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

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Adrenoceptor antagonists adrenoceptor antagonists

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


Nonselective receptor antagonists
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


Cardiac effects
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


Therapeutic uses nonselective receptor antagonists
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


Major side effects receptor antagonists
Major Side Effects α-Receptor Antagonists

  • Postural hypotension

  • Reflex tachycardia

  • Inhibition of ejaculation

  • Nasal stuffiness


Selective 1 receptor antagonists
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


Cvs effects
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


Therapeutic uses
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


Beta adrenergic antagonists blockers

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)


Adrenergic antagonists with intrinsic sympathomimetic activity isa
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


Pharmacological actions of blockers
Pharmacological Actions Activity (ISA) 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


Cardiac effects of blockers
Cardiac Effects of β-Blockers Activity (ISA)

  • 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)


Vascular effects of blockers
Vascular Effects Activity (ISA)of 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


Vascular effects of blockers1
Vascular Effects Activity (ISA)of 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


Bronchiolar smooth muscle
Bronchiolar Smooth Muscle Activity (ISA)

  • Propranolol antagonizes the β-adrenoceptor mediated bronchodilation

  • Augmenting ACh- & histamine-induced bronchospasm; airway resistance is increased

  • β-blocker bronchospasm is seriously dangerous in asthmatics


Metabolic effects

Fat metabolism Activity (ISA)

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


Therapeutic uses of blockers
Therapeutic Uses Activity (ISA)of 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


Therapeutic uses of blockers1
Therapeutic Uses Activity (ISA)of 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


Therapeutic uses of blockers2
Therapeutic Uses Activity (ISA)of 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


Side effects of blockers
Side Effects of β-blockers Activity (ISA)

  • 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


Side effects of blockers1
Side Effects of β-blockers Activity (ISA)

  • 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


Side effects of blockers2
Side Effects of β-blockers Activity (ISA)

  • 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


Combined adrenoceptor antagonists
Combined α- & β-adrenoceptor Antagonists Activity (ISA)

  • 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


Indirectly acting adrenergic blockers
Indirectly Acting Adrenergic Blockers Activity (ISA)

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)


Reserpine
Reserpine Activity (ISA)

  • 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


Guanethidine
Guanethidine Activity (ISA)

  • 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


Effects of adrenergic receptor antagonists
Effects of Activity (ISA)-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


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