exam 1 Lecture 3 Adrenergic antagonists (Ch7)

What are adrenergic antagonists?

May be called adrenergic blockers or sympatholytics

-bind to adrenergic receptors but do not trigger usual receptor mediated actions

Actions are due to reversible to irreversible binding to adrenoceptors and blocking binding of agonists

Classified according to relative affinity for either alpha or B receptors in sympathetic NS

What are alpha adrenergic blockers

Antagonists with specificity for alpha receptors profoundly effect BP

-magnitude of response dependent upon a patients sympathetic tone

-decreased peripheral vascular resistance

-followed by reflex tachycardia caused by lower BP

Antagonists with specificity for alpha 2 receptors have limited clinical uses

Phenoxybenzamine (class/mechanism)

No selective alpha adrenergic blocker that binds A1 and A2 receptors

Blockade is irreversible and no competitive

Effects last approximately 24 hrs

Phenoxybenzamine Effects

Cardiovascular: blocks A1 mediated vasoconstriction, decreases peripheral resistance, results in reflex tachycardia

-blockade of A2 increases norepi release to bind to B1 —→ increase cardiac output

Epi reversal: interrupts vasoconstriction caused by epi but not vasodilation by B2 —> decrease BP

Phenoxybenzamine uses

Pheochromocytoma: adrenal medulla tumor that causes catecholamine secretion

-prevents hypertensive crisis prior to surgical removal or chronic management

Raynaud’s disease, frostbite

Adverse effects of Phenoxybenzamine

Postural hypotension, nasal stuffiness, N/V, reflex tachycardia, inhibition of ejaculation

Use with caution in pts with cerebro vascular or cardiovascular disease

Phentolamine class and MOA

Alpha adrenergic blocker

Complete blockade of a1 and a2 receptors but do

Duration of effect about 4 hours after one injection

Actions and uses of Phentolamine

Actions: hypotension and epinephrine reversal

Uses:

-short term management and diagnosis of pheochromocytoma

-prevents dermal necrosis caused by norepi extravasation

-hypertensive crisis secondary to abrupt clonidine discontinuation or ingestion of tyramine by pt using MAOIs

Adverse effects and contraindications of Phentolamine

Postural hypotension

Arrhythmia and angina

Contraindicated in pts with CAD

Therapeutic uses of A1 adrenergic blockers

HTN (prazosin, terazosin, dozazosin)

-not used as monotherapy

-decrease first dose due to risk of orthostatic hypotension

Benign prostatic hypertrophy (tamsulosin,calfuzosin, silodosin)

Improvement of lipid profiles and glucose metabolism

Pharmacokinetics of A1 adrenergic blockers

Metabolized to inactive products and eliminated via urinary excretion

Mechanism of action of A1 adrenergic blockers

Relaxation of arterial and venous smooth muscle

Decrease peripheral vascular resistance, decreases BP

Minimal changes in CO, renal perfusion, and GFR

Adverse effects of prazosin and doxazosin (a1 adrenergic blockers)

Dizziness, decreased energy, nasal congestion, HA, drowsiness, orthostatic HoTn

Additive anti hypertensive effects with vasodilators (nitrates and PDE-5 inhibitors)

Inhibits ejaculation, retrograde ejaculation

Floppy iris syndrome (problematic during eye surgery)

Yohimbine class and MOA

selective, competitive A2 blocker

Works in the CNS to increase sympathetic outflow to periphery

Used as a sexual stimulant and treatment for ED

Contraindications of yohimbine

CVD, psychiatric conditions, renal insufficiency

B adrenergic blockers

Competitive antagonists

Lower BP but do not cause postural hypotension (no effect on alpha)

Non selective b blockers act on…

B1 and B2

Cardioselective b blockers act on..

Mostly B1

Uses of b blockers

HTN, angina, arrhythmia, MI, heart failure, hyperthyroidism, glaucoma, migraines prophylaxis

Propranolol class

Non selective B antagonist

Propranolol actions

Cardiovascular

-negative inotropic and chronotropic effects - decreased CO

-depress SA/AV activity

-attenuates increased HR due to SNS activity

attenuates SVT (ventricular arrhythmia due to exercise)

Peripheral vasoconstriction

-decreases BP

Bronchoconstriction

Glucose metabolism

-decreased glycogenolysis and glucagon secretion

Blocks actions of Isoproterenol

Uses of propranolol

HTN

-reduces CO, inhibits renin release, decreases TPR, decreases SNS output

MI

-reduces size of infarct, decreases early mortality, can shorten recovery time

-decreases O2 demand by blocking catecholamine actinvty

-reduces incidence of sudden arrhythmic death after MI

-prevention of second MI

ANGINA

Migraine

Hyperthyroidism

-blunts widescreen sympathetic stimulation

-protects against arrhythmia during thyroid storm

Adverse effects of propranolol

Bronchoconstriction

-contraindicated in pts with asthma/copd

Arrhythmias

Sexual impairment

Metabolic disturbances

-hypoglycemia

-increased LDL and TG, reduced HDL

CNS SIDE EFFECTS

-depression, dizziness, lethargy, fatigue, weakness, visual disturbances, hallucinations, short term memory loss, emotional lability, vivid dreams

Propranolol drug interactions

Block rescue effects of epi for anaphylaxis

Cimetidine, fluoxetine, paroxetine, and ritonavir block metabolism of drug (increased effect)

Barbiturates, phenytoin, and rifampin stimulate/induce metabolism (decreased effect)

timolol

Non selective B1 and B2 blockers

Occasionally administered systemically for tx of HTN

Treats open angle glaucoma

-decreased production of aqueous humor in eyes by ciliary body

Function of b blockers in glaucoma

Diminish intraocular pressure in glaucoma

Do not effect ability of eye to focus or change pupil size

Onset of action: 30 min

Duration: 12-24 hrs

Medications for chronic mgmt of glaucoma

Timolol, betaxolol, carteolol

What medication is used for emergency management of glaucoma

Pilocarpine

What are the MANBABE cardioselective drugs

Metoprolol, atenolol, nebivolol, betaxolol, acebutolol , bisoprolol, esmolol

Actions of selective B1 antagonists

Decrease BP in pts with HTN

Increase exercise tolerance in pts with angina

Fewer effects on pulmonary function, peripheral resistance, and carb metabolism

Therapeutic uses of selective B1 antagonists

Used in pts with HTN and impaired pulmonary function

First line for stable chronic angina

Management of CHF

What is the mechanism of action of nebivolol

Releases nitric oxide from endothelial cells, vasodilation

Antagonists with partial agonist actions - actions and therapeutic uses

acebutolol and pindolol

Cardiovascular:

weak stimulation of B1 and B2 receptors

-intrinsic sympathomimetic activity

-stimulate the B receptor they are bound to and inhibit additional stimulation from catecholamines

Decrease sympathetic action on HR and CO

Decreased metabolic effects on lipid and carb metabolism

Use: HTN in pts with moderate bradycardia that cannot tolerate further decrease in HR

Alpha and B receptor antagonists -actions

Labetalol and carvedilol

Nonselective B blockers with A1 blocker activity

-decrease BP, A1 causes orthostatic hotn and dizziness

Tx of HTN in pts who cannot tolerate increased peripheral vascular resistance

Carvedilol decreases lipid per oxidation and thickening of vessel walls

-useful in pts with heart failure

Therapeutic uses of A and B receptor antagonists

labetalol

-used to treat HTN in pregnancy

-HTN emergency

Carvedilol, metoprolol, and bisoprolol used to treat stable chronic heart failure

-blocks effects of sympathetic stimulation on heart

CONTRAINDICATIONS: B blockers not given to pts with acute CHF. Can worsen Condition

Reserpine

Plant alkaloid that acts on adrenergic neurons

-interfered with NT release from vesicles and uptake into adrenergic neurons

Blocks mg2+/ATP dependent transport of bio genie amines from cytoplasm into storage vesicles of adrenergic nerve terminal

-depletes norepi, dopamine, and serotonin

-impaired sympathetic function due to decreased NE release

Largely replaced by more effective meds with less adverse effects for tx of HTN