Pharmacology lecture 1 Dr. Sameer Al- Rekabi

1. Pharmacology lecture 1Dr. Sameer Al- Rekabi Autacoids = local hormones

2. DEFINITION These are heterogeneous group of chemical substances with wide spectrum of biological effects , synthesized by different tissues and exerting local effect with no or very minute serum level. Autacoids' include histamine , serotonin , prostaglandins , leukotriens , vaso-active intestinal polypeptides (VIPs), kinins, Angiotensin , Nitric oxide (NO), endothelin,…………etc.

3. HISTAMINE and ANTI-HISTAMINES Histamine : is a bioactive amine , widely distributed in animal and plant tissues. In human body, histamine present in skin , GIT , lungs , CNS , CVS, basophiles. It is stored in granules in mast cell, it is released in response to many physical and chemical agents that lead to de-granulation of the mast cells.

4. Synthesis: Histamine is synthesized by 2 enzymes: 1- Histidine de-carboxylase that converts histidine to histamine. This enzyme is inhibited by methyl histidine. 2- Aromatic amino acid de-carboxylase which is non specific enzyme and inhibited by methyl-dopamine .

5. Release: Histamine is released by the process of de-granulation in response to: 1- Immunological reactions : Ag-Ab complex stimulates mast cell de-granulation. 2- Chemical and mechanical reactions like histamine release by drugs like morphine codeine , Vancomycin , polymexin,……….etc. Mechanical reaction like in triple response of Lewis.

6. Metabolism : By 2 routs 1- By histaminase or di-amine oxidase. 2- By histamine methylating enzymes.

7. Mechanism of action of histamine: Histamine acts by binding to 4 subclasses of receptors [ H1 , H2 , H3 , H4] which distributed in different tissues.

8. Physiological role of histamine: 1- neurotransmitter in CNS. 2- Micro-circulatory regulation. 3- control sleep and alertness . 4- correlates with fetal development . 5- wounds healing. 6- Has a role in thermal and body weight regulation. 7- WBC chemotaxis. 8- Gastric acid secretion.

9. Pharmacological action of histamine: 1- CVS : ↓ in systolic and diastolic blood pressure. On heart : -ve inotropic effect through H1 receptor . +ve inotropic and chronotrpic effect through H2 receptor.

10. 2- Gastric acid secretion: histamine is a potent stimulator of gastric acid secretion , and to lesser extent pepsin and intrinsic factor.

11. 3- Effect on smooth muscles: It has a stimulatory action , it causes profound bronchiospasm in patient with bronchial asthma .It increases intestinal motility and may causes diarrhea in large dose.Histamine has no significant action on smooth muscle of genitor-urinary tract and eyes.

12. 4- Gland secretion : has no significant action.5- Suprarenal medulla : stimulates the release of adrenalin and noradrenalin in normal subject. It causes massive secretion of catecholamines in patients with pheochromocytoma.6- On nerve endings: It stimulates the sensory nerve endings causing pain and itching.

13. Triple response of Lewis: Injection of small dose of histamine (10 micrograms) intradermally causes the triple response of Lewis which includes: 1- Local redness due to local vasodilatation . 2- Wheal (oedema) due to increase in the permeability of blood capillaries. 3- Diffused redness ( flare) due to general vasodilatation related to neural mechanism ( axonal reflex).

14. Clinical indication of histamine: Histamine has no therapeutic roles but can be used clinically in: 1- Diagnosis of pernicious anemia. 2- Measurement of gastric acid secretion . 3- Diagnosis of pheochromocytoma.

15. Side effects of histamine : Headache , flushing , hypotension , tachycardia , bronchiospasm , GI upset.

16. Contraindications : 1- Bronchial asthma . 2- Active peptic ulcer. 3- Pheochromocytoma.

17. Histamine agonists : 1- Betazole : Isomer of histamine and acts on H2 receptor . It is used for diagnosis of gastric acid secretion but it is contraindicated in case of bronchial asthma. 2- Betahistine : It is analogue of histamine and acts on H1 receptor , it is used in the treatment of Meneire,s disease . IT should be used cautiously in patients with bronchial asthma and pheochromocytoma.

18. Histamine antagonists : The action of histamine can be antagonized by : 1- Physiological antagonist : By adrenalin . 2- Competitive pharmacological antagonists : we have H1 and H2 blockers . 3- Mast cells stabilizers (drugs that prevent mast cell de-granulation ) like chromolyin and nedochromil.

19. Anti-histamines (H1 blockers) These are heterogeneous group of drugs that antagonize the effect of histamine on H1 receptor , rapidly absorbed from GIT , extensively metabolized by liver , excreted by kidney , also secreted into milk of lactating woman.

20. Pharmacological actions of H1 blockers: 1- they produce CNS depression in therapeutic doses BUT may produce CNS stimulation , convulsion and hyperthermia when they are given in large doses especially in children. 2- they have anti-nausea and anti-vomiting effects. 3- Anti-cholinergic effect (dry mouth, constipation , urine retention , glaucoma ,….) 4- Local anesthetic effect. 5- Anti- parkinsonism effect. 6- Antiserotoninergic effect 7- α- adrenoceptor blocking effects. 8- they inhibit P-glycoprotein (P-glycoprotein responsible for cytotoxic drugs efflux outside of tumor cells).

21. Classification of H1-blockers: 1- 1st generation H1-blockers General properties include : a- Great CNS depression . b- relatively of short duration of action. c- relatively of little dangerous drug interaction with macrolides antibiotics and antifungal drugs.

22. 1st generation H1 blockers includes :1- Ethanolamine group : like Diphenhydramine (allermin) .2- Ethylenediamine group : like Antazoline.3- Alkylamine group: like chlorpheneramine (Histadine).4- Piperazin group: like Hydroxyzine , cyclizine. 5- Phenothiazines group: like promethazine.6- Miscellaneous group : like cyproheptadine (periactin) which used as appetite stimulant especially in children , in carcinoid syndrome (it has antiserotoninergic effect), in hay fever , in dumping syndrome after gasterectomy, as prophylactic in migraine .Other drugs like acrivastin , clemastin , loratidine ,des-loratidine , ketotifen,………

23. 2- 2nd generation H1 blockers : General properties includes: a- Low or no CNS depression. b- relatively of long duration of action. c- relatively of dangerous drug interaction with macrolides antibiotics(erythromycin and Clarithromycin) and anti-fungal (Ketocanazole) drugs that may lead to prolonged QT interval and ventricular arrhythmias.

24. 2nd generation H1 blockers includes : Astimazole , Terfenadine , Fexofenadine, Cetrizine.

25. Clinical indications : 1- Angio-noretic oedema ., 2- Allergic dermatosis , 3- Urticaria , 4- Hay fever , 5- Motion sickness , 6- insect bite , 7- anaphylactic shock, 8- blood transfusion allergic reactions.

26. Side effects of H1-blockers Sedation , dizziness , insomnia , blurred vision, tinnitus , parasthesia .

27. Drug interactions : 1- Non- specific CNS depressants like Alcohol , Barbiturates . 2- Anti-cholinergic drugs. 3- α- adrenoceptor blockers.

28. Contraindications of H1 blockers : 1- Hypersensitivity to the drugs. 2- Sever bronchial asthma. 3- Prostatic hyperplasia. 4- Closed angle glaucoma. 5- Bladder neck obstruction . 6- breast feeding.

29. Serotonin and anti-serotonin Serotonin is a bioactive amine that can be synthesized by hydroxylation of amino acid tryptophan to 5-hydroxy tryptophan ( by enzyme = tryptophan hydroxylase) then by enzyme aromatic amino acid decarboxylase to 5-hydroxy tryptamine= serotonin.

30. Serotonin is one of most important autacoid , has many physiological roles and serotonin agonists and antagonists have many clinical applications . Serotonin is widely distributed in plants and animal tissues. In human , about 90% of total body serotonin present in enterochromaffin tissues , 8% in platelets and 2% in CNS .

31. Serotonin metabolism : By mono-amino oxidase enzyme to form 5- hydroxy indol acetic acid which is excreted in the urine in amount of about 3-10 mg /day. The excretion of 5-hydroxy indol acetic acid ↑ in the following conditions : 1- Carcinoid syndrome ( tumor of enterochromaffin cells). 2- in case of using some of old anti-hypertensive drugs (reserpine). 3- ingestion of banana.

32. Physiological roles of serotonin: 1- It acts as a neurotransmitter in the brain. 2- Regulation of temperature. 3- Pain perception . 4- In pathogenesis of migraine. 5- In pathogenesis of depression. 6- In pathogenesis of anxiety. 7- Involved in intestinal motility . 8- Control of vomiting. 9- Control of appetite. 10- Pathogenesis of carcinoid syndrome.

33. Mechanism of action of serotonin: Serotonin exerts its action by binding to 7 subtypes of receptor [ 6 of them are G-protein coupled and one of them "5-HT3" is ionic channels coupled. The second messenger of G-protein coupled receptors is either cyclic AMP or IP3 and DAG.

34. Pharmacological action of serotonin: 1- CVS: - On heart : serotonin has small +ve inotropic and +ve chronotropic effect on the heart. Elevated plasma level of serotonin in carcinoid syndrome lead to pathogenic endocardial changes. - On blood vessels : serotonin produces triphasic response which includes: 1- early depressor phase due to ↓ heart rate and cardiac output due to chemoreceptor reflex. 2- Presser effect due to ↑ peripheral vascular resistance and cardiac output. 3- Late depressor phase : related to vasodilatation in skeletal muscle.

35. 2- Respiratory system: Serotonin produces a small direct stimulation to bronchial smooth muscle in normal person but produce a bronchiospasm in patients with carcinoid syndrome. Serotonin produces hyperventilation due to stimulation of bronchial sensory nerve endings.

36. 3- GIT: serotonin has a potent stimulation on the smooth muscle of the gut which increases the tone and facilitate peristalsis that related to the action of serotonin on 5HT receptor in smooth muscle and ganglionic stimulation of the enteric plexus .

37. 4- CNS : Stimulation of sensory nerve endings leads to pain and itching.

38. 5- Glandular secretion: Serotonin has little inhibitory effects on exocrine glands.

39. 6- Uterus: Large dose of serotonin impairs placental blood supply and may lead to fetal distress.

40. Serotonin syndrome : It is related to the interactions of serotonin re-uptake inhibitors with mono-amino oxidase inhibitors (MAOIs) or interactions of serotonin agonists with MAOIs. It is a clinical emergency with high mortality rate and characterized by rigidity , hyperthermia , myoclonus , mental changes, tachycardia. Treatment is supportive.

41. Serotonin agonists : 1- Buspirone : acts on 5-HT1A receptor .It is an anxiolytic drug ( non benzodiazepines non barbiturates anxiolytic). 2- Dexfenfluramine : Suppresses appetite and used to ↓ body weight. 3- Sumatriptan ,Amlotriptan , Eletriptan , Naratriptan , Rizatriptan , Zolmitryptan : They act on 5-HT 1 B and D receptors and used in treatment of acute migraine. 4- Cisapride : It is used in the management of reflux esophagitis but now rarely used because it causes serious ventricular arrhythmias .It acts on 5-HT4 receptors .Other 5-HT4 receptor agonists are: Tagaserol and metaclopromide .

42. Serotonin antagonists: 1- Cyproheptadine (periactin): It is H1 and 5-HT2 blocker , used mainly as appetite stimulant. Other uses include : Allergic rhinitis , cold urticaria , prophylaxis of migraine , in Dumping syndrome after gasterectomy and in carcinoid syndrome. 2- Ketanserin: It is 5-HT 2 and α-blocker . It was used in the treatment of hypertension . 3- Ritanserin : It is 5-HT2 blocker and has no α- blocking effect.

43. 4- Ondansetron , Granisetron ,Tropisetron and Alosetron: Acts on 5-HT3 receptor as antagonists and used mainly in cytotoxic induced nausea and vomiting.5- Ergot Alkaloids : They are produced by fungus that infects grain . Ergots act on the following receptors:a- Serotonin receptor.b- α adrenoceptor.c- Dopamine receptor. Ergots act as agonist , partial agonist or antagonist.

44. Ergotism: It is the clinical manifestation of ergot alkaloid poisoning and characterized by nausea , vomiting , abdominal pain , abortion of pregnant woman , gangrene , hallucination , confusion and convulsion.

45. Ergot alkaloid drugs and their clinical uses:1- Bromocriptine: used in acromegaly and hyperprolactinaemia. 2- Ergotamine : used in acute migraine .3- Ergonovine: used in post-partum hemorrhage and diagnosis of Varian angina .4- Lysergic acid diethylamide (LSD) :It is a hallucinogenic agent.5- Methysergide: used in migraine prophylaxis.6- Dihydroergotoxin : Used in cerebral insufficiency.

46. Side effects of Ergot Alkaloids:Nausea , vomiting , abdominal pain , drowsiness , hallucination , confusion , abortion, retro-peritoneal fibrosis, gangrene.

47. Migraine Syndrome: It is a syndrome of recurrent throbbing unilateral headache with or without aura ( visual halos) with nausea , vomiting , phonophobia and photophobia.

48. Aetiology: It is poorly understood , it is precipitated by stress , anger , fatigue , diet , rich in chocolate and cheese , alcohol , menses in female or using contraceptive , hypoglycemia. Changes in vascularity between intra and extra- cranial blood vessels and stimulation of trigeminal nerve by calcitonin genes related peptides are the most popular concept concerning Aetiology of migraine.

49. Treatment of migraine : 1- Treatment of acute attack : by using Paracetamol , NSAIDs (aspirin), serotonin agonists like Sumatriptan , ……..other serotonin agonists or by ergot alkaloid derivatives like ergotamine. Other supportive treatment like anti-emetic , sedative.

50. 2- prophylactic treatment : many drugs are used with different outcome like calcium channel blockers ( Verapamil), B-blockers (propranolol ) , ergot alkaloid ( Methysergide) , clonidine, tricyclic anti-depressant (imipramine), anti-serotonin ( cyproheptadine and pizotifen) .