Adrenoceptor Antagonists Adrenoceptor Antagonists Nonselective Selective q Irreversible

Adrenoceptor Antagonists α-Adrenoceptor Antagonists Non-selective Selective q Irreversible antagonist q α adrenergic 1 phenoxybenzamine, antagonists: that binds covalently prazosin, doxazocin to receptor, long & tamsulosin (α 1 A duration of action of blocker) 14 48 hours q α 2 adrenergic q Reversible competitive antagonists: antagonist yohimbine & phentolamine & rauwolscine tolazoline

Nonselective α-receptor antagonists Vascular & Blood Pressure Effects n By blocking postsynaptic α 1 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 α 2 adrenoceptors n Postural hypotension via blockade of reflex sympathetic control of capacitance vessels upon standing

Cardiac Effects n Reflex tachycardia mainly via α 2 receptor blockade because the inhibitory effect on NE release is blocked and peripheral NE release is increased stimulating β 1 cardiac receptors

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

Major Side Effects αReceptor Antagonists Ø Postural hypotension Ø Reflex tachycardia Ø Inhibition of ejaculation Ø Nasal stuffiness

Selective α 1 -receptor antagonists Vascular & Blood Pressure Effects Ø Blocking the vascular postsynaptic α 1 adrenoceptors, produce vasodilation, & decrease total peripheral resistance and a powerful fall in blood pressure Ø Unopposed by blockade of the presynaptic α 2 adrenoceptors that doesn’t occur and hence the blood pressure lowering efficacy is high

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

Therapeutic Uses n Treatment of mild hypertension alone or in combination with other antihypertensives such as thiazide diuretics or β blockers in moderate or severe hypertension n Treatment of benign prostatic hypertrophy. Blockade of α 1 adrenoceptors at the base of the bladder and the prostate possibly reduces the symptoms of obstruction and the urinary urgency o Tamsulosin has antagonistic affinity to α 1 A receptors (in vas deferens) more than to α 1 B in vascular smooth muscles

Beta (β)-Adrenergic Antagonists (β-blockers) Non-selective βCardioselective β 1 adrenergic adrenoceptor antagonists Antagonists q blocking the effects q preferentially block of sympathetic the cardiac β 1 stimulation upon all adrenergic receptors subtypes β receptors with little effect on β 2 q propranolol, pindolol, receptors nadolol, and timolol q metoprolol, atenolol, acebutalol & esmolol

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

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

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

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

Vascular Effects of β-blockers Chronic administration q o o q Ø Ø 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

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

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

Therapeutic Uses of β-blockers q Treatment of hypertension: Selective β 1 blockers are preferable in asthmatic & diabetic patients and in patients with Raynaud’s disease q Myocardial Infarction (MI): • β blockers administered 1 4 weeks 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

Therapeutic Uses of β-blockers q Chronic Treatment of Glaucoma (Mainly Propranolol, Ø Ø Ø q o 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

Therapeutic Uses of β-blockers q Treatment of effort angina but not variant angina q Hyperthyroidism: β-blockers control the symptoms of q • • • q excessive sympathetic stimulation (adjuvant therapy) Cardiac supraventricular arrhythmias to stop conversion of atrial to ventricular arrhythmia. β 1 -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 β 1 -blocker that is used only by IV route for emergency treatment of supraventricular arrhythmias arising during surgery

Side Effects of β-blockers Ø Hypoglycemia that is much pronounced in patients with diabetes especially after insulin injection or oral hypoglycemic Ø 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

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

Side Effects of β-blockers n Bronchoconstriction: β 2 -receptor blockade can produce an increase airway resistance in patients with asthma; selective β 1 -blockers should be used in asthmatics n Peripheral vascular disease vasoconstriction is aggravated in presence of β-blockers because of uncovering the α 1 -adrenoceptor-mediated vasoconstriction in response to endogenous catecholamines n Sexual dysfunction via undetermined mechanism, apparently β-adrenoceptorsindependent

Combined α- & β-adrenoceptor Antagonists n Labetalol and carvedilol are competitive antagonists for n n o o catecholamines at α 1 -, β 1 - and β 2 -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 βblockers IV labetalol is used in hypertensive emergencies & preoperative pheochromocytma management

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

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

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

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) n Decreased O 2 consumption n Reduced renin release (decreased ang II) n Edema formation (decrased cardiac output n n 2 Adrenergic Receptor n Peripheral vasoconstriction in some areas n Decreased glcogenolysis & insulin release n Decreased adrenergic mediated tremors