Autacoids Pharmacology PDF

Autacoids Pharmacology Martin Amanya  Autacoids Pharmacology  Histamine agonists & antagonists  Serotonin (5-Hydroxytryptamine or 5-HT,) Agonists & antagonists  Ergot Alkaloids  Lipid-derived autacoids(Prostaglandins, leukotrienes & Thromboxanes)  Peptide autacoids Plasma...

Autacoids Pharmacology Martin Amanya  Autacoids Pharmacology  Histamine agonists & antagonists  Serotonin (5-Hydroxytryptamine or 5-HT,) Agonists & antagonists  Ergot Alkaloids  Lipid-derived autacoids(Prostaglandins, leukotrienes & Thromboxanes)  Peptide autacoids Plasma kinins (Bradykinin, Kallidin), Neuropeptides; cytokines; Angiotensin Learning objectives. After completing this chapter, you should be able to: Describe the role of histamine ,serotonin, & prostaglandins as a chemical modulators of certain physiological functions Describe the mechanism of action & pharmacological effects of autacoids (H,5HT, ergots & PGs) Identify the various therapeutic uses of autacoids(H,5HT, ergots & PGs) 10/30/2024 Autacoid Pharmacology 3 Autacoids & Related Drugs Autacoids: Derived from Greek: autos—self, akos—healing substance or remedy. Autacoids are diverse substances produced by a wide variety of cells in the body, having intense biological activity, but generally act locally (e.g. within inflammatory pockets) at the site of synthesis and release. They have also been called ‘local hormones’. o They differ from ‘hormones’ in two important ways—hormones are produced by specific cells, & are transported through circulation to act on distant target tissues. Autacoids are involved in a number of physiological & pathological processes. 10/30/2024 4 10/30/2024 Systemic Pharmacology , Autacoids 5 Major classes of Autacoids 1. Biogenic amines: Histamine, Serotonin (5-hydroxytryptamine) 2. Polypeptides: Plasma kinins (Bradykinin, Kallidin, angiotensin) 3. Lipid-derived autacoids a. Eicosanoids. Prostaglandins, leukotrienes, thromboxane b. Platelet activating factor 4. In addition, cytokines (interleukins, TNFα, Granulocyte- macrophage colony-stimulating factor(GM-CSF) & several peptides like gastrin, somatostatin, vasoactive intestinal peptide & many others may be considered as autacoids. 10/30/2024 6 Biogenic amines 1. HISTAMINE & RELATED DRUGS Histamine is a biogenic amine produced primarily by mast cells & basophils, which are particularly abundant in the skin, gastrointestinal tract, & respiratory tract. Histamine is also produced by paracrine cells in the gastric fundus, where it stimulates acid secretion by parietal cells. Histamine also functions as a neurotransmitter in the CNS. 10/30/2024 7 Synthesis & Degradation of histamine 10/30/2024 Autacoid Pharmacology 8 Distribution & storage sites. a. Primary tissue sites storing histamine are the lungs, skin, mucosal layer of the stomach & basophils. b. Mast cells are the primary cells that store histamine where it exists in a complex with heparin sulfate & chondroitin sulfate E in storage granules. c. Histamine is also found in CNS where it may act as a neurotransmitter 10/30/2024 Autacoid Pharmacology 9 Distribution & storage sites cont’d d. Many venoms and insect stings contain histamine, as well as other biologically active substances. e. Histamine is found in the digesta where it is formed in large part by bacterial action. This histamine normally does not reach the systemic circulation since it is metabolized by enzymes in the gut wall & liver. 10/30/2024 10 Release of Histamine a. Energy- & Ca 2+-dependent degranulation reaction (Immune release) Release of histamine from mast cells is induced by immunoglobulin E (IgE) fixation to mast cells (sensitization) & subsequent exposure to a specific antigen; complement activation (mediated by immunoglobulin G or immunoglobulin M) may also induce degranulation. This is also referred to type I IgE-mediated hypersensitivity reaction. 10/30/2024 11 b. Energy- & Ca2+-independent release (displacement) or Drug- induced release. i. Displacement is induced by drugs such as morphine, tubocurarine, guanethidine, & amine antibiotics. ii. Mast cell damage, which is caused by noxious agents such as venom or by mechanical trauma, can release histamine. 10/30/2024 12 Drug-induced release. Drugs, usually strong bases (morphine, polymyxin, tubocurarine, codeine, lidocaine, penicillin), &/or their vehicles are capable of releasing histamine but this release does not involve degranulation or mast cell injury.  Polymers like dextran, polyvinyl pyrrolidone (PVP).  These drugs displace or compete with histamine for the binding sites with heparin 10/30/2024 13 Release of Histamine conti… c. Plant & animal stings are capable of releasing histamine, which is an important component of the physiologic reaction (erythema, pain, itch) to these stings. d. Physical injury such as heat, cold, or trauma can disrupt the mast cells thereby releasing histamine. 10/30/2024 14 10/30/2024 Autacoid Pharmacology 15 Histamine liberators & its effects 10/30/2024 16 Mast cells are found along blood vessels or in the circulation as basophils. In response to an allergic stimulus, mast cells release histamine. 10/30/2024 17 Symptoms of Histaminic Response in Allergy: Red, Watery, Itchy Eyes & Runny Nose 10/30/2024 18 Lewis Triple response of histamine If histamine is injected intradermally or when the skin is exposed to a physical trauma a triple response will be elicited. That consists of: 1. Localized red spot: Immediate redness of the skin, extending for a few (mm) around the site of injection, that appears within few seconds & recovers maximally in a bout minute (direct vasodilation) due to capillary dilation. 2. Bright red flush (Flare): Red & irregular extending about (1cm) beyond the original red spot and develops slowly. Results in itching % pain, due to arteriolar dilatation. 10/30/2024 19 Lewis Triple response of histamine cont’d 3. Wheal (edema): It occurs in 1 or 2 minutes. Occupying the same area at the original red spot of injection site. Due to increased capillary permeability & due to exudation of fluid from capillaries & veins. 10/30/2024 20 Histamine receptors Four classes of receptors (H1, H2, H3, & H4) mediate the action of histamine Histamine (H1)-receptors H1-receptors are found in the brain, heart, bronchi, GI tract, vascular smooth muscles, & leukocytes Histamine (H2)-receptors H2-receptors are membrane bound; they are found in the brain, heart, vascular smooth muscles, leukocytes, & parietal cells. Histamine (H3)-receptors H3-receptors are found in the central nervous system (CNS) & peripheral nervous system (PNS) at presynaptic nerve terminals Histamine (H4)-receptors H4-receptors are found on hematopoietic cells, in the spleen, thymus, & colon. 10/30/2024 21 10/30/2024 Autacoid Pharmacology 22 Mechanism of action & effects of histamine Histamine exerts its effects by binding to histamine (H) receptors 10/30/2024 Autacoid Pharmacology 23 Physiologic Responses Following Histamine Stimulation 10/30/2024 Autacoid Pharmacology 24 PHARMACOLOGICAL ACTIONS 1. Blood vessels Histamine causes marked dilatation of smaller blood vessels, including arterioles, capillaries & venules. Larger arteries & veins are constricted by histamine: mediated by H1 receptor on vascular smooth muscle. Histamine also causes increased capillary permeability due to separation of endothelial cells → exudation of plasma. This is primarily a H1 response. 10/30/2024 Autacoid Pharmacology 25 2. Heart Direct effects of histamine on in situ heart are not prominent, but the isolated heart, especially of guinea pig, is stimulated: rate as well as force of contraction is increased. These are primarily H2 responses but a H1 mediated negative dromotropic (slowing of A-V conduction) effect has also been demonstrated. 3. Bronchial tissue Histamine causes bronchoconstriction. Smooth muscle contraction is a H1 response. 4. Glands Histamine causes marked increase in gastric secretion This is a direct action exerted on parietal cells through H2 receptors and is mediated by increased cAMP generation, which in turn activates the membrane proton pump (H+ K+ ATPase). 10/30/2024 Autacoid Pharmacology 26 5. Sensory nerve endings Itching occurs when histamine is injected i.v. or intracutaneously. Higher concentrations injected more deeply cause pain. These are reflections of the capacity of histamine to stimulate nerve endings. 6. Autonomic ganglia & adrenal medulla These are stimulated and release of Adrenaline occurs, which can cause a secondary rise in BP. 7. CNS Histamine does not penetrate blood brain barrier—no central effects are seen on i.v. injection. However, intra- cerebroventricular administration produces rise in BP, cardiac stimulation, behavioural arousal, hypothermia, vomiting & ADH release. These effects are mediated through both H1 & H2 receptors 10/30/2024 Autacoid Pharmacology 27 8. Skin Intradermal injection of histamine produces a triple response. Insect & plant stings mimic many of these responses. 1) A reddening at the site of injection is due to dilation of the small arterioles. 2) Dilation of arterioles extends beyond injection site 3) Swelling (Wheal) occurs at the injection site due to separation of the endothelial cells and edema caused by the increased capillary permeability, which is due to H1-receptor-mediated contraction of endothelial cells 4) The intradermal injection of histamine causes pain & itching by stimulation of H1-receptors on sensory nerve endings. 10/30/2024 28 PATHOPHYSIOLOGICAL ROLES 1. Gastric secretion Histamine has dominant physiological role in mediating secretion of HCl in the stomach 2. As transmitter Histamine is believed to be the afferent transmitter which initiates the sensation of itch and pain at sensory nerve endings. 3. Inflammation Histamine is a mediator of vasodilatation & other changes that occur during inflammation. It promotes adhesion of leukocytes to vascular endothelium by expressing adhesion molecule P-selectin on endothelial cell surface, sequestrating leukocytes at the inflammatory site. 4. Headache Histamine has been implicated in certain vascular headaches, but there is no conclusive evidence. 10/30/2024 29 5. Tissue growth & repair Because growing & regenerating tissues contain high concentrations of histamine, it has been suggested to play an essential role in the process of growth and repair. 6. Allergic phenomena Histamine is causes in urticaria, angioedema, bronchoconstriction & anaphylactic shock. 7. Histamine is involved in IgE type of allergic reactions. i.e. in immediate type of hypersensitivity reactions. Histamine is not involved in delayed or retarded type of allergic reactions. 10/30/2024 Autacoid Pharmacology 30  Histamine agonists Prototypes. These agents include histamine, betahistine, Betazole & impromidine. Uses Histamine is of no therapeutic value. It is occasionally used in some diagnostic tests like: i. Testing gastric acid secretion: To test the acid secreting ability of the stomach. Now pentagastrin is preferred for this purpose. ii. Diagnosis of pheochromocytoma: Histamine releases catecholamines & raises BP— now not used. iii. Pulmonary function: To test for bronchial hyper-reactivity. 10/30/2024 Autacoid Pharmacology 31 Histamine agonists Adverse effects histamine agonists. The adverse effects of these agents can be quite severe; they include:  flushing,  a burning sensation,  hypotension,  tachycardia, &  bronchoconstriction. 10/30/2024 Autacoid Pharmacology 32 ANTIHISTAMINE DRUGS Classification 10/30/2024 Autacoid Pharmacology 33 Mechanism of action of H1-blockers H1-antihistamines antagonize the effects of histamine by competitively blocking H1-receptors (competitive antagonism). 10/30/2024 Autacoid Pharmacology 34 HI antihistaminic agents HIGHLY SEDATIVE MILD SEDATIVE Chlorpheniramine Diphenhydramine Dexchlorpheniramine Dimenhydrinate Dimethindene Promethazine Triprolidine Hydroxyzine Cyclizine MODERATELY SEDATIVE Clemastine Pheniramine SECOND GENERATION ANTIHISTAMINICS Cyproheptadine Fexofenadine Meclizine Loratadine Buclizine Cetirizine Levocetirizine 10/30/2024 Systemic Pharmacology , Autacoids 35  A major difference in the two groups is that the first-generation antihistamines are distributed to the CNS and can cause sedation, whereas the second-generation antihistamines do not cross the blood-brain barrier significantly. First-generation H1-blockers They are the conventional antihistamines. Pharmacological actions 1. H1-blockers cause central nervous system (CNS) depression—sedation & drowsiness. Certain antihistamines have antiemetic & antiparkinsonian effects. 2. They have antiallergic action, hence most of the manifestations of Type-I reactions are suppressed. 3. They have anticholinergic actions —dryness of mouth, blurring of vision, constipation, urinary retention, etc. 10/30/2024 36 Pharmacological Actions Most of the anti-histaminics (H1-receptor antagonists) have similar pharmacological actions 1. Antihistaminic action: The antihistaminics blocks histamine effects at a variety of sites. They inhibit most responses of smooth muscles to histamine They antagonize the stimulant actions of histamine on various smooth muscles of the respiratory system, gastrointestinal tract, the uterus & the blood vessels. 2. Action on central nervous system: Majority of antihistaminic drugs produce variable degree of CNS depression i.e. sedation, drowsiness & sleep. Drugs like diphenhydramine, promethazine are potent sedatives & is often accompanied by inability to concentrate. 10/30/2024 37 3. Antimotion sickness effect: Several H1-antagonists have significant property in preventing motion sickness. This effect was first observed with drug, dimenhydrinate & subsequently with other drugs like diphenhydramine, promethazine and other piperazine derivatives. 4. Anticholinergic effects: Many of the H1-antagonists also tend to inhibit responses to acetylcholine that are mediated by muscarinic receptors. The newer agents, terfenadine & astemizole have no effect on muscarinic receptors. 5. Adrenergic blocking effect: H1- antagonists, specially of phenothiazine subgroups have weak alpha-receptor blocking effect. 6. Antiparkinsonism effects: Because of anticholinergic property, some H1- antagonists have significant suppressant effect on the parkinsonism like symptoms. 10/30/2024 Autacoid Pharmacology 38 7.Local anaesthesia: Most of the H1 antagonists block sodium channels in excitable membranes in the same way as procaine and lignocaine. The drugs like diphenhydramine and promethazine are occasionally used to produce local anaesthesia in patients allergic to local anaesthetic drugs. 8. Antiserotonin effect: Drugs, like cyproheptadine has an anti-serotonin effect. 10/30/2024 39 Pharmacokinetics H1-antagonists are well absorbed from the gastrointestinal tract. Following oral administration, antihistaminic effect is manifested within 30 minutes, peak plasma concentration is achieved in 2 to 3 hours & effects usually last 4 to 6 hours. However, drugs in piperazine subgroups especially chlorcyclizine & meclizine, the actions persists for 8 to 12 & 12 to 24 hours respectively. The drugs are mainly metabolized in the liver by hydroxylation & glucuronide conjugation, widely distributed throughout the body & excreted in the urine. 10/30/2024 Autacoid Pharmacology 40  Therapeutic Uses antihistamines H1 antagonists have a widespread value in the symptomatic treatment of various disorders. 1. Hypersensitivity reactions: To prevent allergic reactions or to treat their symptoms, in which histamine is the primary mediator, the H1-antagonists are the drugs of choice and are often quite effective. They are used primarily to treat allergic reactions produced by the release of histamine e.g., edematous states, pruritus, atopic dermatitis, allergic rhinitis & urticaria & transfusion reactions. They are generally more effective in acute conditions & are used only for symptomatic relief. 10/30/2024 Autacoid Pharmacology 41 2. Motion sickness: Drugs like promethazine, promethazine chlorotheophyllinate,diphenhydramine, dimenhydrinate, cyclizine & meclizine have value in prophylaxis of motion sickness. The antihistamines prevent or diminish nausea & vomiting mediated by both the chemoreceptor & vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 & M1 muscarinic receptors. 3. Antivertigo: Drugs line cyclizine, cinnarizine, dimenhydrinate, diphenhydramine are used in the treatment of vertigo. 10/30/2024 Autacoid Pharmacology 42 4. Antiparkinsonism: Based on anticholinergic property, some H1- antagonists such as diphenhydramine can be used in the early stages of treatment of parkinsonism. 5. Local anaesthetics: In patients allergic to procaine H1-antagonists, such as diphenhydramine & tripelennamine have been used successfully as local anaesthetic. 6. Appetite stimulant.eg.fexofenadine & desloratadine 10/30/2024 Autacoid Pharmacology 43 Adverse Reactions The most common side effect, common to all H1 antagonists other than terfenadine and astemizole is sedation. Other reactions include fatigue, dizziness, tinnitus, lassitude, blurred vision, diplopia, euphoria, nervousness, tremor and insomnia. Other Side effects include loss of appetite, nausea, vomiting, epigastric distress, constipation or diarrhoea. Side effects due to anti-muscarinic actions of H1-antagonists include dryness of mouth, bladder disturbances. 10/30/2024 44 Drug interactions. Additive CNS depressant effects may occur when antihistamines are administered concomitantly with other CNS depressants, including barbiturates, Benzodiazepines, alcohol, and other sedatives. Additive anticholinergic: effect also may occur when used in combination with other anticholinergic agents. 10/30/2024 45 Effects of H1 antihistamines at histamine, adrenergic, cholinergic, & serotonin-binding receptors 10/30/2024 Autacoid Pharmacology 46 Second-generation Antihistamines or Non-sedative Antihistamines Non-sedative antihistamines have the following advantages over first- generation antihistamines: 1. They are selective H1 blockers. 2. No sedation because they poorly cross the blood–brain barrier. 3. No anticholinergic side effects as these agents are pure H1 blockers & do not block cholinergic receptors. 4. Some of them are long-acting—given Once Daily(OD). 10/30/2024 Autacoid Pharmacology 47 Disadvantages of 2nd -generation Antihistamines  Therapeutic uses of these agents are limited to allergic disorders like allergic rhinitis & chronic urticaria.  They are ineffective in motion sickness, cough, rhinorrhoea, vomiting & to produce sedation. 10/30/2024 Autacoid Pharmacology 48 2nd generation H1-antihistamines 10/30/2024 Autacoid Pharmacology 49 H2-receptor blockers H2-receptor blockers: cimetidine, ranitidine, famotidine, & nizatidine Gastric acid secretion is stimulated by acetylcholine, histamine, and gastrin The receptor-mediated binding of acetylcholine, histamine, or gastrin results in the activation of protein kinases, which in turn stimulates the H+/K+-adenosine triphosphatase (ATPase) proton pump to secrete hydrogen ions in exchange for K+ into the lumen of the stomach. 10/30/2024 Autacoid Pharmacology 50 MOA of H2-receptor blockers These agents competitively block the binding of histamine to H2 receptors & reduce the secretion of gastric acid. Therapeutic uses 1. Peptic ulcers Effective in promoting the healing of duodenal & gastric ulcers. Patients with NSAID-induced ulcers should be treated with PPIs, because these agents heal & prevent future ulcers more effectively than H2 antagonists do. 10/30/2024 Autacoid Pharmacology 51 2. Acute stress ulcers These drugs are given as an intravenous infusion to prevent and manage acute stress ulcers associated with high-risk patients in intensive care units. Because tolerance may occur with these agents in this setting, PPIs have gained favor for this indication. 3. Gastroesophageal reflux disease (GERD) Low doses of H2 antagonists are effective for the treatment of heartburn (GERD) in only about 50% of patients. 10/30/2024 Autacoid Pharmacology 52 Pharmacokinetics Can be given orally, H2 antagonists distribute widely throughout the body (including into breast milk & across the placenta) & are excreted mainly in urine. Cimetidine, ranitidine, & famotidine are also available in intravenous formulations. The half-life of all of these agents may be increased in patients with renal dysfunction, & dosage adjustments are needed. 10/30/2024 Autacoid Pharmacology 53 Adverse effects H2 antagonists are well tolerated generally Cimetidine can have endocrine effects because it acts as a nonsteroidal antiandrogen & its effects include gynecomastia (enlarged breasts in men) & galactorrhea (continuous release/discharge of milk). Can cause Impotence men. CNS effects such as confusion & altered mentation occur primarily in elderly patients & after intravenous administration. 10/30/2024 Autacoid Pharmacology 54 Drug interactions Cimetidine inhibits several cytochrome P450 iso-enzymes and can interfere with the metabolism of many other drugs, such as warfarin, phenytoin, and clopidogrel All H2 antagonists may reduce the efficacy of drugs that require an acidic environment for absorption, such as ketoconazole. 10/30/2024 Autacoid Pharmacology 55 Case 1 X is a 23-year-old woman with no medical conditions, who comes into the clinic requesting medication for hay fever. She has been experiencing frequent sneezing, watery itchy eyes. and congestion. She works at a law firm during the day and would prefer a Quick-acting agent that does not cause sedation i. What is the pharmacology of antihistamines? ii. What are the differences between first- and second generation antihistamines? iii. Other than allergies and allergic reactions. what other conditions are antihistamines used for? iv. What side effects are associated with H1 blocker treatments? 10/30/2024 Autacoid Pharmacology 56 Case 2 An 8-year-old girl is brought in by her mother for evaluation of allergies. Each year in the rain season the child develops a runny nose; itchy, watery eyes; & sneezing. She has been treated in the past with diphenhydramine, but the child’s teacher says that she is very drowsy during school. She has no other medical problems & is on no chronic medications. Her examination is unremarkable today. You diagnose her with seasonal allergic rhinitis & prescribe fexofenadine. i. What is the mechanism of action of fexofenadine? ii. What is the pharmacologic basis of switching to fexofenadine? iii. What are the common side effects of antihistamine medications? iv. Discuss the drug interactions that are associated with fexofenadine medication A taxi driver aged 30 years presented with sudden onset running & itchy nose, bouts of sneezing, partial nasal blockage, redness and watering from the eyes, but no fever, bodyache or malaise. He gave history of similar episodes occurring off and on during the spring season. A diagnosis of seasonal allergic rhinitis was made & the doctor prescribed an oral anti-allergic medication to be taken once a day till symptoms subside. a. Which anti-allergic medicine would be suitable for this patient? Which anti-allergic drugs should be avoided? b. Will the above medication prevent/reduce recurrent episodes of rhinitis that this patient gets during rain season. If not, can some medications be added to prevent/subdue the episodes during the vulnerable season.