Alpha blockers Pharmacology CBME MBBS 2nd year

2nd year MBBS presentation on alpha blockers

1. Alpha blockers Dr Sirisha A MBBS,MD Assistant professor Dept of Pharmacology

2. Competency PH 1.13 Describe mechanism of action, types, doses, side effects, indications and contraindications of adrenergic and anti-adrenergic drugs

3. Contents Introduction Classification Pharmacological actions Adverse effects & contraindications Uses Individual drugs 7/12/2023

4. Introduction

5. Differences between ∝ 1 & ∝ 2 ∝ 1 ∝ 2 Location Post junctional on effector organs Prejunctional Function Smooth Ms – contraction Bl.vessels – Constriction Glands – Secretion Gut – relaxation Liver – Glycogenolysis Heart - arrhythmias Inhibition of transmitter release Bl.vessels – Constriction ↓ Central sympathetic flow, insulin release Plt . aggregation Selective agonist Phenylephrine Clonidine Sel. Antagonist Prazosin Yohimbine Effector pathway IP3/DAG,PLA 2 K + cAMP or IP3/DAG, K + , Ca +2

6. Pharmacological actions Blockade of vasoconstrictor ∝ 1 receptors reduces peripheral resistance and causes pooling of blood in capacitance vessels Venous return and cardiac output are reduced Fall in BP. Patients receiving an ∝ blocker (e.g. Prazosin for hypertension or benign prostatic hypertrophy) do not suddenly stand up after being supine on the dental chair.

7. The ∝ blockers abolish pressor action of Adr (injected i.v. in animals) which then produces only fall in BP due to β2 mediated vasodilatation— vasomotor reversal of Dale . Pressor and other actions of selective α agonists (NA, phenylephrine) are suppressed Pharmacological actions

8. Reflex tachycardia occurs due to fall in mean arterial pressure and increased release of NA due to blockade of presynaptic α 2 receptors. Pharmacological actions

9. Nasal stuffiness nasal blood vessels Miosis radial muscles of iris Intestinal motility is increased — inhibition of relaxant influences— diarrhoea may occur. α blockers can inhibit ejaculation may manifest as impotence. Pharmacological actions

10. Reduced renal blood flow G.F.R. is reduced Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α 1 receptors urine flow in patients with benign hypertrophy of prostate (BHP) is improved Pharmacological actions

11. Uses Pheochromocytoma Hypertension Benign prostatic hypertrophy Secondary shock Peripheral vascular diseases

12. Pheochromocytoma It is a tumour of the adrenal medulla, where excess CA are secreted Causes intermittent or persistent hypertension. Phenoxybenzamine can be used as definitive therapy for inoperable and malignant tumours . Used before and during surgical removal of the tumour .

13. Hypertension Phentolamine/phenoxybenzamine In controlling episodes of rise in BP during clonidine withdrawal and cheese reaction in patients on MAO inhibitors

14. Benign hypertrophy of prostate (BHP) Causes urinary obstruction  1 receptors blockade causes Relaxes smooth muscles, Reducing dynamic obstruction, Increasing urinary flow rate Causes more complete emptying of bladder in many patients of BHP. Terazosin, doxazosin and tamsulosin are the peferred  1 blockers because of once daily dosing.

15. Side effects Palpitation Postural hypotension Nasal blockage Loose motions Inhibition of ejaculation and impotence.

16. Selective vs Non selective

17. Ergot alkaloids  - blocking Ergotamine & ergotoxine – Vasoconstriction – direct, bradycardia, vomiting. Uses Ergotamine 1mg + caffeine 100mg for treatment of migraine

18. Phentolamine  1 and  2 receptor blocker Uses: For diagnosis and intra operative management of pheochromocytoma 5mg/ i.v – fail of B.P > 35 mm Hg. Systolic & >25 mm hg diastolic →diagnosed as pheochromocytoma, 2.5 to 10 mg i.v during intra operative removal of pheochromocytoma. To treat severe hypertension during clonidine with drawal .

19. Prazosin Block  1 receptor ↓B.P (supine & standing) Less reflex tachycardia Therapeutic – uses Moderate to severe hypertension Benign hypertrophy of prostrate by ↓urinary bladder sphincter tone and Improves urinary flow. Raynaud’s disease. 7/12/2023

20. Tamsulosin  1A /  1D blocker  1A pre dominate in bladder & prostate. Relieve urinary symptoms of BPH patient Uses: BPH. 7/12/2023

21. Yohimbine Selective  2 blocker ↑BP ↑HR Excitation & tremor Uses: No clinical use.

22. Ganglion blockers Dr.A.Sirisha MBBS, MD

23. Ganglion A ganglion is a nerve cell cluster or a group of nerve cell bodies located in the autonomic nervous system and sensory system

24. Ganglionic stimulants

25. Nicotine Principal alkaloid in tobacco ( nicotiana tabacum ). It acts as an agonist on both N N and N M subtypes of nicotinic cholinergic receptors ( nrs ) Sympathetic as well as parasympathetic ganglia are stimulated, but larger doses cause persistent depolarization and ganglionic blockade

26. Smoking cessation Most important measure to help smokers quit is counselling and motivation . Goals of such pharmacotherapy are: To reduce the craving for the satisfying (reward) effects of nicotine. To suppress the physical withdrawal symptoms of nicotine which manifest as restlessness, irritability, anxiety, aggression, inability to concentrate, depressed mood and unhappiness.

27. Pharmacotherapy of Smoking cessation Nicotine replacement : Nicotine transdermal, Nicotine chewing gum Varenicline Bupropion

28. Pharmacotherapy of Smoking cessation Nicotine replacement : Nicotine transdermal, Nicotine chewing gum Varenicline Bupropion

29. Nicotine replacement Actions : Ameliorates the symptoms of nicotine withdrawal Partially suppresses the craving Side effects: headache, dyspepsia, abdominal cramps, loose motions, insomnia, flu-like symptoms and local irritation, Vasospastic angina. Contraindications: Cardiac arrhythmias and ischaemic heart disease

30. Nicotine transdermal: Disadvantage: Intermittent peak nicotine blood levels that occur during smoking are not reproduced by the patch. 10, 20, 30 cm2 patches releasing 7, 14, 21 mg nicotine per 24 hr respectively. In those smoking > 20 cigarettes every day-start with 30 cm2 patch, shift to smaller patches every 5–8 days, treat for 3–4 weeks (max. 12 weeks) Nicotine replacement

31. Nicotine chewing gum: Developed as an alternative to nicotine transdermal, this formulation is found more satisfying by some dependent subjects. 1, 2, 4 mg chewing gum; for those smoking >20 cigarettes/day—start with 4 mg gum chewed and retained in mouth for 30 min when urge to smoke is felt. After a few days change over to 2 mg gum and then to 1 mg gum. Not more than 15 pieces are to be allowed in a day. Nicotine replacement

32. A nasal spray delivering 0.5 mg per activation, and an inhaler with nicotine cartridge Nicotine replacement

33. Pharmacotherapy of Smoking cessation Nicotine replacement : Nicotine transdermal, Nicotine chewing gum Varenicline Bupropion

34. Varenicline Mechanism of action: α4β2 subtype NR in nucleus accumbens and other mesolimbic areas selective partial agonist Actions : induces DA release which produces feelings of reward and reinforcing effect Reduces craving Reduces nicotine withdrawal symptoms.

35. Dose: initially 0.25 mg BD; gradually increase upto 1 mg for not more than 12 weeks; then taper off Side effects: Mood changes, irrational behaviour , Appetite and taste disturbances, sleep disorder and agitation. May promote suicidal thoughts Varenicline

36. Pharmacotherapy of Smoking cessation Nicotine replacement : Nicotine transdermal, Nicotine chewing gum Varenicline Bupropion

37. Bupropion Atypical antidepressant Mechanism of action: Inhibits reuptake of DA and NA Sustained release tablet specifically for smoking cessation Side effects : insomnia, agitation, dry mouth and nausea, Seizures Contraindications: Eating disorders, bipolar illness