1) Block the interaction of adrenergic agents (i.e., NE, Epi) with their receptors.

Epi) 2) Most are competitive antagonists, except phenoxybenzamine that binds receptor covalently 3) Some antogonists act selectively on or receptors

1 Antagonists:
BLOOD VESSELS: inhibit vasoconstriction > BP TPR * Depend on the status of the system, i.e. more marked in supine * Baroreex may increase HR and CO ( MAP-> Vagus/NE ( release->1 effect) release-> * Block effects of sympathomimetic drugs, i.e. Epi reversal: vasodepressor effect * Side effects: orthostatic hypotension, tachycardia (reex), nasal stufness, myosis

2 Antagonists (Yohimbine): (Yohimbine):

Effects on CNS and Nerve Endings -> regulate cardiovascular effects: * Can potentiate release of NE by blocking the receptor on nerve endings * Increase in NE-> activates 1 and 1->increase in BP

Baroreceptors (response to changes in MAP)

MAP

Inhibitory Neuron Vasomotor Center

Nucleus Tractus Solitarius

Excitatory Neuron

Motor Nucleus Vagus NE HR Orthostatic hypotension Vasoconstriction

NE 1 or 2 Antagonists

There are 3 groups of Adrenergic Antagonists:

Imidazoline Derivatives
CH2 N N H

-Haloalkylamine Derivatives
CH3 O CH2 CH N CH2CH2Cl CH2

Tolazolina (rarely used)

HO N CH2 N N H

CH3

(1=2>5HT) 1= Uses: Pheochr., Hypert. Pheochr., Hypert. Crisis, Amphetamine OD Side Eff: increase HR, Sexual Dysf. Eff: Dysf.

Phentolamina (Regitine) Regitine)

Blocks 1=2>5HT,Ach 1= receptors irreversibly Used in Pheochr. Pheochr.

Phenoxybenzamine

Piperazynil Quinazoline Derivatives

O CH3O CH3O N N NH2 N N C O CH3O CH3O CH3O N N N O N C (CH3)2 OCH2C OH

NH2 Prazosin (Minipress) Minipress) Trimazosin (1>>>2) 1>>> ( Similar to Prazosin * vascular resistance Preload * CNS sympathetic outow Others: Terazosin and Baroreex->HR unchanged Baroreex->HR (Half-life 9-12hr) * Side effects: syncope and postural hypot. hypot. and * Indications: Hypertension, CHF ( pre ( Doxazosin and afterload= lung congestion), Benign and (Half-life 22hr.) Prostate hyperplasia. Half-life 3hr.

*They are important in the treatment of hypertension, arrhythmias, and ischemic heart disease * Propanolol is the prototype (blocks 1 and 2) * They can be distinguish by properties such as: Relative afnity for 1 and 2 receptors (i.e. metoprolol 1>>2) 1>> Intrinsic sympathomimetic activity, ISA (i.e. pindolol, acebutolol) pindolol, acebutolol) Induction of vasodilation (celiprolol blocks 1 and activates 2) Membrane Stabilizing Activity, MSA, Quinidine-like (higher doses) Cross BBB * -Blocker have little effect on normal heart, but block effects of exercise and stress

CARDIOVASCULAR SYSTEM (most effects are modest when stimulation is low): Lower BP: * HR Contratility = CO * Increase in TPR (reex) * Block 2 presynap-> 2 presynap-> NE presynap-> presynap-> * Some -Blockers produce vasodilation by: -blocking receptors, i.e. labetalol/carvedilol -2 agonist effect, celiprolol -independent mechanisms Anti-Arrythmic: * Increase PR interval->Refract. Period AV node Anti-Arrythmic: * Sinus Rate, Depolarization of ectopic pacemakers Slow conductivity in atria and AV node Reduce ischimia:* O2 consumption->increase cardiac efciency ischimia:* Side Effects: * Asthma; Hypoglycemia; block increase HR during exercise

PULMONARY SYSTEM (effect modest in normal persons): * COPD and ASTHMA patients can develop severe bronchoconstriction METABLIC EFFECTS: * Carbohydrates: Inhibit glycogenolysis (2), caution in labile diabetes, but rarely affect insulin secretion * Lipids: May cause modes increase in TG and decrease in HDLP * Propanolol blocks renin release CNS: * Decrease release of NE from presynaptic terminals resulting in an increase in the 2 effect. Sedation.

tyrosine
Tyr Hydroxylase

metyrosine DA

Reserpine

Dopa

Amphetamine

2 2
Intake Transport Cocaine metabolites

DA NE NE
& AO MT M O C

Bretylium

Agonists or Antagonists

OH O CH2 CH CH2 NH CH(CH3)2 O CH2 CH CH2 NH CH(CH3)2 OH CH2CH2OCH3 O CH2

Propanolol (1=2) (1=

N N S N CH3 OH OCH3 C CH2NHC CH3 CH3 H

Metoprolol (1>>>2) (1>>>

CH CH2 NH CH(CH3)2 OH

Timolol (1>2) (1>

O CH2

CH2CNH2 O CH3 C CH3 CH3 N O CH2

Atenolol (1>>>2) (1>>>

CH CH2 NH CH(CH3)2 OH

OH CH CH2 NH

Nadolol (1>2) (1>

Pindolol (1>>2) (1>>

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Agent Propanolol Nadolol Pindolol Labetalol Carteolol Carvedilol Penbutolo Sotalol Metoprolol Atenolol Acetobutolol Betaxolol Bisoprolol Celiprolol Esmolol Timolol

Selectivity 1=2 1= 1=2 1= 1=2 1= 1=2 1= 1=2 1= 1=2 1= 1=2 1= 1=2 1= 1>>2 1>> 1>>2 1>> 1>>2 1>> 1>>2 1>> 1>>2 1>> 1>>2 1>> 1>>2 1>> 1>>2 1>>

ISA ++ + + + + + -

MSA ++ ++ + ++ + -

lipo.Sol lipo.Sol +++ + ++ + N/A +++ + ++ + + + N/A ++

T1/2 3-6h

(availability) (30%) (35%) (90%) (30%) (85%) (30%) (>90%) (90%) (50%) (40%) (50%) (90%) (80%) (70%) (50%)

12-24h 3-4h 5h 6h 6-8h 5h 12h 3-4h 6-9h 3-4h 14-22h 9-12h 4-5h 4-5h

10 min (0%)

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Adverse effects due to -receptor blockade: Broncoconstriction, Exacerbate heart failure, Bradycardia, Broncoconstriction, Bradycardia, worsen peripheral vasc. disease, CNS (fatigue, insomnia). vasc. May precipitate and/or block recognition of hypoglycemia and delay recovery from insulin-induced hypoglycemia.

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Therapeutic Uses: 1) Hypertension 2) Angina (reduce cardiac work) 3) Supraventricular and Vetricular Arrythmias 4) MI 5) Hypertrophic Obstructive Myocardiopathy 6) Other: hyperthyroidsm, migrane hyperthyroidsm, (prophylaxis), panic, glaucoma.

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