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Pharmacology – IPHL-313
By
Majid Ahmad Ganaie M. Pharm., Ph.D.Assistant ProfessorDepartment of Pharmacology E mail: [email protected]
Chapter 4:
AUTACOIDS
Autacoids Auto = self ; Coids = Remedy
Autacoids - Endogenous substances with biological activity.
some times called Local Hormones with important roles in mediating Inflammation, pain and allergies Smooth muscle tone and blood pressure GI functions Hemostasis Many others
Autacoid types:
Types of autacoids we will study: Amines: Histamine and 5-HT (Serotonin) Eicosanoids: Prostaglandins, Leukotrienes and
thromboxane Vasoactive peptides: Kinins, Renin, Angiotensin,
Natriuretic peptide, Vasopressin peptide, Substance P
Endothelin derived: Nitric oxide
HISTAMINE
Locations: mediators of allergic and inflammatory reactions; also involved in Gastric Acid Secretions; and as Neurotransmitter & Neuromodulator.
It is located in: a) Mast cells b) Basophiles, Platelets, Enterochromaffin- like (ECL) cells of the stomach c) Brain
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Histamine
Synthesis: it is synthesized from amino acid histidine.
It is present in high amounts in lungs, skin, GIT (sites where inside meet the out side).
It present in ↑concentration in mast cells & basophilis.
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In mast cells and basophils, histamine is complexed in intracellular granules with acidic protein.
Release: is it may be primarily in response to some stimuli as a mediator of inflammation & allergic reactions. Stimuli causing histamine release include destruction of cells as a result of cold, bacterial toxins, bee sting venoms or trauma.
Allergies & anaphylaxis trigger histamine release.
Its also plays an important physiological role in control gastric acid secretion & as neurotransmitter.
Histamine is metabolised by histaminase &/or by methylating enzyme imidazole N-methyltransferase.
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Mechanism of action of histamine:
It acts on specific receptors
H1-receptors occurs at postsynaptic sites-Smooth muscle
Exocrine glands
Brain
Endothelium
H2-receptors occurs at postsynaptic sites-Gastric mucosa
Heart, Mast cells
H3-receptors occurs at prestsynaptic sites-Nerve endings &
Brain, inhibit the release of neurotransmitters.
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Actions of histamine
Histamine receptors and the effects they mediate in various peripheral organs
Receptor Physiologic Response Result
H1
Endothelium
Smooth muscle
Brain
Nerve Endings
-Vasodilation of small blood vessels(rapid response to low concentrations of histamine)
-Increased permeability of post-capillary venules
-Stimulation of sensory neuronal receptors
-contraction of smooth muscle of the ileum, bronchi, bronchioles and uterus
Redness, flushing,Hypotension
Edema, urticaria
Itching, pain, flare
Bronchoconstric-tion, especially in asthmatics
Histamine receptors and the effects they mediate in various organs
Receptor Physiologic Response Result
H2
Gastric mucosa
Cardiac muscle
Vascular smooth muscle
Mast cells
Brain
-Secretion of gastric acid
-Direct Cardiac stimulation
-Vasodilation (slower, prolonged response to high concentrations of histamine)
Contribute to peptic ulcer
less important than baroreceptor reflex
Hypotension
Histamine receptors and the effects they mediate in various organs
Receptor Physiologic Response Result
H3
Presynaptic
-Presynaptic inhibition of the release of neurotransmitters
unknown
Many drugs familiar from everyday life are histamine antagonists:
First generation H1 antagonists:Diphenhydramine (Benadryl)Dimenhydrinate (Dramamine, Travamine)
Second generation (nonsedating) H1 antagonists:Loratadine (Clarintin, Lorastin)Fexofenadine (Allegra, Telfast)
H2 antagonists:Cimetidine (Tagamet, Cimi)Ranitidine (Zantac, Zanidex)Famotidine (Pepcid, Gastro)
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First generation H1 antagonists: Are absorbed from the GIT. Can also be given parenterally & topically. Most of them appear widely distributed throughout the body, but
some do not penetrate the BBB, Are most effective when use prophylactically. Most of the them are metabolized extensively in the liver. Are the older. Still widely used because they are effective & inexpensive. ↑Penetration to the CNS→ cause sedation. Interact with other receptors producing a variety of unwanted side
effects. Example: chlorpheniramine, promethazine, meclizine,
diphenhydramine
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Second generation (nonsedating) H1 antagonists:
Are specific for H1 receptors.
Do not penetrate the BBB so they show less CNS toxicity. E.g. loratadine & fexofinadine show the least sedation. Other example: cetirizine.
Additional effects of H1-blockers
1. CNS→ sedation, dizziness & fatigue.
2. Anticholinergic effect → dry mouth, urinary retention, tachycardia
3. α- blocking effect →postural hypotension, reflex tachycardia.
4. Antiserotonin effect → ↑appetite
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Clinical uses of H1-blockers
1. For allergic reactions. DRUGS That lack sedative or muscarinic antagonist actions( e.g. cetirizine or fexofinadine) are preferred.
2. As antiemetics for prevention of motion sickness or other causes of nausea. Muscarinic receptor antagonist actions of some antihistamines (e.g. diphenhydramine, meclizine, cyclizine) are most effective agents.
3. For sedation: some H1 antagonists (e.g. promethazine, diphenhydramine) are strong sedatives & may be used for this action.
The use of first generation H1 antihistamines is contraindicated in treatment of individuals working in jobs where wakefulness is critical.
Other preparations:
Cyproheptedine→ has potent antiserotonin→ gain in weight.
Loratidine→ has long duration of action → once daily dosing
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S/Es: some adverse effects observed with first generation antihistamines
H2 Receptor Antagonists
Competitive inhibitors at H2 receptors
Reduce acid secretion by 60-70% for about 10 hours
Basal secretion of gastric acid reduced more than stimulated secretion >90% of nocturnal acid secretion (basal) 60-70% of daytime acid secretion (meal stimulated)
Drug and its metabolites are excreted by kidney by glomerular filtration and renal tubular secretion=> important to reduce dose in patients with renal insufficiency
Generally few side effects, though Cimetidine is more problamatic than others, since it inhibits cytochrome P450 (potential for drug interactions)
H2 Antagonists, therapeutic uses
First line treatment for frequent GERD, that does not respond to lifestyle changes,Treatment of persistent heartburn requires twice daily dosage.
No longer recommended for treatment of peptic ulcers, PPIs are preferable
May heal NSAID-induced ulcers, if NSAID use is discontinued
If NSAID use is continued, PPI is required to prevent recurrence
Serotonin (5-HT)
Functions both as neurotransmitter and as local hormone
“Involved in everything, but responsible for nothing”
5-HT = 5-Hydroxytryptamine = Serotonin
CH2 NH2CH2OH
NH
5-hydroxytryptamine
Powerful vasoconstrictor substance found in the serum, after blood has clotted
Functions Regulated by 5-HT
In PeripheryPeristalsis
Vomiting
Functions Regulated by 5-HT
In PeripheryPeristalsis
Vomiting
Platelet aggregation, haemostasis
Microvascular control
Functions Regulated by 5-HT
In PeripheryPeristalsis
Vomiting
Platelet aggregation, haemostasis
Microvascular control
Sensitization of nociceptors (pain, itch)
Inflammatory mediator
Functions Regulated by 5-HT
In Periphery In CNSPeristalsis Control of appetite
Vomiting Sleep
Platelet aggregation, haemostasis Mood
Microvascular control Hallucinations
Sensitization of nociceptors (pain, itch)
Stereotyped behavior
Inflammatory mediator Pain perception
Vomiting
Temperature regulation
Regulation of blood pressure
interspersed in mucosa of stomach and small intestine90% of 5-HT in body
in localized regions of the CNS - Raphe nuclei of the brain stem
in the Enteric Nervous System
don’t synthesize 5-HT but accumulate it from the plasma as they pass through the intestinal circulation
Distribution of 5-HT in body
Enterochromaffin cells
Neurons
Platelets
Plants, venoms and stings
Roles of 5-HT in GI tract
GI tract Increased gastrointestinal motility and contraction -via direct excitation of smooth muscle (5-HT2) -via indirect activation of enteric neurons (5-HT3 and 5-HT4)
Vomiting Stimulates vomiting -via 5-HT3 receptors in GI tract on vagal nerve
(5HT released in mucosa upon irritation by chemotherapy, radiation therapy, distention, etc)
-via 5-HT3 receptors in the chemoreceptor trigger zone and vomiting center of brain
Ondansetron
5-HT3 antagonist
Used to prevent:-chemotherapy-induced nausea and emesis -radiotherapy-induced nausea and emesis-postoperative nausea and emesis
Not known whether it acts centrally or peripherally, but serotonin is released from enterochromaffin cells upon chemotherapy
5-HT4 Agonists and their use in gastrointestinal disorders
5-HT4 agonists promote GI motility - stimulate coordinated peristaltic activity
Tegaserod – Newer and more specific 5-HT4 agonist.
Used to treat irritable bowel syndrome with constipation (abdominal pain, swelling and constipation)
Found effective in women only
Cardio-vascular system
Mixture of vasoconstriction of large peripheral blood vessels via 5-HT2A
-via direct effect on vascular smooth muscle of cranial blood vessels via 5-HT1
and vasodilation in skeletal muscle and heart -via indirect effect on vascular endothelium => production of NO
-via inhibition of NA release from sympathetic nerve terminals
Reflex Bradycardia (Chemoreceptor reflex) -via 5-HT3 on chemoreceptor nerve endings, triggering vagal output to the heart=>bradycardia
Venoconstriction leading to increased capilary filling and flushing
Physiologic effects of 5-HT
Opposing effects of 5-HT on vasculature
1. Initial decrease in heart rate, cardiac output and blood pressure, due to the chemoreceptor response (5-HT3 receptors on nerve endings)
2. Increase in blood pressure due to vasoconstriction
3. Decrease in blood pressure due to vasodilation in skeletal muscle
Triphasic response follows injection of 5-HT:
Platelets Platelet aggregation,
In the case of blood clotting there is release of 5T by the aggregating platelets => vasodilation if endothelium is intact => vasoconstriction if endothelium is damaged
Physiologic effects of 5-HT
Physiologic effects of 5-HT
Nerve Endings Stimulates nociceptive nerve endings (5HT3)
Inhibits transmitter release from peripheral adrenergic neurons
Stimulates autonomic chemoreceptor reflex in heart and lungs (bradycardia and hypotension)
Stimulates vomiting via 5-HT3 receptors in GI tract on vagal nerve via vomiting center of brain
Physiologic effects of 5-HT
CNS Excitation
Inhibition
Presynaptic inhibition of neurotransmitter release Sleep/Wake Cycle
Aggression and ImpulsivityAnxiety and DepressionCognitionSensory PerceptionMotor ActivityTemperature RegulationNociceptionAppetiteSexual BehaviorHormone Secretion
Depression -TCA (tricyclic antidepressants) -SSRI (selective serotonin reuptake inhibitors) (fluoxetine = prozac) -MAOI (monoamine oxidase inhibitors)Obesity(fenfluramine, dexfenfluramine) (inhibitors of 5-HT reuptake) Induce weight loss but can cause pulmonary hypertension and heart valve defectsMigraine
The complex (poorly understood, but convincing) role of 5-HT in many diseases
Some pathologic conditions may be treated with drugs that influence 5-HT levels or 5-HT function For Example:
Buspirone
5-HT1A partial agonist
Anti-anxiety drug
Anxiolytic, but not sedative
Effects take days or weeks to develop - not effective for panic attacks
Migraine - a poorly understood disorder
Affects 10-15% of population
Symptoms: Aura, followed by severe throbbing headache, starting unilaterally, often with photophobia, nausea, vomiting, prostration, and lasting for several hours
Or Migraine without aura (more common):episodic attacks of headache lasting 4-72 hrs with at least two of the following (unilateral pain, throbbing, aggravation on movement, moderate to severe intensity) and one of the following (nausea, vomiting, photophobia, phonophobia)
Migraine - a poorly understood disorder
Pathophysiology not well understood and hotly contested:Cause may be vascular, neural, inflammatory, or associated with platelet function
Strong evidence implicates 5-HT:
-sharp increase in urinary excretion of 5-HIAA during the attack with concomitant fall in blood concentration of 5-HT
-migraines may be precipitated by agents like reserpine and fenfluramine that release 5-HT from intracellular storage sites
-many effective drugs are 5-HT agonists or antagonists
Sumatriptan- an effective antimigraine drug
5-HT1D (and 5-HT1B) agonistlow or no affinity for other receptor subtypes
The clinical effect of triptans correlates with their affinity for 5-HT1D and 5-HT1B
Causes constriction of intracranial blood vessels
Used to treat acute attacks of migraine but not useful for prophylaxis
Reduces the nausea and vomiting associated with migraine
Sumatriptan- an effective antimigraine drug
For fast onset, can give subcutaneously (12 min) or as a nasal spray (15 min) rather than orally (1-2 hrs)
Short acting (half life of 2 hours)metabolized by MAO
Side effects:-rare but serious cardiac events, especially in patients at risk for coronary artery disease (causative relationship not clear)Tendency to cause chest pain due to coronary artery spasm
Contraindicated in patients with cardiovascular disease or uncontrolled hypertension or in patients who are taking MAO inhibitors
Eicosanoids
Overview Eicosanoids are a large group of autocoids with potent effects on
virtually every tissue in the body these agents are derived from metabolism of 20-carbon, unsaturated
fatty acids (eicosanoic acids).
The eicosanoids include:
1. Prostaglandins
2. Thromboxanes
3. Leukotrienes
4. Hydroperoxyeicosatetraenoic acids (HPETEs)
5. Hydroxyeicosatetraenoic acids (HETEs).
Biosynthesis
Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:1. Phospholipase A2-mediated production
from membrane phospholipids; this pathway is inhibited by glucocorticoids.
2. Phospholipase C.
The eicosanoids all have short plasma half-lives (typically 0.5—5 min). Most catabolism occurs in the lung.Metabolites are excreted in the urine.
Thromboxane A2 (TXA2) is rapidly hydrated to the less active TXB2.
PGI2 is hydrolyzed to 6-keto-PGF1α.Various eicosanoids are synthesized throughout the body synthesis can be very tissue specific:
PGI2 is synthesized in endothelial and vascular smooth muscle cells.
Thromboxane synthesis occurs primarily in platelets. HPETEs, HETEs, and the leukotrienes are synthesized
predominantly in mast cells, white blood cells, airway epithelium, and platelets.
Actions: Vascular smooth muscle
PGE2 and PGI2 are potent vasodilators in most vascular beds. Thromboxane is a potent vasoconstrictor.
Inflammation PGE2 and PGI2 cause an increase in blood flow and promote,
but do not cause, edema. HETEs (5-HETE, 12-HETE, 15-HETE) and leukotrienes
cause chemotaxis of neutrophils and eosinophils. Bronchial smooth muscle
PGFs cause smooth muscle contraction. PGEs cause smooth muscle relaxation. Leukotrienes and thromboxane are potent bronchoconstrictors
and are the most likely candidates for mediating allergic bronchospasm.
Uterine smooth muscle. PGE2 and PGF2a cause contraction of uterine smooth muscle in pregnant women.
PGF2a causes contraction
PGE2 causes relaxation.
Gastrointestinal tract PGE2 and PGF2a : increase the rate of longitudinal contraction in the gut and decrease
transit time. The leukotrienes are potent stimulators of gastrointestinal smooth muscle. PGE2 and PGI2 : inhibit acid and pepsinogen secretion in the stomach. Prostaglandins: increase mucus, water, and electrolyte secretion in the stomach and the
intestine.
Blood TXA2
• is a potent inducer of platelet aggregation. PGI2 and PGE2
• inhibit platelet aggregation. PGEs
• induce erythropoiesis by stimulating the renal release of erythropoietin.
5-HPETE • stimulates release of histamine
PGI2 and PGD
• inhibit histamine release.
Therapeutic uses Induction of labor at term. Induction of labor is produced by:
infusion of PGF2 (carboprost tromethamine) [Hemabate] or
PGE2 (dinoprostone) [Prostin E].
Therapeutic abortion:
A. Inducing abortion in the second trimester: Infusion of carboprost tromethamine or Administration of vaginal suppositories containing
dinoprostone
B. Inducing first-trimester abortion:these prostaglandins are combined with mifepristone
(RU486)
Maintenance of ductus arteriosus is produced by PGE1 [Prostin VR] infusion
PGE1 will maintain patency of the ductus arteriosus, which may be desirable before surgery.
Treatment of peptic ulcer. Misoprostol [Cytotec]
a methylated derivative of PGE1
is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.
Erectile dysfunction: Alprostadil (PGE1) can be injected directly into the corpus cavernosum or administered as a
transurethral suppository to cause vasodilation and enhance tumescence.
Adverse effects of eicosanoids
local pain and irritation
bronchospasm
gastrointestinal disturbances: nausea, vomiting, cramping, and diarrhea.
Vasoactive Peptides
Vasoactive Peptides
A. Vasoconstrictors (angiotensin II;
vasopressin; endothelins and neuropeptide Y.
B. Vasodilators (Bradykinin and related
Kinins; Natriuretic Pepties; Vasoactive Intestinal Peptide; substance P; Neurotensin)
Kinins : (e.g. : Bradykinin & kallidin)
Polypeptides present in plasma and several tissues including the kidneys, pancreas, intestine, sweat and salivary glands.
ACTIONS :
CVS : Very potent vasodilator (direct and via increase EDRF). Also, increases the body capillary permeability
Bronchioles : Contraction of bronchial smooth muscles (cough).
Inflammation : Kinins can produce all the symptoms of inflammation (pain and edema when injected to tissue).
Pain : Intradermal injection of kinins elicited potent pain (Stimulate nociceptive nerve afferent fibers)
Natriuretic peptides:Locations: Atrial (ANB) and Brain (BNP) (Found in ventricle as well)
Clinical significant:
(increase in heart failure; renal failureActions: decrease the secretion of renin, aldosterone and vasopressin; decrease blood pressure and increase sodium excretion. Act via activation of guanalyl cyclase.
Calcitonin: from thyroid and the most potent vasodilators in the body.
Vasoactive-intestinal peptides:
Vasopressin (Antidiuretic hormone ADH)
Supstnace P: is an arteriolar vasodilator that is also pain-mediating neurotransmitter but causes venoconstriction and bronchoconstriction. Capsaisin releases substance P from nerve ending (used for arthritic joints and for postherpetic neuralgia).
The Natriuretic Peptide FamilyInclude atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) ANP derived from a 126 amino acids prohormone, secreted primarily from cardiac atria BNP, identified initially in brain, is secreted from both atria & ventriclesCNP identified in brain & in vascular endothelial cells Stretch receptors in the atria and ventricles detect changes in cardiac chamber volume related to increased cardiac filling pressures, resulting in release of both ANP and BNP but not CNP
The Natriuretic Peptide Family
The actions of the natriuretic peptides are mediated by natriuretic peptide receptors (NPRs), NPR-A/B/CNPR-A & NPR-B are coupled to membrane-bound GC, increases levels of cGMPNPRs are localized in vascular SM, endothelium, platelets, the adrenal glomerulosa, & the kidneyANP & BNP increase urine volume & sodium excretion, decrease vascular resistance, and inhibit release of renin and secretion of aldosterone & vasopressinNeutral endopeptidases (NEPs) inactivate NPs
Vasoconstrictor peptides: Angiotensin II
You should remember its synthesis? (See FigureActions:
1. the most potent vasoactive agent in the body (direct and vai NE)
2. Stim release of aldosterone and renin as well.
3. Centrally, stim. Drinking and increase the secretion of vasopressin and ACTH.
Endothelins:Widely distributed in the body (in endothelial cells of blood vessels)ACTIONS: Dose-depen. Vasoconstriction in most vascular beds, Thus: Decrease GFR Increase aldosterone, vasopressin and ANP Potent bronchoconstriction
Endothelin Antagonists: Endothelin-converting enzyme inhibitors:(Bosentan) (4 pulmonary HTN)
Kinins: Receptors, Actions & Therapy
The activate B1, B2, B3 receptors linked to PLC/A2
Powerful Vasodilation→ decreased blood pressure via B2 receptor stimulation (NO-dependent)
Increase in capillary permeability inducing edema.It produces inflammation & algesia (B2)
Cardiac stimulation: Compensatory indirect & direct tachycardia & increase in cardiac output
It produces coronary vasodilation
Bradykinin has a cardiac anti-ischemic effect, inhibited by B2 antagonists (NO & PI2 dependent)
Kinins: Actions & Therapy
Kinins produce broncho-constriction & itching in respiratory system (antagonized by ASA)
Therapeutic Use: No current use of kinin analogues Increased bradykinin is possibly involved in the therapeutic
efficiency & cough produced by ACEIs Aprotinin (Trasylolol), a kallekrein inhibitor, used in treatment of
acute pancreatitis, carcinoid syndrome & hyperfibrinolysis
THANKS