Adrenergic Antagonists

What are the key features of nonselective adrenergic antagonists?

• phenethylamine backbone

• any non-hydroxy substitution → antagonist

• Labetalol HCl → Normodyne

  • nonselective adrenergic antagonist

    • blocks A1 = vasodilation

    • blocks B1 = decreased CO

    • blocks B2 = bronchoconstriction

  • asthma is a contraindication

What are the key features of nonselective alpha antagonists?

• imidazoline ring = increased affinity to alpha

CH2 - imidazoline and a heavily subbed benzene ring indicates…

alpha 1 agonist

NH2-imidazoline indicates…

alpha 2 agonist

• tolazoline - Priscoline

  • nonselective alpha antagonist

  • antagonist structure where it is less lipophilic than the agonist

  • indication: pulmonary HTN

    • IV administration

• phentolamine - Oraverse, Regitine

  • nonselective alpha antagonist

  • indication: pheochromocytoma

    • tumor of adrenal medulla → increased release of NE → HTN

What is the effect of alpha 1 selective antagonists?

dilate blood vessels

What are key features of alpha 1 selective antagonists?

• quinazoline nucleus (benzene + pyridine)

• all have amino group

• 6,7 dimethoxy

• 2-piperazine ring system

• carbonyl

• NOT a phenethylamine backbone

• prazosin - Minipress

  • alpha 1 selective antagonist

  • blocks BOTH A1A + A1B

  • furan group

  • piperazine

  • quinazoline

  • indication: HTN

terazosin - Hytrin

• alpha 1 selective antagonist

• indication: HTN

• doxazosin - Cardura

  • alpha 1 selective antagonist

    • indication: BPH, CHF, HTN

• trimazosin

  • alpha 1 selective antagonist

    • OH group → short acting

      • metabolizeddirectly to phase II conjugation

• tamsulosin - Flomax

  • alpha 1 selective antagonist

  • has a phenethylamine backbone

  • no affinity to BVs

  • more selective to alpha 1A

  • sulfur group

    • drug goes directly to kidneys

  • indication: BPH

• alfuzosin - Uroxatral

  • alpha 1 selective antagonist

  • quinoline nucleus

  • NO piperazine → less affinity to circulatory alpha 1 → increased selectivity to alpha 1A

  • indication: BPH

Which of the alpha 1 selective antagonists does NOT have a quinoline backbone?

tamsulosin - Flomax

• yohimbine

  • alpha 2 selective antagonist

  • indication: sexual dysfunction

What are the indications for nonselective beta antagonists?

• CV disease

• glaucoma

What are the effects of nonselective beta antagonists?

• B1 = renin release → angiotensin II (powerful vasoconstrictor)

• B2 = liver, skeletal muscle, uterus, vascular SM, eye, bronchi

What are the contraindications of nonselective beta antagonists?

• diabetes

• asthma

What are the key features of nonselective beta antagonists?

• NE but without OH → antagonist

  • nonhydroxyl sub

• OH-CH2 b/w ethylamine + phenyl

• additional ring → increases lipophilicity

A tertbutyl structure in nonselective beta antagonists increases selectivity for which receptor?

beta 2

An isopropyl structure in nonselective beta antagonists increases selectivity for which receptor?

BOTH B1 and B2

fused rings usually indicate 

nonselectivity

• propranolol - Inderal

  • nonselective beta antagonist

  • isopropyl group

  • naphthalene (fused benzene rings) → very lipophilic!

  • indication: angina, HTN, arrhythmia

What is the contraindication to propranolol?

cirrhosis

How is propranolol metabolized?

• aromatic hydroxylation by CYP in liver

• pindolol - Visken

  • nonselective beta antagonist

  • indole nucleus

  • lipophilic → metabolized by liver

  • indication: angina, HTN, arrhythmia

What is a contraindication of Visken?

• cirrhosis

• nadolol - Corgard

  • nonselective beta antagonist

  • tertbutyl group

  • NOT a catechol since OH isn’t in position 3,4

  • indication: angina, HTN, arrhythmias

What is a contraindication of Corgard?

• cirrhosis

  • drug will be conjugated in phase II

• timolol - Timoptic, Istalol

  • nonselective beta antagonist

  • thiadiazole group

  • tertbutyl group

  • more polar

    • hydrophilic side chain

    • will not cross BBB

  • indication: glaucoma

What are the indications for selective beta 1 antagonists?

• HTN

• arrhythmia

• angina

What are the key features of selective B1 antagonists?

• isopropyl N-substitution

• O-CH2 spacer

• single benzene ring w/ substitution at position 4

• atenolol - Tenormin

  • B1 selective antagonist

  • amide group

  • isopropyl → increased selectivity to B1

How is atenolol metabolized?

• amidases

  • result: NH4 + COOH

• esmolol - Brevibloc

  • B1 selective antagonist

  • short acting due to ester group being easily hydrolyzed

  • indication: acute MI, HTN, arrhythmia

    • injection (HCl)

• metoprolol succinate - Toprol Xl

• metoprolol tartrate - Lopressor

  • B1 selective antagonist

  • indication: angina, HTN, arrhythmia

How is Toprol XL/Lopressor metabolized?

• O demethylation by CYP in liver

• bisoprolol fumarate - Zebeta

  • B1 selective antagonist

  • isopropyl group on ether → less likely to be metabolized by O-demethylation

  • longer duration of action than metoprolol

  • indication: CHF, HTN

• betaxolol - Betoptic S/Kerlone

  • B1 selective antagonist

  • less likely to be metabolized by O-demethylation

  • longer duration of action than metoprolol

  • indication: glaucoma, HTN, angina