Pharmacology of Autacoids PDF

Pharmacology of Autacoids  Autacoids: biological factors act locally near their site of synthesis and release have a brief duration of action participate in physiologic or pathophysiologic processes Classes of Autacoids:  Biogenic amines:  Hi...

Pharmacology of Autacoids  Autacoids: biological factors act locally near their site of synthesis and release have a brief duration of action participate in physiologic or pathophysiologic processes Classes of Autacoids:  Biogenic amines:  Histamine  serotonin (5-hydroxytryptamine, 5HT)  Polypeptides:  Angiotensin  Lipid-derived autacoids  Eicosanoids  Prostaglandins  Leukotrienes  Thromboxane  General Physiologic function modulate blood flow in specific tissues. modulate secretory processes (gastric acid secretion). modulate smooth muscle function (vascular and bronchial). play a key role in allergy, inflammation, pain, and certain types of drug reactions (Anaphylaxis).  Histamine Biosynthesis: synthesized from dietary histidine by histidine decarboxylase Distribution and storage sites:  Mast cells and Basophils: synthesized and store histamine in vesicles  Stomach mucosa: (Enterochromaffin-like cells releases histamine which causes gastric acid secretion)  Lungs and skin: (release from mast cells causes allergic responses)  CNS act as a neurotransmitter.  Many venoms and insect stings contain histamine  Physiologic and pathologic roles Stimulate gastric acid secretion Involved in allergic reactions and anaphylactic shock Increase capillary permeability associated with Inflammation Decrease blood pressure because it relaxes arterioles Causes bronchial occlusion and increase mucus secretion associated with asthma Cause pain and itching by activating sensory nerves Histamine Release Immune (allergy) Release: binding of antigenic substances to IgE on mast cells or basophils causes degranulation and release of histamine which is associated with hypersensitivity reactions Drugs and Chemicals Morphine Tubucurarine Codeine Penicillin Physical Injury Heat Cold Trauma Plant and animal stings  Histamine Receptors Receptor H1 H2 Signal Gq protein Gs protein phospholipase c adenylyl cyclase Response Contraction of GI muscle Gastric secretions Contraction of bronchial muscles Salivary secretion (bronchoconstriction) Lacrimation Dilation of Decrease Arterioles Blood Hypotension Capillaries Pressure Veins Increase heart rate Increase vascular permeability Edema and leakage  Histamine Antagonists Receptor Antagonist Release Inhibitors Physiologic Antagonists  H1 Antihistamine Inverse agonist of H1 receptor First generation Second generation Diphenhydramine Dimenhydrinate Loratadine Hydroxyzyline Cetirizine Meclizine Fexofenadine Promethazine Cyproheptadine Unionized at physiological pH and ionized at physiological easily cross the blood–brain barrier pH and is difficult to cross BBB (BBB). Therefore, they produce CNS side effects, in particular, sedation. Pharmacologic effects of H1-antihistamines Relaxation of contracted bronchiolar smooth muscle. Relaxation of contracted intestinal smooth muscle. Inhibition of histamine-induced vasodilation and capillary permeability Inhibition of itch sensation (inhibits stimulation of sensory nerves) Sedation (effect of first-generation H1-antihistamines) Antimuscarinic effects (diphenhydramine and promethazine) decrease saliva secretion, intestinal atony and might increase heart rate. Antimotion sickness (antiemetic) effects. This effect is due to the inhibition of histaminergic signals from the vestibular nucleus Note: H1-antihistamines alone are not effective for treatment of systemic anaphylaxis because large amount of other autacoids are released during anaphylaxis.  Therapeutic uses: (orally, parenterally, topically) Treatment of allergic conditions: Urticaria and pruritus Allergic reactions to drugs Anaphylaxis Prevention of motion sickness: Diphenhydramine, dimenhydrinate Sedation induction: Promethazine and diphenhydramine Adverse effects CNS depression: (lethargy, somnolence, ataxia) Antimuscarinic effects: (dry mouth, urinary retention, and intestinal atony)  H2-antihistamines  Cimetidine and Ranitidine Pharmacologic effects:  competitively inhibits histamine (H2-receptors) in parietal cell and thereby decreases gastric acid production Therapeutic uses:  Ulcer treatment (gastric, abomasal and duodenal)  Erosive gastritis induced by drugs  Gastro-Esophageal reflux Adverse effects: ▪ Uncommon when used as recommended Drug interactions: ▪ Cimetidine can inhibit the hepatic cytochrome P450 enzymes, Thereby prolonging the concentration of drugs metabolized by the liver.  Inhibitors of histamine release: Cromolyn sodium: Inhibits histamine release from mast cells. Therapeutic uses: Recurrent airway obstruction and heaves in horses Control allergic conjunctivitis (eye drop) Physiologic antagonists to histamine: sympathomimetic drugs: Epinephrine Phenylephrine Ephedrine (antagonize histamine’s physiological function) Activate α- and β-adrenoceptors to elevate blood pressure and relax the bronchi. Epinephrine: preferred to treat immediate effects of anaphylaxis. Serotonin (5-hydroxytryptamine, 5-HT) Biosynthesis: tryptophan L-aromatic acid hydroxylase decarboxylase Dietary tryptophan 5-hydroxytryptophan 5-hydroxytryptamine (serotonin) distribution and function GI tract: (enterochromaffin cells) is involved in regulating motility. Platelets: store 5HT and lower its free 5-HT in blood. When released upon activation it cause vasoconstriction and platelet aggregation CNS: acts as a neurotransmitter. Serotonin-receptor modifying drugs: GI prokinetic: agents increase GI motility by increasing Ach release Cisapride: Agonist of 5-HT4 receptor which increase Ach release Therapeutic uses: Gastric/intestinal stasis Reflux esophagitis Constipation Adverse effects: Diarrhea and abdominal pain Metoclopramide: D2-receptor antagonist and 5-HT4 agonist Therapeutic uses: vomiting disorders (antiemetic) Reflux esophagitis Gastric stasis or hypomotility. Adverse effects: Restlessness, drowsiness and depression  Cyproheptadine: 5-HT2 antagonist and H1-antihistamine Therapeutic uses: Appetite stimulant in cats Treatment of feline asthma and pruritus in cats managing hives in horses (H1-antagonist) Adverse effects: sedation, anticholinergic activity and lethargy.  PHOSPHOLIPID-DERIVED MEDIATORS A. Eicosanoids Synthesis of Eicosanoids Membrane Phospholipid Phospholipase A2 Arachidonic Acid Cyclooxygenase Cyclic Endoperoxides Lipoxygenase Prostaglandins Thromboxanes Leukotrienes PGs TXs LT Pharmacologic effects Vasodilatation Bronchoconsrictiion Increase gastric mucus secretion PGE2 Decrease gastric acid secretion Fever  Vasodilatation PGI2  Inhibits platelet aggregation Prostacyclin  Bronchodilation  Luteolysis  ovulation PGF2a  Parturition  Vasoconstriction  Bronchoconstriction  Synthesized by platelet  Vasoconstriction TXA2  Promote platelet aggregation Therapeutic uses: (Only PGE and PGF2α analogs are used therapeutically) Misoprostol: PGE analog  inhibits gastric acid secretion by parietal cells and stimulate mucus secretion  Used to treat gastric ulceration caused by NSAIDS Dinoprost and cloprostenol. Dinoprost is the drug name for PGF2α cloprostenol is a synthetic PGF2α analog.  Uses  Induce luteolysis for the control of estrous cycle  Terminate pregnancy  Induce parturition  Precautions: to the use of PGF2α drugs:  Might cause bronchoconstriction and asthma  Abortion of pregnant animals  Leukotrienes (LTs) synthesized by the 5-lipoxygenase (5-LOX) in neutrophils, monocytes, macrophages, mast cells, keratinocyte, lungs, spleen, brain, and heart.  Pharmacologic effects.  potent vasoconstrictors.  potent bronchoconstrictors (more potent than histamine)  increase capillary permeability.  increase mucous secretion by respiratory pathway. LT antagonists. LOX inhibitors: Block LTs production Zileuton Receptor antagonists: Block LT receptor  Montelukast (Singulair)  Used for treatment of asthma symptoms.  Reduce bronchial spasm and improve pulmonary ventilation POLYPEPTIDES (Angiotensin) Antagonists of the renin–angiotensin system ACE Inhibitors. (Captopril, Enalapril, Lisinopril, Benazepril) pharmacologic/therapeutic effects: ▪ decrease blood pressure in hypertensive patients ▪ Causes vasodilation ▪ Increase sodium and water excretion and Increase urine output β1-Adrenergic antagonists: ▪ Sympathetic system promotes the release of renin from juxtaglomerular cells via β1-receptors. ▪ Propranolol inhibit activation of β1-receptors and reduce renin release. Angiotensin I (AT1) receptor antagonists: (losartan, and valsartan) competitive angiotensin II receptor type-1 and act to reduce responses to angiotensin II Block vasoconstriction and aldosterone secretion  Used as antihypertensive drugs. Renin receptor inhibitor: (aliskiren).  inhibits the conversion of angiotensinogen to angiotensin I.  Used for controlling hypertension