocytose urate crystals
–Results in rapid lyses of these cells
•Discharge of proteolytic enzymes
–Further exacerbation of the inflammatory process
•Associated with intense pain, erythema, warmth & swelling.
•Untreated gouty attacks may last from 3-14 days before
spontaneous recovery.
135

136. •figure
136

137. Gout: pathophysiology
Foodintake Cell breakdown
Purines
Uricacid
HYPERURICAEMIA
Kidney Soft tissue of
the joints
Other tissue
Ear
Overproduction Underexcretion
137

138. Risk Factors
•Male
•Postmenopausal female
•Age (Older)
•Hypertension
•Drugs: Diuretics, ASA, cyclosporine
•Alcohol intake:
–Highest with beer
–Not increased with wine
•High BMI (obesity)
•Diet high in meat & seafood.
138

139. Chemistry of Uric Acid
•Humans excrete approximately 0.7 g uric acid daily.
•Most UA is derived from the metabolic breakdown of the
purine bases adenine and guanine.
•It exists mostly as the monovalent salt sodium urate.
•Synovial fluid is a poorer solventfor monosodium urate
than plasma.
•With hyperuricemia the urates in the joint fluid become
supersaturated, particularly in the peripheral joints.
139

140. Treatment of gout
•Goal of treatment
–Decrease symptoms of acute attacks
–Decrease the risk of recurrent attacks
–Lower serum urate levels
•Treatment of acute gout
–NSAIDs, corticosteroids, or colchicine are first-line drugs for
acute gout.
i. NSAIDs
Several NSAIDs are effective in the treatment of acute gout
Be given at relatively high doses for 3-4 days & then tapered for a
total of 7-10 days.
Ibuprofen, Indomethacin, Sulindac, naproxen, celecoxib are effective
Aspirin not used in treatment of gout (causes renal retention of UA at
low doses (≤2.6 g/d)
140

141. Treatment of gout, cont’d
ii. Glucocorticoids
Sometimes used for severe symptomatic gout, by intra-articular,
systemic, or Sc. routes, depending on the degree of pain and
inflammation.
Most commonly used oral corticosteroid is prednisone (orally 30–
50 mg/d for 1–2 days, tapered over 7–10 days).
Intra-articular inj. of 10 mg (small joints), 30 mg (wrist, ankle,
elbow), & 40 mg (knee) of triamcinolone acetonide can be given
if ptis unable to take oral medications.
iii. Colchicine
Is also used in treatment of acute gout
Prevention of recurrent attacks
Recurrent attacks of gout can be prevented with use of:
Colchicine, NSAIDs, Allopurinol, Uricosuric agents, Pegloticase.
141

142. Treatment of gout, cont’d
Colchicine
•One of the oldest available therapies for acute gout
•Relieves pain & inflammation of gouty arthritis in 12–24 hours
without altering metabolism or excretion of urates and without other
analgesic effects.
•Narrow therapeutic index
•High rate of side effects at higher doses
•MOA:produces its anti-inflammatory effects by binding to the
intracellular protein tubulin, thereby preventing its polymerization
into microtubules and leading to the inhibition of leukocyte migration
and phagocytosis.
•It also inhibits the formation of leukotriene B4 and IL-1β.
•Several of colchicine’s adverse effects are produced by its inhibition
of tubulin polymerization and cell mitosis.
142

143. Treatment of gout, cont’d
Colchicine
•Antimitotic effects
–Interfere with microtubule & spindle formation
–Arrest cells at G1 phase
•Effect more pronounced in cells with rapid turnover:
neutrophils, GI cells.
•Pharmacokinetics
–Rapid but variable absorption
–About 50% bound to plasma proteins.
–Significant enterohepatic recirculation
•t
1/2about 9 hours but can be detected up to 9 days after single
iv dose.
–Metabolites (CYP3A4), excreted in urine & faces.
143

144. Treatment of gout, cont’d
Colchicine
•Therapeutic uses
–in the treatment of acute gout
–Administered orally in hourly doses of …….
•0.5 to 0.6mg until pain and inflammation have resolved
or
•until GI side effects prevent further use.
•Max dose ………6mg/24hr
•prevention of recurrent attacks of gout.
144

145. Treatment of gout,cont’d
145

146. Treatment of gout, cont’d
Allopurinol
•Purine analog
•MOA
–Inhibits xanthine oxidase & prevent synthesis of UA from
hypoxanthine & xanthine.
–Both allopurinol & its active metabolite (oxypurinol) inhibit
xanthine oxidase.
–Allopurinol facilitates dissolution of tophi & prevent
progression of chronic gouty arthritis by lowering UA
concentration.
146

147. Drugs used in chronic gout (antihyperuricemic
drugs) : sites of action
Purines
Hypoxanthine
Xanthine
Uric acid
Xanthine
oxidase
Xanthine
oxidase
PROBENECID
SULFINPYRAZONE
-
OXYPURINOL
-
-
Overproducers:
Allopurinol
Underexcretors:
Probenecid
Sulfinpyrazone
ALLOPURINOL
-
1.Why is allopurinol
administered once daily
although its half-life is only
1-2 hours?
147

148. Treatment of gout, cont’d
Allopurinol: Pharmacokinetics
Rapid absorption from oral administration
C
maxreaches within 60-90 minutes
Distributed to TBW, not bound to plasma protein
Like uric acid, allopurinol is metabolized by xanthine oxidase,
Excreted
Unchanged drug in urine (10-30%), unabsorbed drug in faces
(20%)
The remainder undergoes metabolism to alloxanthine (oxypurinol)
Active metabolite (inhibits xanthine oxidase) & slowly excreted
in the urine
T
1/2of allopurinol is 1-2 hours & oxypurinol is 18-30 hours
Allows once daily dosing of allopurinol
Makes it first-line agent for the treatment of chronic gout.
148

149. Treatment of gout, cont’d
Allopurinol: Drug interactions
•Increases t
1/2of Probenecid (inhibit metabolism)
–enhances uricosuric effect.
•Probenecid increases excretion of oxypurinol,
–need dose adjustment of allopurinol
•Inhibits metabolism of antineoplastic agents
–Mercaptopurine & azathioprine
–By inhibiting xanthine oxidase
–Dosage must be reduced by about 75%.
–Also interferes with hepatic inactivation of other drugs
•E.g. warfarin (inhibit CYP1A2, CYP3A4)
149

150. Treatment of gout, cont’d
Allopurinol: Therapeutic uses
•often the first-line agent for chronic gout in the period b/n attacks
& it tends to prolong the intercritical period.
•Colchicine or NSAID should be used untilsteady-state serum UA
is normalized or ↓ed to < 6 mg/dL, to avoid gout flares.
•Dosing
–Initial: 100mg/day, Increased by 100mg weekly (Max.
600mg/day)
–Most patients maintained at 300mg/day
•Adverse effects
–Well tolerated by most patients,
–Most common ADR is hypersensitivityreaction.
–Patients who develop rash should discontinue allopurinol.
150

151. Treatment of gout,cont’d
Febuxostat
•a non-purine, potent & selective xanthine oxidase inhibitor
•Reduce formation of xanthine and UA.
•>80% absorbed orally, t
1/25–8 hours,
•Extensively metabolized in the liver (95%).
•approved for chronic hyperuricemia in gout pts.
•Adverse Effects:
–Most frequent: liver function abnormalities, D, N, headache.
–prophylactic treatment with colchicine or NSAIDs should be
started at the beginning of therapy to avoid gout flares.
–well tolerated in pts with a history of allopurinol intolerance.
151

152. Treatment of gout, cont’d
Uricosuric agents
•Increase the rate of excretion of uric acid
•In humans UA is filtered, secreted & reabsorbed
•Reabsorption predominates
–10% of filtered UA is excreted.
•Reabsorption is mediated by specific transporter
–Transporter could be inhibited.
•Uricosuric drugs competewith UA for the transporter
–Inhibit UA secretion at lower doses.
–Inhibit its reabsorption at higher doses.
152

153. Treatment of gout, cont’d
•Probenecid
–MOA: works by inhibiting inorganic acid transporter
(reabsorption) & thereby increase UA excretion.
•Pharmacokinetics
–Complete absorption after oral dosing
–C
maxreaches within 2-4 hours
–Up to 95% plasma protein binding (albumin)
–Majority of the drug is secreted actively by PCT
•Highly lipid soluble & is reabsorbed.
–metabolized slowly with a terminal serum half-life of 5–8 hrs.
153

154. Treatment of gout, cont’d
Therapeutic uses of Probenecid
•Gout
–Orally; starting dose of 250mg bid
•Increasing within 1-2 weeks to 500-1000mg bid
–Increases urinary UA levels
•Adequate fluid intake should be maintained throughout
therapy to minimize risk of renal stones
–Should not be used in gouty patients with nephrolithiasis
•Not effective in the treatment of acute gout attacks;
–does not eliminate the need to use colchicine or NSAIDs to
relieve an attack.
154

155. Treatment of gout, cont’d
•Adverse drug reactions
–Probenecid is well tolerated
–2% of patients develop GI irritations
•Risk increases with increased doses
–Caution be taken in patients with PUD
–Mild hypersensitivity reactions can occur(2-4%)
–Substantial overdosage of Probenecid results in:
•CNS stimulation
•Convulsions
•Respiratory failure & death
155

156. Treatment of gout, cont’d
•Sulfinpyrazone
–MOA: inhibits renal tubular reabsorption of UA
•Pharmacokinetics
–Well absorbed after oral administration
–Strongly bound to plasma albumin (98-99%)
–T
1/2up to 3 hours
–Mostly excreted in urine as unchanged drug.
156

157. Treatment of gout, cont’d
Therapeutic uses of Sulfinpyrazone
•Chronic gout
–Initial dose 100-200mg bid, ↑ed until UA levels decrease
•200-400mg per day in divided doses
–Adequate fluid intake should be taken
•Ineffective in patients with renal insufficiency
Adverse drug reactions
–GIT irritations (10-20%)
•Reduced when the drug is administered with meals
–Less frequent hypersensitivity reactions can occur
–Depression of haematopoiesis can occur rarely
157

158. Treatment of gout,cont’d
Pegloticase
•Uricase, An enzyme that catalyses oxidation ofuric acidto 5-
hydroxyisourate & H
2O
2,
–Subsequent hydrolysis & decarboxylation forms allantoin (5-
10X more H
2O soluble than UA)as the end product ofpurine
metabolism in most prokaryotic and eukaryotic organisms.
•Humans and some primates are lacking activeuricase.
•Pegloticase is a recombinant mammalian uricase that is covalently
attached to methoxy polyethylene glycol (mPEG) to prolong the
circulating t
1/2& diminish immunogenic response.
•approved for the treatment of refractory chronic gout.
•8 mg every 2 weeks, IV infusion.
•rapidly acting drug, serum t
1/2ranges from 6 to 14 days.
158

159. Treatment of gout,cont’d
Pegloticase
•Adverse effects:
–Gout flare (give prophylaxis with NSAIDs or colchicine)
–Immune responses, presence of antipegloticase antibodies is
associated with ↓t
1/2, loss of response.
–Anaphylaxis occurs in > 6–15% of pts receiving pegloticase.
–Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, N
–Concern for hemolytic anemia in pts with glucose-6-phosphate
dehydrogenase deficiency
•b/c of formation of H
2O
2by uricase; avoid in these pts.
159

160. 160

161. Non-Pharmacologic Treatments
•Immobilization of Joint
•Use of Ice Packs
•Abstinence of Alcohol
•Consumption can increase serum uratelevels by increasing uric acid
production. When used in excess it can be converted to lactic acid which
inhibits uric acid excretion in the kidney
•Dietary modification
–Low carbohydrates
–↑protein and unsaturated fats
–↓dietary purine-meat and seafood.
–Dairy and vegetables ……..

162. 162

163. 163

165. STG-Ethiopia
165