BY DR. ABIDEMI J. AKINDELE

Department of Pharmacology, Therapeutics & Toxicology Faculty of Basic Medical Sciences

College of Medicine, University of Lagos, Lagos, Nigeria

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ADRENOCEPTORS Adrenoceptors mediate central and peripheral actions of

NA (NT) & Adr. (hormone & NT).

Found in nearly all peripheral tissues & on many neuronal

populations within the CNS.

NA & Adr. play important roles in BP control, myocardial

contractile rate & force, airway reactivity and variety of

metabolic & CNS functions.

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ADRENOCEPTORS CONT’D

Agonists & antagonists have proved useful in treatment of

variety of diseases including hypertension, angina pectoris,

CHF, asthma, depression, BPH & glaucoma.

Also useful in therapeutic situations e.g. shock, premature

labour, opioid withdrawal & as adjuncts to general

anaesthesia.

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HISTORICAL PERSPECTIVE

Oliver & Schafer (1896)

Demonstrated that injection of extracts of adrenal gland

caused rise in arterial pressure.

Adrenaline was subsequently isolated as the active

compound in the adrenal gland extracts.

Dale (1913)

Demonstrated that Adr. Caused 2 distinct effects:

vasoconstriction in certain vascular beds and vasodilation

in others.

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HISTORICAL PERSPECTIVE

Vasoconstriction component was observed to be abolished

by pre-treatment of animal with an ergot derivative

[selective α- adrenoceptor antagonist(s)].

Adr. then caused fall in arterial pressure [α-blockade

resulted in transition to β-adrenoceptor agonist effect(s)].

Ahlquist (1948)

Proposed existence of more than one adrenergic receptor

based on abilities of Adr., NA & other agonists to regulate

various physiological processes.

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These drugs were found to cause either contraction or

relaxation of smooth muscles depending on site, dose and

agent.

Ahlquist proposed designations α & β: αRs on smooth

muscles where catecholamines produce excitatory

responses & βRs where inhibitory responses are produced.

GIT presents an exception as it is relaxed by either α or β

agonist action.

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Rank order of potency: β → Isoprenaline > Adr. ≥ NA; α →

Adr. ≥ NA ≥ Isoprenaline.

1955

Selective β-adrenoceptor antagonists were developed,

Ahlquist’s original classification was confirmed & further

subdivisions of α & β adrenoceptors were suggested.

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Initial classification corroborated by finding that certain

antagonists produce selective blockade of effects of

adrenergic nerve impulses & sympathomimetic agents @ α-

adrenoceptors (e.g. phenoxybenzamine) & others produce

selective β-adrenoceptor blockade (e.g. propranolol).

Lands et al. (1967)

Compared rank order of potency in a way similar to work

of Ahlquist and concluded that there are two subtypes of β-

adrenoceptor (β1 & β2).

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β1-ADR (dominant receptor in heart and adipose tissue)

was equally sensitive to NA & Adr.

β2-ADR (responsible for relaxation of vascular, uterine &

airway smooth muscles) was much less sensitive to NA vis-

à-vis Adr.

Subsequent studies with agonists & antagonists have

confirmed existence of α1, α2, β1, β2 & β3 – ADRs, all being

GPCRs with distinct 2nd messenger systems.

Pharmacological & molecular evidences have throw-up

subtypes of ADRs.

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Adrenoceptors

α β

β1 β2 β3 β4

α1 α2

α2A α2B α2C (α2D)

α1A α1B α1D (α1L)

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α1L may represent a particular conformational state of the

α1A-ADR.

α2D is a species orthologue of the human α2A subtype hence

it is not considered to be a separate subtype.

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α1A α1B α1D α1L α2A α2B α2C α2D β1 β2 β3 β4

AGONISTS

Methoxamine

Phenylephrine

Mephentermine

Metaraminol

Midodrine

Oxymetazoline

Tetrahydrozoline

Xylometazoline

Clonidine

Apraclonidine

Guanfacine

Guanabenz

Brimonidine

α-methyldopa

Dexmedetomidine

Clenbuterol

Dobutamine

Denopamine

Xamoterol

Albuterol

Bitolterol

Fenoterol

Isoetharine

Metaproterenol

Procaterol

Terbutaline

Ritodrine

Formoterol

Salmeterol

Salbuterol

Salbutamol

Amibegron

Mirabegron

Ro40-2148

Solabegron

Vibegron

ANTAGONISTS

Prazosin

Terazosin

Doxazosin

Alfuzosin

Tamsulosin

Indoramin

Urapidil

Bunazosin

Trimazosin

Niguldipine

Yohimbine

Imiloxan

Idazoxan

Acebutolol

Atenolol

Bisoprolol

Esmolol

Metoprolol

Betaxolol

Celiprolol

Nebilolol

Butoxamine

ICI-118,551

L-748,328

L-748,337

SR 59230A (also an

antagonist of α1

receptor)

AGONISTS

Non-selective agonists: Adr. (α1, α2, β1 , β2 , β3); NA (α1, α2, β1

>> β2 ); Isoprenalol (β1 + β2).

α1 agonists: Methoxamine, Phenylephrine,

Mephentermine, Metaraminol, Midodrine,

Oxymetazoline, Tetrahydrozoline and Xylometazoline.

Mephentermine & Metaraminol also act indirectly to

release NA.

Midodrine is a pro-drug.

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AGONISTS (α1 agonists)

Prominent Pharmacological Action (PPA): Vasoconstriction

Principal Therapeutic Uses (PTUs): Pressor agents (Rx of

hypotension & shock – methoxamine & phenylephrine), nasal

decongestants (oxymetazoline, tetrahydrozoline, xylometazoline

& some preparations of phenylephrine).

Adverse Effects (AEs): Hypertension, headache, reflex

bradycardia, excitability, restlessness, dry mouth, sedation &

rebound hypertension ff. abrupt withdrawal.

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AGONISTS

α2 agonists: Clonidine, Apraclonidine, Guanfacine, Guanabenz,

Brimonidine, α-methyldopa, dexmedetomidine and Clenbuterol.

Apraclonidine & Brimonidine are used topically for glaucoma

and ocular hypertension.

Methyldopa is converted in CNS to α-methylNA (α2 agonist).

Used very occasionally as centrally-acting sympatholytic

vasodilators for the Rx of hypertension.

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AGONISTS (α2 agonists)

PPAs: ↓ sympathetic outflow resulting in ↓ peripheral

vascular resistance and ↓ production of aqueous humour.

PTUs: Adjunct therapy in shock; hypertension; to ↓

sympathetic response to withdrawal from narcotics,

alcohol & tobacco; glaucoma.

AEs: Sedation, dry mouth & nasal mucosa, bradycardia,

orthostatic hypotension, impotence, constipation, nausea

& gastric upset, bradyarrythmia, ↓ CO, hypotension etc.

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β1 agonists: Dobutamine, Denopamine and Xamoterol.

Use with caution in patients with hypertension or cardiac

arrhythmias; used only IV.

PPAs: ↑ in cardiac contractility; some ↑ in HR; ↑ AV

conduction.

PTUs: short term Rx of cardiac decompensation after

surgery or in patients with CHF or myocardial infarction.

AEs: ↑ BP and HR.

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β2 agonists: Albuterol, Bitolterol, Fenoterol, Isoetharine,

Metaproterenol, Procaterol, Terbutaline, Ritodrine (all

intermediate acting), Formoterol, Salmeterol (long acting)

& Salbutamol.

Use with caution in patients with CV disease (reduced by

inhalational administration); minimal side effects →

intermediate acting.

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Agonists (β2 agonists)

PPAs: Relaxation of bronchial smooth muscle; relaxation of

uterine SM; activation of other β2Rs after systemic

administration.

PTUs: Asthma & chronic obstructive pulmonary disease; acute

bronchospasm (short & intermediate acting drugs); premature

labour (Ritodrine); prophylaxis (long acting agents).

AEs: Headache, anxiety, nausea, muscle tremors, nervousness,

palpitations etc.

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β3 agonists: BRL 37344, CGP 12177 and CL 316243.

β4 agonists: ?

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ANTAGONISTS

α-non selective antagonists: Phenoxybenzamine,

Phentolamine and Tolazoline.

α1-selective antagonists: Prazosin, Terazosin, Doxazosin,

Alfuzosin, Tamsulosin, Indoramin, Urapidil, Bunazosin,

Trimazosin and Niguldipine.

PPAs: ↓peripheral vascular resistance; relax smooth

muscles in neck of bladder & in prostate.

PTUs: Primary hypertension; ↑ urine flow in BPH.

AEs: Postural hypotension when therapy is instituted.

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ANTAGONISTS CONT’D

α2-selective antagonists: Yohimbine, Imiloxan and

Idazoxan.

Blockade ↑ sympathetic outflow & potentiate release of NA

from nerve endings.

Results in activation of α1 & β1 Rs in the heart & peripheral

vasculature → ↑ BP.

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ANTAGONISTS CONT’D

β-non selective antagonists: Nadolol, Penbutolol, Pindolol,

Propranolol, Timolol, Carteolol, Carvedilol, Bucindolol

and Labetalol.

Carvedilol & Labetalol also block α1Rs.

β 1-selective antagonists: Acebutolol, Atenolol, Bisoprolol,

Esmolol, Metoprolol, Betaxolol, Celiprolol and Nebivolol.

β 2-selective antagonists: Butoxamine

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β-BLOCKERS

PPAs: ↓ HR; ↓ contractility; ↓ CO; slow conduction in atria & AV

node; ↑ refractory period, AV node; bronchoconstriction;

prolonged hypoglycaemia; ↓ plasma free fatty acids; ↓ HDLc; ↑

LDLc & triglycerides; hypokalemia.

PTUs: Angina pectoris; hypertension; cardiac arrhythmias; CHF;

pheochromocytoma; glaucoma; hypertropic obstructive

cardiomyopathy; hyperthyroidism; migraine prophylaxis; acute

panic symptoms; substance withdrawal; variceal bleeding in

portal hypertension.

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β-BLOCKERS CONT’D

AEs: Bradycardia; -ve ionotropic effect; ↓ CO;

bradyarrythmias; ↓ AV conduction; bronchoconstriction;

fatigue; sleep disturbances (insomnia, nightmares);

prolongation of hypoglycemia; sexual dysfunction in men;

drug interactions.

NB: Pharmacological effects depend largely on degree of

sympathoadrenal tone.

Bronchoconstriction is of concern in asthmatics & COPD.

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β-BLOCKERS CONT’D

Hypoglycemia is of concern in hypoglycemics and

diabetics.

Membrane stabilization effect associated with propranolol,

acebutolol, carvedilol & betaxolol only.

Intrinsic sympathomimetic activity (ISA) strong for

pindolol & weak for penbutolol, carteolol, labetalol &

betaxolol.

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β-BLOCKERS CONT’D

3rd generation non-selective agents (carteolol, carvedilol,

bucindolol & labetalol) have as their PPAs – membrane

stabilizing effect; ISA; vasodilation.

Their multiple mechanism of action includes – α1

antagonism; β2 agonism; release of NO; Ca2+ channel

blockade; opening of K+ channels.

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