DR. RAHUL

Antiadrenegics

Antiadrenegics

These are the drugs which antagonize the actions of adrenaline and related drugs.

They are both competitive antagonist of alpha or beta or both.

ALHA 1 receptors• Radial fibers –

contraction –mydriasis

Eye

• Contraction – can increase peripheral resistance

Arterioles and veins –.

• Contraction – urinary retention

Bladder trigone and sphincter –

• Glycogenolysis.Liver

• Ejaculation.Vas deferens

ALPHA 2

• AggregationPlatelets

• Decrease release of transmitter (NE)

Presynaptic

receptors • Decrease insulin

release (predominant)

Pancrease -

Alpha adrenergic blockersNon selective

Irreversible type : Phenoxybenzamine

• Ergot alkaloids : Ergotoxine, Ergotamine• Hydrogenated ergot alkaloids:

Dihydroergotoxine• Imidazolines : Phentolamine,

Tolazoline

Reversible type

• Prazosin, Terazosin, Doxazosin, Tamsulosin

Alpha1 selective-

Alpha2 selective- Yohimbine

Pharmacological Effects

Cardiovascular system: Fall in BP (alpha1 & 2 blockade)

Postural hypotension

Reflex tachycardia

Vasomotor reversal of Dale

Hypovolemia accentuates hypotension

• Na & water retention• renin release BP

Hypotension-g.f.r reduced

Pharmacological EffectsNasal stuffiness

Eye – miosis

• decreased tone in sphincter and prostate (alpha1a blockade)

Urinary bladder

Metabolic effects – increased insulin secretion

Reproductive systemInhibition of contraction of Vas defrence and related organs is blocked by alpha1

blockade…..inhibition of ejaculation…impotence

PhenoxybenzamineAlpha blockade develops gradually and lasts for 3-4days. Fall in BP by Phenoxy. is mainly due to venodilatation…postural hypotension.

Shifts blood from pulmonary to systemic circulation, extra vascular to vascular compartments.

Lipid soluble drug can penetrate CNS may cause nausea & vomiting on rapid iv administration

Management of pheochromocytoma.Pheripheral vascular diseases.

Imidazoline derivatives - Phentolamine

Congener of Tolazoline

Rapidly acting alpha blocker with short DOA

Many other effects including:

• Parasympathomimetic• Increased gastric acid secretion

Cardiac stimulation

Increased secretion from exocrine glands, such as salivary, sweat, lacrimal, pancreaticCoronary artery disease and peptic ulcer relative contraindication to it.

Phentolamine : uses

Diagnostic and intraoperative management of pheochromocytoma

For control of hypertension due to clonidine withdrawal.

Cheese reaction.

To counteract vasoconstriction due to extravasation of noradrenaline / Dopamine given IV.

Ergot alkaloids

Ergotoxine, Ergotamine are partial agonist and antagonist at adrenergic alpha, serotonergic and dopaminergic receptors.

Ergotoxine, dihydroergotoxine are more potent alpha blocker and less potent vasoconstrictor than ergotamine.

USE: Migraine

Alpha-1 selective blockersPrazosin

Highly selective Alpha1 blocker, selectivity ratio 1000: 1Less cardiac stimulation since it preserves alpha2 mediated negative feedback + other mechanismsFall in BP with no/ minimal tachycardia.

Used in hypertension but tolerance develops with time, maybe due to fluid retention.Adverse effects: First dose phenomenon i.e postural hypotension with initial doses.Favorable effect on plasma lipids: increase HDL/LDL ratio

ADR (µg/Kg)

1 10 100 5000.1

1 10 100 500

+PRAZOSIN

BP

HR

Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate Before and After Prazosin

Prazosin : uses

Antihypertensive

DOC: Benign prostatic hyperplagia ( BPH)• Blocks alpha 1 in bladder trigone & prostate• Decreases tone• Improves urine flow• Decreases residual urine

Dose :1-4 mg BD/ TDS

Terazosin : longer t1/2 , OD dosing

Tamsulosin

Dizziness and retrograde ejaculation are the only AE.

No effect on BP and heart rate.

Alpha Ia are predominant in bladder base and prostate. 30 times high

affinity for alpha1a.

As effective as Terazosin in BPH

Uroselective alpha 1a/ alpha 1d blocker.

Alpha-2 selective blockersYohimbine

Cardiovascular effects – peripheral and central effects

Blocks other receptors also – serotonin, dopamine

Increases ADH release

Enhances sexual activity – aphrodisiac

Potential uses: depression, obesity, NIDDM

Alpha Blockade—Adverse Effects

Orthostatic hypotension• Reduces blood flow to brain causing dizziness,

lightheadedness and fainting • Due to vasodilation of veins lowering blood flow to brainReflex tachycardia

• Increase heart rate by stimulating baroreceptor reflex which causes and increased heart rate to compensateNasal Congestion

• Dilates vessels of nasal mucosaInhibition of ejaculation

• Alpha1, sympathetic reaction neededSodium retention

• Decreased blood pressure decreases filtering by kidneys and causes retention of water and salt

Menu B F

Alpha Blockade—Uses•Essential hypertension

•Benign prostatic hyperplasia

•Pheochromocytoma

•Overdose of alpha1 agonist

Therapeutic

Applications

Therapeutic Uses ofAlpha-Adrenergic Blockers

Hypertension - alpha-1 selective

Conditions associated with increased sympathetic activity – e.g. pheochromocytoma

Hemodynamic shock

Peripheral vascular disease – Raynaud’s

Congestive heart failure

Benign prostatic hyperplasia-prazosin

Pulmonary hypertension – tolazoline

Yohimbine or intracavernous Phentolamine+ papaverine for impotence

BETA BLOCKERS

DR. RAHUL

Beta blockers

These drugs inhibit adrenergic responses mediated through beta receptors.

All beta blockers are competitive antagonists.

History: Dichloroisoproterenol- 1958Propranolol-1963

Classification NONSELECTIVE: (BETA 1 & 2)A) Without intrinsic symphathomimetic

activity Propranolol Sotalol : Class III antiarrhythmic Timolol : topical use in eye

B) With intrinsic symphathomimetic activity

PindololC) With alpha blockade activity (alpha +

beta blockade) Labetalol carvedilol

CARDIOSELECTIVE (BETA 1 )

Metoprolol Atenolol Bisoprolol Esmolol Acebutolol (intrinsic symphathomimetic and membrane

stabilizing activity)

Celiprolol (Beta 1 blocker + beta 2 agonism)

Nebivolol

Pharmacological actions : CVS: Heart:

Propranolol decreases heart rate, force of contraction, COP. Decreases cardiac work and oxygen consumption.

Blood vessels: Fall in BP both diastolic and systolic after continuous treatment.

Decrease in COP Initial increase followed by decrease in

TPR Decrease renin release from kidney Central action decreasing symphathetic

outflow

OTHER SYSTEMS Respiratory system :

Bronchoconstriction CNS: Decreases anxiety, tremors,

other actions. Metabolic :

Increases LDL, triglycerides, decreases HDL by inhibiting lipolysis.

Adversely effects recovery from insulin induced hypoglycemia.

Skeletal muscles : Pnl inhibits adrenegically evoked tremors.

Eye : synthesis and releases of aqueous humour … iop

Contraindication

CHF Bradycardia COPD Bronchial asthma Diabetis mellitus Hypertriglygeridemia

Adverse effects Adverse Effects of beta1 blockade

BradycardiaReduced cardiac outputHeart failureAV block

COPD, Bronchial asthma Tiredness , reduced exercise capacity. Rebound hypertension on abrupt withdrawl. Cold hands and feets Hypoglycemia Others: gi upset, lack of drive,

lightheadedness, forgetfulness, nightmares, rarely hallucinations

CARDIOSELECTIVE (BETA 1 )

Metoprolol Atenolol Acebutolol Bisoprolol Esmolol

No effect on bronchus, carbohydrate metabolism, lipids.

Lower incidences of Cold hands and feets.

Less liable to impair essential tremors.

CARDIOSELECTIVE (BETA 1 )

DRUG FEATURES USE

Metoprolol Preferred in diabetics on insulin or oral hypoglycemics.

AMI without bradycardia

Atenolol Low lipid solubility.Longer duration action. (OD)

HypertentionAngina

Acebutolol Cardioselective with intrinsic symphathomimetic and membrane stabilizing activity

Preferred in severe bradycardia and low cardiac reserve

Esmolol Ultra short acting cardioselective beta blocker.DOA 15-20mins after iv infusion

To terminate supraventricular tachycardiaAtrial fibrillation or flutterEarly treatment of AMI

Celiprolol Nebivolol

Beta 1 blocker + beta 2 agonismActs as NO donor (vasodilatation)

Hypertension CHF

Without intrinsic symphathomimetic activity

Sotalol : Class III antiarrhythmic Timolol : topical use in eye

Uses of Beta blockers Hypertension Angina pectoris Cardiac arryhythmias AMI

Secondary prophylaxis of AMI Myocardial salvage

CHF Pheochromocytoma Thyrotoxicosis Migraine Essential tremors. Glaucoma Anxiety

Carvedilol

β 1 + β2+ α1 blocker, calcium channel blocker.

Antioxidant property. Use:

Hypertension CHF Angina.

With alpha blockade activity (alpha + beta

blockade) Labetalol

β 1 + β2+ α1 blocking aswellas β2 agonism.

5 times more potent β blocker than α. Effects at low dose resembles

propranolol while at high dose ppn + prazosin

Fall in BP is due to decrease in COP and TPR

Uses : pheochromocytoma, clonidine withdrawl, essential hypertention.

A/E: postural hypotension, impotence.