Autacoids and Related drugs

Zebenay B. (B. Pharm, MSc in Pharmacology)

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 Autacoids
• Autos; self, akos; remedy – autacoids (Greek, – self remedy)

• Considered as local hormones

 Act at the site of synthesis or release [autocrine/paracrine]

• Produced by several cells in the body, but short duration of action

• Myriad biologic effects

 Mayact as hormones, NT, inflam. mediators, immunologic

modulators etc
 Usually involved in a response to injury or inflammation
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 Autacoids…
• Amine autacoids: Histamine, 5-HT(Serotonin)

• Lipid derived: PGs, LTs, TXA2

• Peptide autacoids: Kinins (Bradykinin,Kallidin), gastrin…

• Cytokines: Interleukins, TNF-, GM-CSF etc.

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 Autacoids

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 Histamine and its antagonists
• Histamine is basic amine produced from L-histidine by histidine
decarboxylase

• Mast cells are the predominant storage site in most tissues

• Large number of mast cells in skin, bronchial mucosa, GIT mucosa

• Effects of histamine

 Important mediator of allergic (immediate hypersens.) rxns

 Stimulate gastric acid secretion
 Functions as a neurotransmitter and neuromodulator

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 Histamine and its antagonists…
 Cells for histamine storage and release
• Mast cell : Chief cellular site of histamine storage (in the blood,
the basophil)
• Non-mast cells:
o Enterochromaffin-like (ECL) cells
 Cells in the fundus of the stomach
 Stimulate acid secretion
o Histaminergic neurons in the brain
 Functions as a neurotransmitter
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 Histamine and its antagonists…
 Mechanisms of histamine release from storage cells

 Immunologic release

• Triggered by antigen-antibody [IgE, IgG, IgM] interaction

 Degranulation of mast cells and basophils

 Non-immunoligic release

• Triggered by drugs (morphine, tubocurarine, succinylcholine,

amphotericin B), peptides, venoms, thermal, radiation energy...
• Agents that increase cAMP(e.g. β2-adrenoceptor agonists,
Histamine;H2) inhibit release
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 Histamine and its antagonists…
 Termination of Histamine Action

 Metabolism (enzymatic metabolism of the amine)

 Diamine oxidase(histaminase) (tissues and blood)

 Imidazole N-methyltransferase (tissues)

 Cellular uptake

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 Histamine and its antagonists…
Histamine Receptors [all are GPCRs]

Receptor Location Signaling

subtype mechanism
H1 Smooth muscle, endothelium, brain  IP3, DAG

H2 Gastric mucosa, cardiac muscle,  cAMP

mast cells, brain
H3 Presynaptic: brain, myenteric  cAMP
plexus
H4 Eosinophils, neutrophils, T cells…  cAMP

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 Physiologic roles of histamine
Nervous System
• H1 receptor is densely found in hypothalamus

 Affect wakefulness (many antihistamines cause drowsiness)

• H 1 & H 3 receptors play important roles in appetite and satiety

 Antipsychotics that block these receptors cause weight gain

• Presynaptic H3 serve as feedback inhibitor of the release of NTs

 Histamine, NE, 5-HT, Ach, dopamine

• H1-Rs on sensory nerve endings mediate itch and pain

• Play a role in nociception in the CNS

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 Physiologic roles of histamine…
Blood vessels
• Dilates blood vessels (H1, and H2 receptors at higher dose)
•  Capillary permeability ( role in edema formation)-H1
Heart
•  HR and force of contraction (H2 receptors)
Smooth Muscle; contraction (H1)
• Bronchial and intestinal smooth muscle

• Uterine smooth muscle ( may cause abortion in pregnant

women suffering from anaphylactic reactions)

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 Physiologic roles of histamine…
Secretory tissue
• Stimulate gastric acid secretion and, to a lesser extent, pepsin

and intrinsic factor

Inflammatory reaction
• The “triple response”
 Intradermal injection of histamine
 Causes a characteristic red spot, edema & flare response

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 Pathophysiological roles of histamine
The main pathophysiological roles of histamine:
• Acid-peptic disease

 Stimulate gastric acid secretion (H2)

 H2 blockers are used for PUD

• Hypersensitivity rxn

 Mediate type I hypersensitivity reactions such as urticaria

and hay fever (H1-Rs)

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 Clinical use of histamine
• Diagnosis of bronchial hyperreactivity

 Histamine aerosol
• As a positive control injection for allergy skin testing.
• ADR: Flushing, hypotension, tachycardia, headache, wheals,
bronchoconstriction, and GI upset

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 Histamine antagonists
 The effects of histamine can be blocked by:

Physiologic antagonism

• Adrenaline has opposite action on smooth muscles

 Release inhibitors: reduce the degranulation of mast

cells

• Cromolyn, nedocromil, and 2-AR agonists

15 Histamine receptor antagonists

 First generation antihistamines
drugs Antimusc comment
activity
Diphenhydramine +++ Marked sedation, anti-motion sickness activity
Dimenhydrinate +++ Marked sedation, anti-motion sickness activity

promethazine +++ Marked sedation, anti-motion sickness activity,

- blocking effect
Chlorpheniramine + Slight sedation, common component of OTC
cold medication
Cyproheptadine + Moderate sedation, antiserotonin activity
Hydroxyzine Marked sedation
Meclizine - Slight sedation, anti-motion sickness activity
Cyclizine - Slight sedation, anti-motion sickness activity
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 First generation antihistamines…
 Selectively block the effect of histamine on H1 receptors

 Some affect cholinergic, adrenergic and serotonergic receptors

 Well absorbed from the GI tract following oral administration

 Distribute through out the body

 Can distribute in to the CNS

• Known to cause significant sedation: those having prominent

sedation are used as ‘sleep aid’ agents
• Children occasionally (and adults rarely) manifest excitation
rather than sedation
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 First generation antihistamines…
Adverse effects
• Sedation, diminished alertness & concentration, light
headedness, motor incoordination, fatigue, dry mouth, blurred
vision, urinary retention
• Allergic reactions

• Convulsions, hallucinations, excitement, ataxia, incoordination,

athetosis
 Acute intoxication syndromes

Managed by centrally acting muscarinic agonists

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 Second generation antihistamines
 Cetirizine, levocetirizine, loratadine, desloratadine, azelastine,

fexofenadine

• Rapidly absorbed after oral administration

• Widely distributed throughout the body

• Can not appreciably distribute in to the CNS

 Considerably less lipid soluble than the first-generation

 Substrates of the P-glycoprotein transporter in the

BBB

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 Second generation antihistamines…
• Several of the second-generation agents are metabolized by

the CYP3A4 system

• Active metabolites of hydroxyzine, terfenadine, & loratadine

are cetirizine, fexofenadine, & desloratadine, resp.

• Overdosage of astemizole or terfenadine may induce cardiac

arrhythmias - block the cardiac K+ channels - prolong the

QT interval

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 Therapeutic uses of antihistamines
Allergic reactions

• Allergic rhinitis, urticaria, conjunctivitis, atopic dermatitis

 Used to prevent or treat the symptoms of allergic reactions

• 1st & 2nd generation drugs have about equal efficacy

 Motion sickness and vestibular disturbances

• Scopolamine and certain first-generation H1 antagonists are the most

effective agents available for the prevention of motion sickness

 Diphenhydramine, promethazine, dimenhydrinate, cyclizine and

meclizine
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 Therapeutic uses of antihistamines…
Extrapyramidal symptoms

• Diphenhydramine is parenterally administered for acute

dystonic rxn to antipsychotics

Sleep aids

• Promethazine, diphenhydramine, hydroxyzine

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 Therapeutic uses of antihistamines…
Local anesthesia

• Several 1st-gener. H1 antagonists are potent local anesthetics

 Block Na+ channels in excitable membranes in the same

fashion as procaine and lidocaine

• Diphenhydramine and promethazine are actually more potent

than procaine as local anesthetics

• Occasionally used to produce local anesthesia in patients allergic

to conventional local anesthetic drugs

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 Eicosanoids
• The principal eicosanoids are PGs, TXA2 and LTs

• Oxygenation products of polyunsaturated long-chain fatty acids

• The main precursor is arachidonic acid

 Generated de novo from membrane phospholipids

• Widely distributed in animals and plants

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 Eicosanoids…

FIG: Pathways of arachidonic acid (AA) release and metabolism

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 Cyclooxygenase (COX) pathway
 There are two distinct COX isoforms, COX-1 and COX-2

 COX-1

• Constitutive enzyme (always present and active) in most cells

• Generates prostanoids for “housekeeping” such as gastric

epithelial cytoprotection

• Inhibition of GI COX-1 is responsible for NSAIDs induced ulcer

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 Cyclooxygenase (COX) pathway…
 COX-2

• Inducible: its expression varies depending on the stimulus

 Markedly up-regulated by shear stress, growth factors,

tumor promoters, and cytokines

• Source of prostanoids in inflammation and cancer

• Renal COX-2-derived prostanoids are important for normal

renal development and maintenance of function

• Endothelial COX-2 is the primary source of vascular PGI2

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The COX pathway produces prostaglandins and thromboxane

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 Lipoxygenase(LOX) pathway

Major roles: LOX containing cells

 Pathogenesis of asthma • Neutrophils
 Inflammation • Basophils
 CV disorders • Eosinophils
 Anaphylactic shock • Monocyet-Macrophages
• Dendritic cells
• Mast cells

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 Lipoxygenase pathway products

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 Prostanoids receptors

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 Pharmacological effects of prostanoids
 Vascular smooth muscle
• TXA2 is a potent vasoconstrictor, smooth muscle cell mitogen
• PGF2 is also a vasoconstrictor
• Vasodilation (PGI2, PGE2, PGD2)
Respiratory smooth muscle
• Relaxation (PGE2 and PGI2)
• Contraction ( TXA2, PGD2 and PGF2)

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 Pharmacological effects of prostanoids…
Gastrointestinal Tract

• Most PGs and TXA2 stimulate GI smooth muscle

 Longitudinal muscle contraction: PGE2 and PGF2α

 Circular muscle contraction: PGF2α(strong), but relaxes in

response to PGE2
• Adm. of either PGE 2 or PGF 2α results in colicky cramps

• Inhibit acid secretion, mucus & bicarbonate secretion:PGE2 &

PGE1
• PGEs and PGFs stimulate the movement of water and
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electrolytes into the intestinal lumen - diarrhea
 Pharmacological effects of prostanoids…
 Uterine smooth muscle
• Myometrial contraction (TXA2, PGF2, PGE2 at low conc.)
• Myometrial relaxation (PGI2, PGE2 at high conc.)

Platelets
• PGD2, and PGI2 inhibit aggregation

• TXA2, major product of platelet COX-1

 Released during platelet activation

 Platelet aggregator
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 Pharmacological effects of prostanoids…
Kidney

PGE2 and PGI2 (major products of renal cortex & medulla)

• Cause renal vasodilatation, inhibit tubular reabsorption

Increase water, Na+ and K +excretion

• PGE2 has a furosemide-like inhibitory effect on Cl-reabs.

• In contrast, TXA2 causes renal vasoconstriction

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 Pharmacological effects of prostanoids…
Kidney…
 Modulate systemic blood pressure
 Under conditions of high salt intake, there is large
production of PGE2 and PGI2   EXCRETION
 COX inhibition may cause salt-sensitive systemic HTN

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 Pharmacological effects of prostanoids…
Kidney…
 Bartter’s syndrome: autosomal recessive trait that is manifested
as hypokalemic metabolic alkalosis
 Dysfunctional mutations in Na+-K+-2Cl– co-transporter

 Dysfunctional alteration of K+ or Cl– channels that affect

the function of the co-transporter
 Dysfunction of K+ channel is associated with high PGE2

o Many of the manifestations are improved by prolonged

use of NSAIDs
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Tubule transport systems and sites of action of diuretics.
40
 Pharmacological effects of prostanoids…
 Nervous system

• PGE2, PGI2 , PGF2 body T0 (pyrogens release interleukin-1,

which in turn promotes the synthesis and release of PGE2)

• PGE2 and PGI2 are involved in the generation of pain

Sensitivity of pain receptors to other chemicals (e. g.

bradykinin)

• Inhibit the release of NE from adrenergic nerve endings

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 Pharmacological effects of prostanoids…
 Eye
• PGE and PGF derivatives lower intraocular pressure

 May be due to increased outflow of aqueous humor from

the anterior chamber via the uveoscleral path way
Inflammation

• PGE2 and PGI2 are the predominant prostanoids associated with

inflammation
Promoting blood flow in the inflamed region

o Markedly enhance edema formation and

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leukocyte infiltration
 Pharmacological effects of prostanoids…
 Cancer
• Both COX-1 & COX-2(predominant source) are sources of
oncogenic prostanoids
• PGE2 is considered the principal oncogenic prostanoid

 Facilitates tumor initiation, progression, and metastasis

through multiple biologic effects
Increase proliferation and angiogenesis

Inhibit apoptosis

Augment cellular invasiveness

43 Modulate immunosuppression
 Therapeutic uses of Prostaglandins
• Alprostadil (PGE1)

• Misoprostol (PGE1 analog)

• Dinoprostone (PGE2)

• Carboprost (PGF2 analog)

• Epoprostenol (PGI2)

• Iloprost (PGI2 analog, half-life about 30 minutes)

• Treprostinil (PGI2 analog, half-life about 4 hours)

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 Therapeutic uses of Prostaglandins…
 Obstetrics
• Dinoprostone
 Induction of abortion in the second trimester of pregnancy,
for missed abortion, for molar pregnancy
 Induction/augmentation of labor at or near term
 Softening of the cervix at term
 Preparations: vaginal insert, vaginal gel
 The plasma half-life is 2.5–5 minutes
 ADR: nausea, vomiting, diarrhea, abdominal pain
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 Therapeutic uses of Prostaglandins…
 Obstetrics…

• Misoprostol in combination with mifepristone

 Termination of early pregnancy (upto 7 weeks)

 Available for oral and intravaginal adm., but the vaginal

route has been associated with an ed incidence of sepsis

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 Therapeutic uses of Prostaglandins…
 Obstetrics…

• Carboprost tromethamine

 Induce second-trimester abortions

 To control postpartum hemorrhage

 ADR: nausea, vomiting, diarrhea, colic pain, transient

bronchospasm and elevation in body TO

 Administered IM

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 Therapeutic uses of Prostaglandins…
Gastric Cytoprotection
• Used for the prevention of ulcers that often occur during long-
term treatment with NSAIDs
Erectile dysfunction
• Alprostadil (Intracavernosal inj. or urethral suppository therapy
 Effect lasts for 1 to 3 hours
• ADR: priapism (long lasting and usually painful erection)
• Used alone or in combination with papaverine or phentolamine
• Its use is superseded largely by the use of PDE5 inhibitors
(inhibit degradation of cGMP)
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 Sildenafil, vardenafil, tadalafil
 Therapeutic uses of Prostaglandins…
 Cardiovascular
• Alprostadil
To temporarily maintain the patency of the ductus arteriosus

• Epoprostenol, iloprost, treprostinil

 Pulmonary hypertension

• Glaucoma
PGF2 derivatives are clinically used for the mgt of open-
angle glaucoma
 Latanoprost, travaprost, bimatoprost, unoprostone

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 Pharmacological effects of leukotrienes
Blood cells and inflammation

• Potent chemo-attractant for T lymphocytes, eosinophils,

monocytes, and mast cells

• Stimulate mast cells and eosinophils

Degranulation, cytokine release and oxygen radical formation

• Increase endothelial permeability

• LTs are strongly implicated in the pathogenesis of chronic infl.

diseases such as asthma and IBD

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 Pharmacological effects of leukotrienes…
 Cardiovascular system
• LTs reduce myocardial contractility and coronary blood flow
 Airways
• Potent bronchoconstrictors
• Microvascular permeability, plasma exudation, and mucus
secretion in the airways
• Involved in bronchial hyper reactivity in asthmatics
GIT
• Human colonic epithelial cells synthesize LTB4
• The colonic mucosa of pts with IBD contains substantially
large amounts of LTB4
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 Eicosanoid antagonists
 Synthesis inhibitors
 Phospholipase A2 inhibitors
• Corticosteroids
Stimulate the synthesis of inhibitor proteins like
annexins and lipocortins
Also inhibit COX-2 gene expression
 COX-inhibitors
• NSAIDs (e.g., aspirin, indomethacin, ibuprofen)
• Block both PGs and TXA2 formation
• They lead to an increased formation of leukotrienes
5-lipoxygenase inhibitor (zileuton)
• Block leukotriene synthesis
53 • Valuable for asthma treatment
 Classification

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 Eicosanoid antagonists…
 Receptor blocking

• Montelukast , zafirlukast, pranlukast

 Orally effective selective antagonists of the CysLT1 receptor

 Approved for the treatment of mild to moderate asthma

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 Serotonin (5- hydroxytryptamine)

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 Serotonin…
• Widely distributed in nature

 Found in plant (e.g. banana, pineapple, tomato) and animal

tissues, venoms, and stings

• Mediates numerous biologic function

 NT in CNS, a local hormone in GIT, and a component of

the platelet aggregation process

 potent stimulant of pain and itch sensory nerve endings

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 Serotonin…
In CNS, serotonergic neurons are involved in different

functions such as mood, sleep, appetite, T0 regulation, sexual

behavior, nociception, regulation of BP, and vomiting
Serotonin also appears to be involved in clinical conditions

such as depression, anxiety, and migraine

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 Serotonin…
Storage sites of serotonin:

• Enterochromaffin cells of the GIT

 Account for 90% of body’s total 5-HT

• Platelets

 Take serotonin in the circulation (can not synthesize)

• Serotonergic neurons of the myenteric plexus (excitatory NT)

• CNS neurons (neurotransmitter) - mediate various brain

functions
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 Serotonin receptors
• Currently, there are 14 known receptor subtypes

Four families (5-HT1, 5-HT2, 5-HT3, 5-HT4-7)

• All, except, 5-HT3, are G-protein coupled that function through

 cAMP: 5-HT1

 cAMP: 5-HT4-7

 Generating IP3/DAG (5-HT2) as second messengers

• The 5-HT3 receptor is a ligand gated cation (Na+, K+) channel

which on activation elicits fast depolarization

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 Serotonin receptors…
5-HT1 receptor

• Six subtypes (5-HT1A, B, D, E, F, P)

• All subtypes of 5-HT1 receptor inhibit adenylyl cyclase

• 5-HT1A also activates K+ channels and inhibits Ca2+ channels

• All receptors function primarily as autoreceptors in brain

 Inhibit release of 5-HT from nerve endings

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 Serotonin receptors…
• 5-HT1A mainly found in raphe nuclei and hippocampus; (plays
an inhibitory role)

 Buspirone acts as a partial agonist (Anxiolytic)

• 5-HT1B regulate dopaminergic tone in substantia nigra-basal

ganglia
• 5-HT1D receptors inhibit release of:

 Inflammatory neuropeptides from nerve endings in

cranial blood vessels
• 5-HTlB/1D cause constriction of cranial blood vessels

63  Sumatriptan is a selective 5-HT1B/1D agonist

 Serotonin receptors…
5-HT2 receptor

• Three subtypes (5HT2 A, B, C)

• Coupled to phospholipase C that generate IP3 & DAG

• 5-HT2A receptor stimulation also inhibits K+ channels

 Resulting in slow depolarization of neurons

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 Serotonin receptors…
• 5-HT2A receptor

 The most widely expressed postjunctional 5-HT receptor

 Location: Vascular and visceral smooth muscle, platelets and

cerebral cortex
 Mediates vasoconstriction, intestinal, uterine and bronchial
muscle contraction, platelet aggregation and activation of
cerebral neurones
 Ketanserin is a 5-HT2 antagonist more selective for 5-HT2A

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 Serotonin receptors
5-HT3 receptor
• Neuronal 5-HT receptor, rapidly depolarizes nerve endings

• Mediate the indirect and reflex effects of 5-HT

 Sensory nerve endings  pain, itching

 Coronary chemoreceptor reflex  bradycardia, fall in BP

 Nerve endings in GIT emetic reflex

• Area postrema and nucleus tractus solitarious in brainstem

nausea, vomiting
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 Serotonin receptors…
5HT4 receptor

• Present in enteric nervous system

 Enhance motility (prokinetic effect)

 Cisapride and renzapride are selective 5-HT4 agonists

• Located in brain

 Slow depolarization by decreasing K+ conductanance

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 Serotonin receptors…
Serotonin receptor subtypes currently recognized

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 Pharmacological effects of serotonin
 Nervous system

• 5-HT3 in the GIT and in CTZ participate in the vomiting

reflex

• 5-HT3 is a powerful activator of chemo-sensitive endings of

vagal afferent located in the coronary vascular bed

 CR reflex  Marked bradycardia and hypotension

• 5-HT4 receptor play a role in enteric nervous system function

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 Pharmacological effects of serotonin…
 Cardiovascular System

• Powerful direct vasoconstrictor (splanchnic, renal,

pulmonary, cerebral)
 Mediated through 5-HT2 receptors

• Dilation of blood vessels supplying skeletal muscle and heart

• A triphasic blood pressure response

 Initially, there is ↓HR, CO,BP(chemoreceptor response)
 Then ↑BP (due vasoconstriction)
 Again ↓BP attributed to vasodilation in vessels supplying
Sk.M.
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 Pharmacological effects of serotonin…
 Platelets
• Cause platelet aggregation by acting on 5-HT2A receptors
 GIT
• Stimulate GI smooth muscle;  tone and facilitate peristalsis
 Mediated by 5-HT2(direct) and 5-HT4 (indirect)
 Stimulation of 5-HT4 receptor of ENS  ↑Ach release 
Mediate motility enhancing/prokinetic effect
• 5-HT acting on 5HT3 on vagal afferent nerve ending in the gut
stimulate emesis
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 Serotonin agonists
 Buspirone

• 5-HT1A partial agonist

• Clinically used as anxiolytics

• ADR: Nonspecific chest pain, tachycardia, palpitations,

dizziness, tinnitus, nervousness, GI distress, paresthesia, and

dose dependent pupillary constriction

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 Serotonin agonists…
 Sumatriptan, zolmitriptan, naratriptan, rizatriptan…

• Selective agonists for 5-HT1D and 5-HT1B receptor

• Vasoconstriction in cerebral and meningeal vessels

• Effective in the treatment of acute migraine

• ADR: altered sensations (tingling, warmth, etc), dizziness,

muscle weakness, neck pain, chest discomfort/pain

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 Serotonin antagonists
 Cyproheptadine

• Has potent H1 and 5-HT2 (5-HT2A) blocking actions

• Prevents the smooth muscle effects of both amines

• Has significant antimuscarinic effects, and causes sedation

• Clinical use

 Cold-induced urticaria

 Intestinal hypermotility of carcinoid tumor

 Postgastrectomy dumping syndrome (rapid gastric

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emptying)
 Serotonin antagonists…
 Ketanserin

• Potently blocks 5-HT2A receptors of smooth muscle and other

tissues

• Inhibits 5-HT-induced platelet aggregation

• Ketanserin also potently blocks vascular 1- adrenoceptors

• Used for the treatment of HTN and vasospastic conditions

 Ritanserin

• 5-HT2 antagonist, has little or no α-blocking

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 Serotonin antagonists…
 Ondansetron , granisetron, tropisetron, dolasetron

• 5-HT3 antagonist

• Used in prevention of nausea and vomiting associated with

surgery and cancer chemotherapy

78
 Kinins
• Potent vasodilator peptides

• Kininogens are precursors of kinins

 LMW kininogen (80- 85%)
Source of both plasma and tissue kinins
79  HMW kininogen(15-20%)
 Kinins
• Kallikreins/kininogenases are enzymes that generate kinins

• Present in plasma, kidneys, pancreas, intestine, sweat glands, &

salivary glands
 Plasma kallikrein

Release bradykinin

 Tissue kallikrein

Release kallidin

 Pepsin and pepsin like enzymes

 Release meth-lys-bradykinin
80
 Formation of kinins in plasma and tissues

The kallikrein-kinin system. Kininase II is identical to

81 peptidyl dipeptidase (ACE)
 Receptors of kinins
• Two types: B1 and B2 (B2A and B2B); G protein coupled

• B2 receptor

 Affinity of BK >Kallidin> Met-Lys-bradykinin)

 Have a widespread distribution that mediates the multitude

biologic effects of kinins
• B1 receptors

 Very limited distribution

 Participate in the inflammatory response

 Expression up-regulated by inflammation, cytokines,

82 endotoxins, and growth factors
 Physiological & pathophysiological effects of kinins
CVS

• Marked arteriolar dilation in several vascular beds

 Heart, skeletal muscle, kidney, liver, and intestine

 MOA

 Direct effect on SM

 Causing release of nitric oxide or vasodilator PGs

such as PGE2 and PGI2

83
 Physiological…

CVS…
• Venous constriction

Direct stimulation of venous smooth muscle or

From the release of venoconstrictor PGs such as PGF2α

• Edema formation

Arterial dilation(inc. capillary pressure and flow), venous

constriction, contraction of endothelial cells

84
 Physiological…
Visceral smooth muscle
• Contraction of GI, uterine & bronchial smooth muscle
Role in inflammation
• Rapidly generated after tissue injury
• Play a pivotal role in the development and maintenance of
inflammatory processes
• Produces the four classic symptoms of inflammation
 Redness, local heat, swelling, and pain

85
 Physiological…
Other effects
• May play a beneficial, protective role in certain CV diseases
and ischemic stroke-induced brain injury

• Have been implicated in cancer and some CNS diseases

86
 Icatibant
• Decapeptide B2 antagonists, has rapid absorption after Sc. adm.

• Effective in the treatment of hereditary angioedema

 Autosomal dominant disorder characterized by recurrent

episodes of bradykinin-mediated angioedema of the
airways, GIT, extremities, and genitalia
• It may also be useful in drug-induced angioedema, airway
disease, thermal injury, ascites, and pancreatitis

87
Drug Therapy for Gout
 What is Gout?
 a common metabolic disorder where there is a vast accumulation

of uric acid onto the joints

 It is due to high levels of uric acid in the blood

(Hyperuricaemia).

 Leads to the formation of monosodium urate crystal in various

tissues in the body

 causes attacks of arthritis, usually in a single joint (often the base

of the big toe).

 Pathophysiology of Gout.

 Urate crystals are initially phagocytosed by synoviocytes which

then release PGs, lysosomal enzymes, interleukin, bradykinin.

 Large numbers of neutrophils then accumulate in the synovium,

which phagocytize urate crystals, thus leading to amplification of

the inflammatory process.

 Subsequently mononuclear phagocytes appear, ingest urate

crystals and release more inflammatory mediators.

ACUTE STAGE

Sever and sudden onset

Involve one or a few joints
Frequently starts nocturnally
Joint is warm, red, and tender
CHRONIC STAGE

Continuous or persistent pain over a

long period of time
Treatment with ULT
tophaceous gout
Not easily or quickly resolved
 Hyperuricemia

Hyperuricemia results when uric acid production exceeds

its excretion
 Uric acid metabolism

dietary intake purine bases cell breakdown

xanthine hypoxanthine
oxidase
catalyzes
hypoxanthine to xanthine
xanthine &
xanthine to uric
acid uric acid
Treatment
 The aims of treatment are to
1. decrease symptoms of an acute attack
2. decrease the risk of recurrent attacks

• Treatment should involve both Pharmacologic

and non-pharmacologic interventions

 Lifestyle Modifications
• Patients should consider lifestyle and dietary changes
to reduce their sUA (serum uric acid):
 Weight loss
 Limiting consumption of purine-rich meat (red meat)
and seafood
 Reducing alcohol intake, particularly beer
 Limiting high-fructose corn syrup intake
 found in sugar-sweetened soft drinks
 avoid peas
 Consuming dairy products: reduce incidence of gout
 Milk proteins have uricosuric properties
Losing weight
 SEAFOOD
Rich in purine
high-fructose corn syrup is found in sugar-
sweetened soft drinks
 Fructose Intake and Urate Excretion
HFCS Purine
Catabolism

Pyruvate Fructose
AMP Uric Acid

Lactate ATP
Fructose 1-
Phosphate

 Dominant dietary source – high-fructose corn syrup (HFCS)

 The principal “sweetener” for humans (found in sugar-sweetened soft drinks)
 High concentration of fructose causes rapid accumulation of AMP
 Increases the body pool of purines (catabolized to uric acid)
 Lactic acid is a by-product of fructose metabolism
 Lactate decreases urate excretion
 Avoid alcohol

Particularly beer can raise sUA upto 1mg/dL

 Drugs used to treat gout

Acute Arthritis Drugs Urate Lowering Drugs

NSAIDs allopurinol

colchicine probenecid

Corticosteroids febuxostat?

rest + analgesia + time

Treating acute gouty arthritis
 NSAIDs

 colchicine

 Corticosteroids
 NSAIDs
 Agents of first choice for acute gouty arthritis.
 Benefits derived from suppressing of pain and inflammation
through COX enzyme inhibition.
 All of the NSAIDs are equally effective for gout trt, but paracetamol
has no anti-inflammatory effect.
 Commonly used drugs:
 Indomethacin
 Naproxen
 Diclofenac sodium

104
 Indomethacin can inhibit urate crystal phagocytosis by
decreasing the migration of granulocytes into the
inflammatory area.
 it may replace colchicine.

 Aspirin in therapeutic doses contraindicates as it compete

with uric acid secretion at proximal tubule.
 2. Colchicine

•Colchicine is one of the oldest and most widely used drugs for acute
gout.
•It is a plant alkaloid
MECHANISM OF ACTIONS
Binds to tubulin - disrupt migration of
granulocytes to affected area

diminishes PMN phagocytosis of crystals,

thereby Prevents release of chemotactic
factors and cytokines from neutrophils

reduces inflammatory response to

deposited crystals
Colchicine
 Colchicine is approved for 2 gout indications:
- Treatment of gout flares
- Prophylaxis of gout flares

 Colchicine is not an analgesic medication and should not be

used to treat pain from other causes
 Adverse effects
 dose-related & more common when patient has
renal or hepatic disease
 Diarrhea is a common adverse effect. May cause
nausea,vomiting ,abdominal cramps.
 Common with oral dose

 Chronic use may cause alopecia, bone marrow

depression, peripheral neuritis, myopathy.
 Also affect fertility
 Preg risk Category C
3. Corticosteroids
 Glucocorticoids
 may be needed in severe cases.
 Candidates for glucocorticoid therapy include
 patients who are hypersensitive/ contraindicated to
NSAIDs/Colchicine
 patients with severe gout that is unresponsive to
NSAIDs/Colchicine
 High doses are used initially and then tapered slowly
off.
 Example: prednisolone 30 to 60 mg/day for 3 days, then
tapered over 12- to 14 days depending on the size and
number of affected joints.
111
 Prevention of
recurrent attack

Inhibitors of uric acid Uricosuric drugs

synthesis
- Probenacid
Allopurinol
-Sulfinpyrazone
Febuxostat
-Large doses of
aspirin
Inhibition of uric acid synthesis
 Allopurinol
 Structural analog of hypoxanthine & xanthine
 Competitive inhibitor of xanthine oxidase
 Xanthine and hypoxanthine are more soluble and better excreted
renally
 Allopurinol is metabolized to oxypurinol
 Oxypurinol accumulates—may be responsible for antigout
effects
 Oxypurinol is not well absorbed orally
 Allopurinol
 The drug of choice for treatment of chronic
tophaceous gout
 effectively blocks formation of uric acid
 Decreases serum and urinary uric acid levels
 Can work in pts with renal insufficiency
 pregnancy category C

allopurinol

115
 Therapeutic Uses of Allopurinol
 It is drug of choice in patient with:
 For high serum uric acid in patients
with impaired renal functions.
 In patients with uric acid stones or
nephropathy.
 used to prevent increased uric acid
levels in patients
receiving cancer chemotherapy
Side Effects (most common)

exacerbation of
an acute attack of gout
due to mobilizing flare
 Allopurinol hypersensitivity
extremely serious problem
prompt recognition required
first sign usually skin rash
progression to toxic epidermal
necrolysis & death

Maculopopular skin rash

nausea, diarrhea
Thrombocytopenia Epistaxis
 Stevens-Johnson syndrome

target skin lesions

mucous membrane
erosions
epidermal necrosis with
skin detachment
sometimes bleeding in
the mucous membranes of the
eyes, mouth, nose, and genitals.

126
Uricosuric drugs
 Probenecid
 Probenecid is a uricosuric drug which
increases uric acid excretion in the urine
 primarily used in treating gout

uric acid
 Probenecid…
 MOA of probenecid
 Inhibits tubular reabsorption of uric acid in kidney

 Enhances renal uric acid excretion, thereby decreases

serum uric acid level

 But, increases urine uric acid level

 increases risk of nephrolithiasis

 not used in patients with renal disease

129
 Probenecid…
 S/Es
 frequent, but mild, side effects
 GI effects(nausea, vomiting, anorexia)
 take the drug with food.
 Hypersensitivity reactions—rash
 Renal injury- can be minimized by
 alkalinizing the urine
 consuming 2.5 to 3 L of fluid daily

 D/Is
 Aspirin and other salicylates interfere with the uricosuric action of
probenecid.

130
Uricosuric drugs
Preferred Urate-lowering therapy
Gout type Drugs
 mild gout  Uricosuric
 renal disease  allopurinol/ Febuxostat
 Nephrolithiasis  allopurinol/ Febuxostat
 Elderly  allopurinol/ Febuxostat
 tophaceous gout  allopurinol/ Febuxostat
 Recommendations From the 2012 American College of Rheumatology
Guidelines for Management of Gout
 ACR recommends a comprehensive treatment plan for the management of gout, including both
nonpharmacologic and pharmacologic approaches
 Patient education including diet and lifestyle modifications is recommended along with the
following pharmacologic approaches for the management of gout

Acute Gout Flares Gout Flare Prophylaxis Chronic Gout Management

• For gout attack prophylaxis,
• Treat an acute
initiate low-dose colchicine or
gout flare with low-dose NSAIDs when initiating
pharmacologic
urate-lowering therapy (ULT)
therapy:
• Anti-inflammatory prophylaxis
• (NSAIDs, should be continued from
corticosteroids, or initiation of ULT for more than:
colchicine) within • At least 6 months, or
24 hours of onset • Following achievement of
target serum urate, for
3 months in patients without
or 6 months in patients with
tophi on physical exam
• When initiating ULT, begin
anti-inflammatory gout flare
prophylaxis
• Initiate first-line ULT, febuxostat or
allopurinol, or if at least one of
these is contraindicated or not
tolerated, probenecid can be used
to treat to sUA target of <6 mg/dL
• sUA should be monitored
regularly (every 2-5 weeks) during
ULT titration, then every 6 months
once target sUA is achieved
Possible treatments
 If all else fails
 Surgery may be needed to remove uric acid build
up
 Rheumatoid arthritis (RA)
 Rheumatoid arthritis (RA) is an autoimmune disease that causes
joint inflammation and progressive erosion of bone,
 leading to joint misalignment, loss of function, and disability.

 Also known as symmetric, inflammatory, peripheral polyarthritis of

unknown etiology.
 Characterized by persistent synovial tissue inflammation.
 Most commonly, the small joints in the hands and feet are affected, but
larger joints (Shoulders, knees etc) can also be affected.
 Extra-articular involvement of multiple organ systems deformity.
Progressive Chronic Inflammation Can Lead to Joint Destruction

Chronic inflammation
in the joint leads to
bone destruction
evident as erosions

Prolonged severe
chronic arthritis
leads to deformity
and disability.
Early Arthritis - soft tissue
swelling
 Cytokine networks are responsible for inflammation & joint
destruction
 Tumor Necrosis Factor-α (TNF-α)
 Interleukins - 1,6,17
 Interferon gamma (IFN-g)
 Produced by mast cells, macrophages, and T lymphocytes
 affects 1% of the population.

 The pharmacological management of RA includes

symptomatic relief through the use of NSAIDs.

 Do not alter progression of joint deformity.

 DMARDs (disease-modifying anti-rheumatic drugs), on

the other hand, reduce the disease activity of rheumatoid

arthritis and retard the progression of arthritic tissue
destruction.
 Disease-Modifying Anti-Rheumatic Drugs
 Methotrexate: Anti-folate - “Gold standard” as DMARD therapy

 Leflunomide:Pyrimidine synthase inhibitor

 Sulfasalazine: Salicylate -Remove toxic free radicals, inhibiting

prostaglandin synthesis
 Azathioprine: Purine synthase inhibitor

 Adalimumab, Infliximab: neutralize the activity of TNF-

 Entanrecept : TNF-  receptor blocker

 Anakinra: IL-1-receptor antagonist

 Short-term glucocorticoids often are used to bring the level of

inflammation quickly under control
 Glucocorticoids are not suitable for long-term use because of adrenal
suppression.
Mechanism of action of disease modifying agents
 Mechanism for many DMARDs is not known.

 All inhibit the release and activity of inflammatory cytokines

 Methotrexate, leflunomide and cyclosporin all inhibit T-cells.

 Leflunominde inhibits proliferation of B - cells and antibody

production
 Entanrecept is a recombinant human soluble TNF receptor

blocker
 Infliximab is a monoclonal antibody that neutralizes the activity

of TNF
Strategies for Monoclonal Antibody (Infliximab & Adalimumab)
Reducing
Effects of TNF

Trans-Membrane Bound
TNF

Macrophage

Soluble TNF