Classification of Adrenoreceptor Antagonists

1. Classification of Adrenoreceptor Antagonists • α– blockers • Non selective • Relatively selective • Selective • β– blockers • Non selective • Relatively selective • Selective • Both α and β adrenergic antagonists

2. α– Adrenoceptor Antagonists (α– blockers) يؤثر على واحدة واذا زدنا الجرعة فانه يؤثر على الأخرى

3. Non selective α– blockers(act on α1 and α2 receptors) • Phentolamine and Tolazoline (Reversible) • Induce reversible competitive blockade for α1–adrenoreceptors which can be overcome by increase of NE • T1/2 = 3 – 5 hours • Phenoxybenzamine (Irreversible) • It alkylates the receptors & binds by methyl covalent bond. Thus, it produces irreversible α– blockade which cannot be overcome by increase of NE • t1/2 = 14 – 48 hours

4. Pharmacological effects of α– blockers • I. Effects Mediated by blocking α–receptors • A. Cardiovascular Effects: • 1) They block • α1 causing VD. So, decrease TVR • The pressor effect of α– agonists So, they decrease BP (hypotension) • But they are of limited clinical use in treating hypertension because they may cause: • Tachycardia (Reflex Type) • Cardiac arrhythmia • Angina pectoris • Peptic ulcer • Sexual dysfunction

5. Cont…. • 2) They produce tachycardia more than the α1 – selective blockers by • Producing reflex tachycardia. • All α blocker (selective and non selective) block α1 to inhibit the effect of sympathetic tone on blood vessels. This leads to VD & decrease BP (more obvious during standing ) leading to postural hypotension. This will stimulate the baroreceptors to send impulses to CNS to increase HR • Increase HR by • Block α2 cause increase NE in synapse. NE will bind to β1 receptor leading to ↑HR • Phenoxy benzamine • Block NE reuptake. This will increase NE in synapse leading to increase HR. So, more tachycardia with Phenoxybenzamine as compared to phentolamine. So both drugs block α2 leading to ↑NE but pehnoxybenzamine block reuptake of NE leading to more NE in synap

6. B. Non-cardiac Effects of α– blockers • A) Miosis • b) Nasal stuffness • c)decrease resistance to the flow of urine • d) They decrease adrenergic sweating. So they • produce dry skin • e) Inhibit ejaculation • II. Effects mediated by non- α–adrenergic blocking effects: • They induce weak blockade for: • H 1 receptors (Histamine) (Sedation; antinausea) • Serotonin receptors • Muscarinic receptors (dry mouth)

7. Side effects of Phenoxybenzamine • Fatigue • Nausea (because it enters CNS) • Diarrhea • Postural hypotension. • Tachycardia.

8. α– blockers Relatively selective • Prazosin • Terazosin • Doxazosin Please remember that they act on α1 only but in case of higher doses they might act on α2

9. 1. PrazosinMechanism of action • It is a relatively selective α1 – adrenoceptor competitive antagonist • Its action can be overcome by increasing agonist concentration(reversible) • T1/2 = 3 hours

10. PrazosinActions: • It produces arterial & venous dilation. So it decreases BP, so it is used for the treatment of hypertension • It causes less tachycardia than non–selective vasodilators (because it doesn’t act on α2 receptors) • It precipitates less angina & cardiac arrhythmia • It may increase HDL / cholesterol ratio. HDL protects against ischemic heart disease • There is tolerance to it’s action • Dose 2 – 3 times daily for Hypertension and congestive heart failure (CHF).

11. Heart failure In heart failure the following happens: Decreased C.O leads to sympathetic stimulation. Sympathetic stimulation  ↑HR & ↑contractility (which increase the pressure on the heart thus, worsening the situation). Furthermore, NE will increase the release of renin and this leads to incerease preload and after load In this case we will use β blockers to decrease HR and contractility and inhibit renin release.

12. Side effect of prazosin • 1st dose produce hypotension & syncope, but this disappears after continuous treatment(we prevent this effect by decreasing the 1st dose and giving it at bedtime) • Infrequent postural hypotension (rare and less than the non selective) • Nasal stiffness due to VD & congestion • Dizziness, headache & faintness . These are caused by hypotension • Sexual dysfunction but less than the non-selective.

13. α– blockers Relatively selective2. Terazosin & Doxazosin: • They are relatively α1 – selective blockers, with higher selectivity than prazosin • T1/2 = Terazosin 12 hours; Doxazosin 22 hrs • They produce VD with less tachycardia than prazosin • Like prazosin they produce postural hypotension • They produce relaxation of smooth muscle of the bladder neck and prostate capsule. So, they facilitate micturition. For this action, they can be used in case of urine retention associated with benign prostatic hyperplasia(BPH) in which prostate compresses the urethra & prevent micturition.

14. α– blockers SelectiveTamsolusin & Alfuzosine • It is selective for α1A–adrenoreceptors in the sphincter of urinary bladder • α1A blockade leads to relaxation of the sphincter. So, it facilitates micturition • Tamsolusin is used clinically in treating urine retention associated with BPH. It is better here than prazosin, Terazosin and Doxazosin • It causes less hypotension than prazosin or terazosin. Because: • It has low potency in inhibiting receptors in vascular smooth muscle

15. TamsolusinAdverse affects: • Retrograde ejaculation 15% • Hypersensitivity reaction: skin rash & urticaria • Nausea and vomiting • Nasal stiffness • Over dose will cause hypotension, tachycardia and fatigue Note: Similar to prazosin but with less magnitude.

16. TamsolusinContraindications: • Renal impairment • Tamsolusin is metabolized in the liver to an active metablite which is entirely excreted via the renal tubules, therefore, • In case of renal impairment, Tamsolusin will accumulate in blood & lead to toxicity

17. Clinical Uses of adrenergic a-antagonists: • Pheochromocytoma (phenoxybenzamine, • phentolamine) with β blockers to reduce • cardiac effect from increased catecholamines • 2) Hypretensive Crisis (Labetalol) • 3) Essential Hypertension (Prazosin, Terazosin) • 4) Peripheral Vascular Occlusion Diseases • (Raynaud’s phenomenon) e.g: Prazosin (but • Calcium Channel Blockers are better choice) • 5) Urinary Obstruction associated with BPH • (Tamsolusin)

19. Adrenoreceptor Antagonists β– blockers: More potent than atenolol

20. How could you distinguish between b-adrenergic Blockers? • b-adrenergic antagonists (blockers) differ from each others in the following: • Selectivity for b1 as compared to b2. or by the following:

21. β– blockersPharmacological actions: • CVS • BP = CO * TVR. Clinically β blockers lower BP By these mechanisms: • Blockade of β1 in the heart will cause decreased HR and CO • Blockade β1 in the kidney will cause decreased rennin leading to decreased angiotensin 2. this will lead to • VD and ultimately decreased BP • decrease aldosterone. This will lead to decerased salt and water retention and finally decreased BP • decrease release of NE that will cause VD and decreased BP • Blockade of central β adrenergic in adrenergic nerve terminals. This will makes NE acts at a2-adrenergic agonist leading to a decrease in its own release and decrease sympathetic tone to blood vessels, leading to VD and decreased BP • Which one of the above mechanism is more important for treating hypertension? Decreasing renin secretion Angiotensin normally induces the release of NE from postganglionic sympathetic fibers بالعربي يطلع NE يلقى الريسيبتور مقفلة يضطر انه يروح لـ α2

22. Cont…. • The respiratory system • Blockade of β2 receptors in bronchi will cause bronchoconstriction • Non–selective β blocker (are contraindicated in the bronchial asthma (propranolol) • The β1 selective blockers (e.g: Atenolol; Bisoprolol) are also should be avoided in the acute bronchial asthma because their selectivity is relative and they may have antagonistic affects on the β2 receptors at therapeutic doses.

23. Cont…. • The eye • β–blockers are used in treatment of glaucoma (Timolol). They act by: • Blocking β2 in ciliary epithelium. This will decrease production of aqueous humor ↓ intraocular pressure (IOP) • Block β2 in ciliary muscle. This will cause of contraction of the ciliary muscle leading to • Opening of the canal of Schlemm this Increases outflow of aqueous humor which leads to Decreased IOP

24. Cont…. • Metabolic and endocrine effects • β blocker inhibit lipolysis • In type 1 diabetes • The patient depends on catecholamines to increase blood glucose if he took overdose of insulin. • If he took β blockers, they will impair the recovery from hypoglycemia • β1 blockers are advised in the case of diabetic patients • β – blockers cause increase VLDL & triglycerides (TG) and decrease HDL / Cholesterol ratio. So, they will • Increase risk of coronary artery disease • contraindicated in a patients with familial hypercholesterolemia because VLDL & TGs are atherogenic & may cause myocardial infarction

25. Cont…. • Intrinsic sympathomimetic activity (ISA ) • Some of the β antagonist produce some action of β agonist e.g. Pindolol & Labetalol…, so, they are less dangerous when given to patients with bronchial asthma or excessive bradycardia • Membrane Stabilizing Action (MSA) • Some β blockers stabilize the cell membrane by blocking Na+ channels. Therefore, produce “local anesthetic action” e.g. Propranolol & Pindolol …

26. β– blockersSide effects of β blockers • Rash & fever • Worsening of asthma • CNS include • Sedation and Depression and sleep disturbances • These are more sever in Lipid – soluble β blockers (e.g. Propranolol) than in water soluble β blocker (e.g. Atenolol) • Heart failure Some β blockers are effective in treating chronic heart failure but not acute because you want to decrease the see slide 11)) work load & O2 consumption on the myocardium

27. β– blockersContraindications of β-blockers: • Bronchial asthma • Peripheral vascular disease • Heart failure (in severe cases only) (acute)

28. β– blockersDrug interactions: • Verapamil (Ca++ ) channel blocker • If it is combined with β – blockers, this can cause : • Congestive heart failure • Severe bradycardia • Severe hypotension

29. β– blockersWithdrawal of β blockers: On chronic use, abrupt withdrawal of β – blockers causes the β receptors to become supersensitive and even the circulating catecholamine can stimulate them & cause severe arrhythmia. So, withdrawal should be very gradual over weeks

30. β– blockers Propranolol • It is non – selective β blocker • T1/2 = 2 – 5 h • It is Lipid soluble • Can be given orally or I.V • It undergoes extensive 1st pass metabolism (90% of the drug)

31. Cont…. • It is excreted in urine as Propranolol or as Glucouronide conjugate • It’s duration of action is increased in • Hepatic disease • Decreased hepatic BF • Metabolic inhibition e.g. when giving Cimetidine, it inhibits the metabolism of propranolol, so, increase t1/2 • It has no ISA • It has MSA . SO, • It is used as antiarrhythmic drug but not in hypertension. • It stabilize the cardiac cell membrane & decrease the activity of ectopic foci

32. Side effect of propranolol Bradycardia Cold extremities Fatigue Sedation Mental depression Sleep disturbances Heart failure A – V block Bronchospasm Impotence

33. β– blockers Timolol: • It is a non – selective β blocker • T1/2 = 4 – 5 h • No ISA • Low MSA so not good for arrethmia. • Lipid – soluble • Pass via the cornea. So, it is used as eye – drops to treat glaucoma

34. β– blockers Labetalol: • It is a non-selective β blocker & selective α1 blocker • T1/2 = 4 – 6 h • Weak lipid – soluble • It has ISA • Has MSA • It differs from other β blockers in that it produce less bradycardia. • It block α1 in blood vessels. So, causes VD and decrease BP (postural hypotension). This will stimulate baroreceptors to send impulses to CNS to increase HR (reflex tachycardia) but this tachycardia is less than seen with other α blockers • It is used in Pheochromocytoma and hypertension of pregnancy

35. Cont…. • Adverse effects include: • Nausea • skin rash • tiredness • Aching limbs • Bronchospasm • Heart failure • Sleep disturbance & nightmares • Sexual dysfunction (more than other β blockers) • Postural hypotension (because it is selective α1 blocker) • Raynaud syndrome (peripheral vasospasm) • It is intermittent claudication or peripheral vascular disease • It is due to decreased blood supply to the periphary by β blockers due to • Bradycardia • Block β 2 in blood vessels to skeletal muscle causing VC and decrease blood supply

36. β– blockers Pindolol: • It is a non-selective β blocker • T1/2 = 3 – 4 h • Has ISA (very important) lead to bradycardia. • Weak lipid soluble • Has MSA but less than Propranolol

37. β– blockers Carvedilol : like labitolol • It is non – selective β blocker and non – selective α blocker • It can be used in patients with heart failure due to: • It is a peripheral vasodilator (unlike other β blockers) • It has antioxidant activity • It can neutralize (scavenge) the free radicals which cause heart failure • It used in renal impairment • Because it improves kidney function. So, it’s used in patients with Renal impairment

38. β– blockers Atenolol: • It is a relative β1 selective blocker • Hydrophilic so it has: • Longer t1/2= 12 – 18 h because it stays in tissue for a long time • For this reason, the dose is once daily • Less severe side effects on CNS • No ISA • No MSA • Adverse effects include • CNS : insomnia, headache & dizziness • Impairment of glucose tolerance • Bradycardia • Bronchospasm • Sexual dysfunction* • Fatigue : due to decreased blood supply to the periphery* • *all β blockers cause sexual dysfunction and fatigue.

39. β– blockers Practolol: • It is a relatively β1 selective blocker • It is used in intensive care unit for severe ventricular arrhythmia • It is not used to treat hypertension because of it’s side effect

40. β– blockers Esmolol : • It is a selective β1 blocker • Has very short duration of action (t1/2 = 8min) • Has low ISA • Has MSA (good for arrhythmia ) • It is given I.V when short term β blockade is required • Safer to use than longer acting antagonists in critically ill patients.

42. Migraine: • Propranolol

43. Centrally acting sympatholytic drugs

44. Centrally acting sympatholytic drugs • These drugs have the opposite effect to those of the sympathomimetic drugs by acting on the CNS. • Examples: • α-methyldopa • Clonidine

45. α– methyldopa • Mechanism of action • α–methyldopa is given orally then absorbed from GIT & enters the circulation • It freely passes BBB & reaches CNS then it is converted to α– methylenorepinephrine which acts as an agonist at central α2 – adrenoreceptors then It will decrease the sympathetic tone to blood vessels (VD)  ↓BP • These α2 – adrenoreceptors are found in the medulla & pons • α– methylenorepinephrine is called “false neurotransmitter” or (reactive metabolic of α– methyldopa) • Action of α– methyldopa • VD lead to decrease TVR without significant effects on CO or HR or renal blood flow

46. Cont…. • Clinical uses: • Treat pregnancy – associated hypertension • Treat mild to moderate hypertension (not common used) • Side effects include: • It may cause fluid retention • Lead to increase ECF and increase in BP slightly • This negates it’s therapeutic use • It may produce postural hypotension when standing from the sleeping position • This not severe like α– blockers • Sedation, insomnia, depression • in the beginning of treatment & disappears after continuous use • Serious extrapyramidal signs • It interferes with neurotransmitter of extra pyramidal tract • May lead to muscle incoordination

47. Cont…. • Lactation • Even in male : the breast may produce milk • Hepatitis & drug fever (can be serious) • Impotence • A lupus – like reaction : skin rash and pustules • Hemolytic anemia • Leukopenia : sometimes

48. Clonidine: • Already mentioned in α2 agonist.

50. قواعد جوهرية: • All adrenergic blockers reduce BP • But : • α blockers produce postural hypotension • Any α2 agonist is considered an antagonist because it inhibits the release of NE. • Relatively selective, means in high dose it may act on other receptors. (α1 blocker may act on α2 in high doses).