P harmacology – I PHL-313 By M ajid A hmad G anaie M. Pharm., P h.D. Assistant Professor Department of Pharmacology E mail: Chapter 4: A UTACOIDS

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

5 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.

6 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.

7 Mechanism of action of histamine: It acts on specific receptors H 1 -receptors occurs at postsynaptic sites-Smooth muscle Exocrine glands Brain Endothelium H 2 -receptors occurs at postsynaptic sites-Gastric mucosa Heart, Mast cells H 3 -receptors occurs at prestsynaptic sites-Nerve endings & Brain, inhibit the release of neurotransmitters.

8 Actions of histamine

Histamine receptors and the effects they mediate in various peripheral organs ReceptorPhysiologic ResponseResult H 1 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 ReceptorPhysiologic ResponseResult H 2 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 ReceptorPhysiologic ResponseResult H 3 Presynaptic -Presynaptic inhibition of the release of neurotransmitters unknown

Many drugs familiar from everyday life are histamine antagonists: First generation H 1 antagonists: Diphenhydramine (Benadryl) Dimenhydrinate (Dramamine, Travamine) Second generation (nonsedating) H 1 antagonists: Loratadine (Clarintin, Lorastin) Fexofenadine(Allegra, Telfast) H 2 antagonists: Cimetidine(Tagamet, Cimi) Ranitidine(Zantac, Zanidex) Famotidine(Pepcid, Gastro)

13 First generation H 1 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

14 Second generation (nonsedating) H 1 antagonists:  Are specific for H 1 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 H 1 -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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16 Clinical uses of H 1 -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 H 1 antagonists (e.g. promethazine, diphenhydramine) are strong sedatives & may be used for this action. The use of first generation H 1 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

17 S/Es: some adverse effects observed with first generation antihistamines

H 2 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 CH 2 NH 2 CH 2 O H N H 5-hydroxytryptamine Powerful vasoconstrictor substance found in the serum, after blood has clotted

Functions Regulated by 5-HT In Periphery Peristalsis Vomiting

Functions Regulated by 5-HT In Periphery Peristalsis Vomiting Platelet aggregation, haemostasis Microvascular control

Functions Regulated by 5-HT In Periphery Peristalsis Vomiting Platelet aggregation, haemostasis Microvascular control Sensitization of nociceptors (pain, itch) Inflammatory mediator

Functions Regulated by 5-HT In PeripheryIn CNS PeristalsisControl of appetite VomitingSleep Platelet aggregation, haemostasisMood Microvascular controlHallucinations Sensitization of nociceptors (pain, itch) Stereotyped behavior Inflammatory mediatorPain perception Vomiting Temperature regulation Regulation of blood pressure

 interspersed in mucosa of stomach and small intestine 90% 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 tractIncreased gastrointestinal motility and contraction -via direct excitation of smooth muscle (5-HT 2 ) -via indirect activation of enteric neurons (5-HT 3 and 5-HT 4 ) VomitingStimulates vomiting - via 5-HT 3 receptors in GI tract on vagal nerve (5HT released in mucosa upon irritation by chemotherapy, radiation therapy, distention, etc) -via 5-HT 3 receptors in the chemoreceptor trigger zone and vomiting center of brain

Ondansetron 5-HT 3 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-HT 4 Agonists and their use in gastrointestinal disorders 5-HT 4 agonists promote GI motility - stimulate coordinated peristaltic activity Tegaserod – Newer and more specific 5-HT 4 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-HT 2A -via direct effect on vascular smooth muscle of cranial blood vessels via 5-HT 1 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-HT 3 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-HT 3 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:

PlateletsPlatelet 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

Platelet released 5-HT may promote thrombus or hemostasis

Physiologic effects of 5-HT Nerve EndingsStimulates nociceptive nerve endings (5HT 3 ) Inhibits transmitter release from peripheral adrenergic neurons Stimulates autonomic chemoreceptor reflex in heart and lungs (bradycardia and hypotension) Stimulates vomiting via 5-HT 3 receptors in GI tract on vagal nerve via vomiting center of brain

Physiologic effects of 5-HT CNSExcitation Inhibition Presynaptic inhibition of neurotransmitter release Sleep/Wake Cycle Aggression and Impulsivity Anxiety and Depression Cognition Sensory Perception Motor Activity Temperature Regulation Nociception Appetite Sexual Behavior Hormone 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 defects Migraine 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-HT 1A 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-HT 1D (and 5-HT 1B ) agonist low or no affinity for other receptor subtypes The clinical effect of triptans correlates with their affinity for 5-HT 1D and 5-HT 1B 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 A 2 -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 A 2 (TXA 2 ) is rapidly hydrated to the less active TXB 2. PGI 2 is hydrolyzed to 6-keto-PGF 1α. Various eicosanoids are synthesized throughout the body synthesis can be very tissue specific: PGI 2 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 PGE 2 and PGI 2 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. PGE 2 and PGF 2a cause contraction of uterine smooth muscle in pregnant women.  PGF 2a causes contraction  PGE 2 causes relaxation. Gastrointestinal tract PGE 2 and PGF 2a : increase the rate of longitudinal contraction in the gut and decrease transit time. The leukotrienes are potent stimulators of gastrointestinal smooth muscle. PGE 2 and PGI 2 : inhibit acid and pepsinogen secretion in the stomach. Prostaglandins: increase mucus, water, and electrolyte secretion in the stomach and the intestine.

Blood TXA 2 is a potent inducer of platelet aggregation. PGI 2 and PGE 2 inhibit platelet aggregation. PGEs induce erythropoiesis by stimulating the renal release of erythropoietin. 5-HPETE stimulates release of histamine PGI 2 and PGD inhibit histamine release.

Therapeutic uses Induction of labor at term. Induction of labor is produced by:  infusion of PGF 2  (carboprost tromethamine) [Hemabate] or  PGE 2 (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 PGE 1 [Prostin VR] infusion PGE 1 will maintain patency of the ductus arteriosus, which may be desirable before surgery. Treatment of peptic ulcer. Misoprostol [Cytotec] a methylated derivative of PGE 1 is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration. Erectile dysfunction:  Alprostadil (PGE 1 ) 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

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 failure Actions: 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 Family Include 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 & ventricles CNP 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/C NPR-A & NPR-B are coupled to membrane-bound GC, increases levels of cGMP NPRs are localized in vascular SM, endothelium, platelets, the adrenal glomerulosa, & the kidney ANP & BNP increase urine volume & sodium excretion, decrease vascular resistance, and inhibit release of renin and secretion of aldosterone & vasopressin Neutral endopeptidases (NEPs) inactivate NPs

Vasoconstrictor peptides: Angiotensin II You should remember its synthesis? (See Figure Actions: 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 B 1, B 2, B 3 receptors linked to PLC/A 2 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 & PI 2 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

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