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Adrenoceptor Antagonists α-Adrenoceptor Antagonists

Adrenoceptor Antagonists α-Adrenoceptor Antagonists

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Adrenoceptor Antagonists α-Adrenoceptor Antagonists

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  1. Non-selective Irreversible antagonist phenoxybenzamine, that binds covalently to receptor, long duration of action of 14-48 hours Reversible competitive antagonist phentolamine& tolazoline Selective α1-adrenergic antagonists: prazosin, doxazocin & tamsulosin (α1A-blocker) α2-adrenergic antagonists: yohimbine & rauwolscine Adrenoceptor Antagonists α-Adrenoceptor Antagonists

  2. Nonselective α-receptor antagonists Vascular & Blood Pressure Effects • By blocking postsynaptic α1-adrenoceptors, they produce vasodilation, & decreased total peripheral resistance and a fall in blood pressure opposed by stimulation of peripheral sympathetic activity via blockade of the presynaptic α2-adrenoceptors • Postural hypotension via blockade of reflex sympathetic control of capacitance vessels upon standing

  3. Cardiac Effects • Reflex tachycardia mainly via α2-receptor blockade because the inhibitory effect on NE release is blocked and peripheral NE release is increased stimulating β1 cardiac receptors

  4. Therapeutic Uses Nonselective α-Receptor Antagonists • Treatment of pheochromocytoma which is a tumor of adrenal gland which secretes NE & EP leading to signs of excessive catecholamine including hypertension, tachycardia & arrhythmias • Preoperative control of severe hypertension resulting from tissue manipulation in patient undergoing pheochromocytoma surgery • Treatment of Raynaud’s disease

  5. Major Side Effects α-Receptor Antagonists • Postural hypotension • Reflex tachycardia • Inhibition of ejaculation • Nasal stuffiness

  6. Selective α1-receptor antagonists Vascular & Blood Pressure Effects • Blocking the vascular postsynaptic α1-adrenoceptors, produce vasodilation, & decrease total peripheral resistance and a powerful fall in blood pressure • Unopposed by blockade of the presynaptic α2-adrenoceptors that doesn’t occur and hence the blood pressure lowering efficacy is high

  7. CVS Effects • Postural hypotension is much less pronounced than the non-selective α-blockers possibly because of lower effect on veins Cardiac effects • They may cause reflex tachycardia mediated via baroreceptors

  8. Therapeutic Uses • Treatment of mild hypertension alone or in combination with other antihypertensives such as thiazide diuretics or β-blockers in moderate or severe hypertension • Treatment of benign prostatic hypertrophy. Blockade of α1-adrenoceptors at the base of the bladder and the prostate possibly reduces the symptoms of obstruction and the urinary urgency • Tamsulosin has antagonistic affinity to α1Areceptors (in vas deferens) more than to α1B in vascular smooth muscles

  9. Non-selective β-adrenergic antagonists blocking the effects of sympathetic stimulation upon all subtypes β-receptors propranolol, pindolol, nadolol, and timolol Cardioselective β1-adrenoceptor Antagonists preferentially block the cardiac β1­ adrenergic receptors with little effect on β2-receptors metoprolol, atenolol, acebutalol & esmolol Beta (β)-Adrenergic Antagonists (β-blockers)

  10. β-Adrenergic Antagonists with Intrinsic Sympathomimetic Activity (ISA) • Pindololandacebutolol are -adrenergic antagonists in presence of catecholamines • In addition, they possess a partial AGONISTIC activity on -adrenergic receptors • Hence, they cause less bradycardia than propranolol, and can be preferred in patients with bradycardia • Acebutolol is a selective -adrenergic antagonist, but metabolised into a non-selective antagonist

  11. Pharmacological Actions of β-Blockers Cardiac effects • Negative chronotropic effects especially at high sympathetic discharge as during exercise • Decreased cardiac force of contraction. Peak cardiac tension & rate of cardiac tension rise (contraction velocity) are reduced leading to lowered stroke volume, and increased end-systolic (residual) cardiac volume • As a result, the cardiac output decreases

  12. Cardiac Effects of β-Blockers • Decreased cardiac oxygen consumption as a result of reduced cardiac work (decreased heart rate, ventricular systolic pressure & contractility) • Blocked sympathetic tone to A-V node & hence vagal action predominates and atrioventricular conduction velocity decreases • Depression of pacemaker activity (automaticity)

  13. Vascular Effectsof β-blockers Acute administration vasoconstriction (increased peripheral resistance) • Unopposed α-mediated vasoconstriction in vascular beds containing both the α- & β-adrenoceptors • Reflex increase in sympathetic tone as a result of reduced cardiac output

  14. Vascular Effectsof β-blockers Chronic administration • Decreased blood pressure possibly • decreased cardiac output • antagonism of β-receptors in the CNS • blocking the facilitator presynaptic β-adrenoceptors on sympathetic nerves • reduction of renin release from juxtaglomerular apparatus and hence reduced angiotensin II and aldosterone levels • Peripheral vasoconstriction through: • Unopposed α-mediated vasoconstriction in vascular beds containing both the α- & β-adrenoceptors • Reflex increase in sympathetic tone as a result of reduced cardiac output

  15. Bronchiolar Smooth Muscle • Propranolol antagonizes the β-adrenoceptor mediated bronchodilation • Augmenting ACh- & histamine-induced bronchospasm; airway resistance is increased • β-blocker bronchospasm is seriously dangerous in asthmatics

  16. Fat metabolism β-blockers inhibit catecholamine-induced increase in lipolysis and the increase of plasma free fatty acids Carbohydrate metabolism β-blockersenhance hypoglycemiaby inhibiting catecholamine-stimulated hepatic glycogenolysis (important for diabetic patients) After insulin injection or exercise, β-blockers delay the recovery of blood glucose (hypoglycemia) Metabolic Effects

  17. Therapeutic Usesof β-blockers • Treatment of hypertension: Selective β1-blockers are preferable in asthmatic & diabetic patients and in patients with Raynaud’s disease • Myocardial Infarction (MI): • β-blockers administered 1-4weeks after MI reduce much the probability of myocardial re-ifarction possibly by reducing cardiac work. • β-blockers given immediately (few hours) after MI reduces the infarct size and enhance cardiac reperfusion and recovery; timolol, propranolol, and metoprolol are used

  18. Therapeutic Usesof β-blockers • Chronic Treatment of Glaucoma(Mainly Propranolol, timolol are used) • They decrease the formation of aqueous humor by ciliary body reducing the IOP • They don’t affect accommodation for near vision nor affect pupil size as cholinergic agonists do • Pilocarpine is of choice in acute attacks • Chronic Migraine: Propranolol is used in treatment of migraine where it reduces the severity of attacks and lowers their frequency • Possibly via inhibition of catecholamine-induced cerebral vasodilation

  19. Therapeutic Usesof β-blockers • Treatment of effort anginabut not variant angina • Hyperthyroidism: β-blockers control the symptoms of excessive sympathetic stimulation (adjuvant therapy) • Cardiac supraventricular arrhythmias to stop conversion of atrial to ventricular arrhythmia. β1-receptor blockade results in the following: • decreased firing rate of SA node • decreased AV conduction & prolongation of AV-nodal refractory period • decreased ventricular response to atrial flutter • Esmolol is a cardio-selective β1-blocker that is used only by IV route for emergency treatment of supraventricular arrhythmias arising during surgery

  20. Side Effects of β-blockers • Hypoglycemia that is much pronounced in patients with diabetes especially after insulin injection or oral hypoglycemic • Severe cardiac slowing & lowered cardiac contractility make the use of β-blockers cautious in cases of sinus bradycardia, partial heart block & severe congestive heart failure

  21. Side Effects of β-blockers • Dysrhythmias or anginal attacks may develop after withdrawal of β-blockers from long term patients • This may be due to adrenergic receptor super-sensitivity mediated by receptor up-regulation or re-enhancement of sympathetic cardiac drive • Dosage of β-blockers should be tapered off gradually over 1-2 weeks

  22. Side Effects of β-blockers • Bronchoconstriction: β2-receptor blockade can produce an increase airway resistance in patients with asthma; selective β1-blockers should be used in asthmatics • Peripheral vascular disease vasoconstriction is aggravated in presence of β-blockers because of uncovering the α1-adrenoceptor-mediated vasoconstriction in response to endogenous catecholamines • Sexual dysfunction via undetermined mechanism, apparently β-adrenoceptors-independent

  23. Combined α- & β-adrenoceptor Antagonists • Labetalol and carvedilol are competitive antagonists for catecholamines at α1-, β1- and β2-adrenergic receptors • They don’t cause peripheral vasoconstriction • Carvedilol, has additive antioxidant activity and protect against vascular thickening (remodeling) • These two extra properties made it of value in treatment of some cases of heart failure • Labetalol is preferable in treatment of hypertension of elderly & black patients to avoid peripheral vasoconstriction • Black hypertensive patients are usually resistant to β-blockers • IV labetalol is used in hypertensive emergencies & preoperative pheochromocytma management

  24. Indirectly Acting Adrenergic Blockers Reserpine Mechanism of Action: • Potent inhibition of transporters responsible for neuronal vesicular NE uptake from neuronal cytoplasm (as well as other biogenic amines) • Inhibition of vesicular storage capacity • Hence, NE leaks into cytoplasm to mitochondria where it is catabolizstores are depleteded by MAO • Ultimately peripheral & central NE (together with DA & 5-HT)

  25. Reserpine • Actions & Uses: • Reduction of vascular tone at small arteries & veins as a result of peripheral adrenergic neurotransmitter depletion • Bradycardia & reduced cardiac output a s a result of decreased 1-mediated actions • It mayy be used in hypertension resistant to other agents • Centrally, it may cause depression, nightmares and parkinsonism • It increases tone & motility of GIT as well as gastric HCl secretion

  26. Guanethidine • It inhibits neuronal release of NE • It is actively taken by adrenergic nerve terminals competing with NE for the same transporter proteins • Therefore, intra-neuronal NE concentration decreases and its release is diminished • It is rarely used in hypertension

  27. Effects of -Adrenergic Receptor Antagonists 1-Adrenergic Receptor: • Bradycardia • Decreased AV nodal conduction velocity • Decreased pacemaker cells activity • Decreased forve of contraction (reduced stroke volume, increased end-systolic volume & decreased cardiac output) • Decreased O2 consumption • Reduced renin release (decreased ang II) • Edema formation (decrased cardiac output 2-Adrenergic Receptor • Peripheral vasoconstriction in some areas • Decreased glcogenolysis & insulin release • Decreased adrenergic mediated tremors