Autonomic drugs: Adrenoceptor Agonists and … · Introduction (review) 5 key ... β2 Respiratory,...

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AUTONOMIC DRUGS: ADRENOCEPTOR AGONISTS AND SYMPATHOMIMETICS Lecture 4

Transcript of Autonomic drugs: Adrenoceptor Agonists and … · Introduction (review) 5 key ... β2 Respiratory,...

AUTONOMIC DRUGS:

ADRENOCEPTOR AGONISTS

AND SYMPATHOMIMETICS

Lecture 4

Introduction (review)

5 key features of neurotransmitter function, which

can be targets for pharmacotherapy

Synthesis

Storage

Release

Termination of action

Receptor effects

Sympathetic agents

MOA

Direct acting

Directly stimulate the receptor

Indirect acting

Displace/release stored catecholamines from the nerve (ex.

tyramine)

Decrease clearance of NE by

Inhibiting reuptake of catecholamines (ex. cocaine and TCAs)

By inhibiting NET (norepinephrine transporter)

By altering NET to become a reverse transporter

Preventing the metabolism of NE (ex. MAO inhibitors)

Normal activity of NET

Blockage of NET by cocaine

Blockage of and reverse transport of

NET by amphetamine

MAO inhibitors

Sympathetic agents

NET EFFECT = increase NE activation or supply to

the receptors

Binding of agonist or drug to receptors

Sympathetic agents

MOA to the adrenoceptors

Act on G-protein coupled receptors, which then

activates the 2nd messenger system

Receptor subtypes

Alpha

Beta

Dopamine

Adrenoceptors

Receptor Location

Alpha 1 Postsynaptic effector cells, especially smooth muscle

Alpha 2 Presynaptic adrenergic nerve terminals, platelets,

lipocytes, smooth muscle

Beta 1 Postsynaptic effector cells (heart, lipocytes, brain)

Presynaptic adrenergic and cholinergic nerve

terminals

Juxtaglumerular (JG) apparatus

Beta 2 Postsynaptic effector cells (smooth and cardiac

muscles)

D1 Brain, effector tissues, kidney vascular bed

D2 Brain, effector tissues, smooth muscles

Sympathetic agents

Alpha receptors

alpha1 (α1)

alpha2 (α2)

Beta receptors

Beta1 (β1)

Beta2 (β2)

Beta3 (β3)

Dopamine receptors

D1

D2

Sympathetic agents

Selective

Majority of the drugs are selective (will preferentially

bind to a specific receptor). But as concentration

increases, the other receptors will also be stimulated.

Ex.

Phenylephrine is a selective α1 agonist. If given at higher

doses, it may eventually stimulate α2 and even β receptors

at toxic doses.

Relative receptor affinities

Alpha agonists

Phenylephrine, methoxamine α1 > α2 >>>>> β

Clonidine α2 > α1 >>>>> β

Mixed alpha and beta agonists

Norepinephrine α1 = α2; β1 >> β2

Epinephrine α1 = α2; β1 = β2

Beta agonists

Dobutamine β1 > β2 >>>> α

Isoproterenol β1 = β2 >>>> α

Albuterol, terbutaline β2 >> β1 >>>> α

Dopamine agonist (Dopamine) D1 = D2 >> β >> α

Sympathetic agents

Receptor regulation

More for adrenoceptors than cholinoceptors

Down regulation or desensitization

There will be less response to the agonist

2 mechanisms

Slow desensitization (hours to days)

Decrease in receptor production (down regulation)

Rapid desensitization (minutes)

Decrease in function of a receptor thru phosphorylation

(rapid negative-feedback effect)

Sympathetic agents

Chemistry of catecholamines

Basic chemistry is that of phenylethylamine

Sympathetic agents

Substitution of H by OH at the 3 and 4 carbon atoms in

the benzene ring will produce the group Catechol-

amines

Epinephrine, Norepinephrine, Isoproterenol, Dopamine

Further substitutions or removal of OH among the

different carbon atoms will alter the characteristics of

the succeeding drugs.

Non-catecholamines: phenylephrine, methoxamine,

ephedrine, amphetamine

Catecholamines

Non-catecholamines

Catecholamines

Maximal alpha and beta activity

Inactivated by COMT (catechol-O-

methyltransferase)

Found in the gut and liver = does not allow oral

administration of epi and norepi

Absence of one or both OH groups on the phenyl ring

susceptibility to COMT bioavailability after oral

adminstration duration of action

entry of drug to the CNS

Ex. non-catecholamines = phenylephrine and amphetamine

Catecholamines

Alterations in the amine side-chain

Increasing the size of the amino group tends to increase

βreceptor activity, with corresponding decreased αreceptor activity (ex. NE Epi Isoproterenol)

Relative receptor affinities

Alpha agonists

Phenylephrine, methoxamine α1 > α2 >>>>> β

Clonidine α2 > α1 >>>>> β

Mixed alpha and beta agonists

NE α1 = α2; β1 >> β2

Epi α1 = α2; β1 = β2

Beta agonists

Dobutamine β1 > β2 >>>> α

Isoproterenol β1 = β2 >>>> α

Albuterol, terbutaline β2 >> β1 >>>> α

Dopamine agonist (Dopamine) D1 = D2 >> β >> α

Catecholamines and non-

catecholamines

Alterations in the amine side-chain

Substitution at the αcarbon blocks metabolism by

monoamine oxidase (MAO) = duration of action

Ex. Ephedrine and amphetamine

Sympathomimetic agents

General Effects

Cardiovascular system

Compensatory reaction by the parasympathetic system

Alpha1

Arterial and venous vasoconstriction

Reflex response of HR

Skin, nasal mucosa and GIT vessels constrict

Alpha2

Mild vasoconstriction

More prominent CNS effect = vasodilation and chronotropy =

BP

Sympathomimetic agents

General Effects

Cardiovascular system

Beta receptors

Heart = inotropy, chronotropy, dromotropy

Beta2 = vasodilation

Net effect = systolic but diastolic pressure

Dopamine receptors

D1 = Vasodilation of renal, splanchnic (GIT), coronary, cerebral

Improve perfusion to kidneys = urine output

Dopamine activates beta receptors in the heart

Sympathomimetic agents

Noncardiac effects

Lungs = beta2 = bronchodilation

Eye

alpha

pupillary dilation and increase outflow of aqueous humor

Beta antagonism

Decrease aqueous humor production

Genito-urinary

Alpha

Increase urinary sphincter tone (improve continence)

Ejaculation and detumescence

Sympathomimetic agents

Noncardiac effects

Fat cells

Beta2 = glycogenolysis and increase insulin secretion

Beta3 = lipolysis

Diabetogenic

Potassium

Beta2 = promote uptake of potassium into cells

Treatment for hyperK (salb, insulin, calcium)

Renin

Beta1 = increase secretion blood volume BP

Sympathomimetic agents

Noncardiac effects

CNS

Most seen among non-catecholamines

Increased alertness, attentiveness

Elevation of mood, insomnia, euphoria and anorexia

Adrenoceptors - Functions

Type Tissue location Action

α1 Most vascular smooth muscle Contraction

Pupillary dilator muscle Contraction (dilates pupil)

Pilomotor smooth muscle Erects hair

Prostate Contraction

Heart inotropy

α2 Post synaptic CNS neurons Probably multiple (BP)

Platelets Aggregation

Adrenergic and cholinergic nerve

terminals

Inhibits transmitter release

Some vascular smooth muscle Contraction

Fat cells Inhibits lipolysis

Type Tissue location Action

β1 Heart, juxtaglomerular cells chronotropy and

inotropy

renin release

β2 Respiratory, uterine and vascular

smooth muscle

Smooth muscle

relaxation

Skeletal muscle Potassium uptake

Human liver Activates glycogenolysis

β3 Fat cells lipolysis

D1 Smooth muscle Dilates renal blood

vessels

D2 Nerve endings Modulates transmitter

release

Sympathomimetic drugs

Endogenous

catecholamines

Receptor

activity

Effect

Epinephrine α1 = α2; β1

= β2

Vasoconstrictor (except in muscles =

vasodilation)

inotropy, chronotropy in heart

Norepinephrine α1 = α2; β1

>> β2

BP

+ Inotropy, chronotropy

Dopamine D1 = D2 >>

β >> α+ inotropy, chronotropy

Reward stimulus

renal perfusion

Sympathomimetic drugs

Direct Acting Receptor

activity

Effect

Phenylephrine α1 > α2

>>>>> βMydriasis, decongestant, slight inc

in BP

Methoxamine α1 > α2

>>>>> βVasoconstriction and vagally

mediated bradycardia

Alpha2 agonists

Clonidine,

methyldopa

α2 > α1

>>>>> βBP.

Mild sedative

Oxymetazoline α2 >>> α1 Topical decongestant (constrict

nasal mucosa)

Isoproterenol β1 = β2 >>>>

αVasodilator, with increase in

cardiac output with a fall in

diastolic pressure

Direct Acting Receptor

activity

Effect

Beta agonists

Isoproterenol β1 = β2 >>>>

αVasodilator, with increase in

cardiac output with a fall in

diastolic pressure

Dobutamine β1 > β2 >>>>

αCO with less reflex tachycardia

Sympathomimetic drugs

Mixed acting Receptor

activity

Effect

Ephedrine β1 > β2 >>>>

αMild stimulant

Phenylpropanolam

ine

α1 > α2

>>>>> βAppetite suppressant

Cocaine Affects pleasure centers

Uses

Treatment of acute hypotension

Fluids first before sympathomimetic agents

Temporary emergency management of complete

heart block

Drug induced cardiac stress test (dobutamine

injection)

Local vasoconstriction

Mucous membrane decongestants rebound

hyperemia may follow.

Uses

Asthma

Anaphylaxis

Mydriatic agent

BREAK

Adrenoceptor Antagonists

Selectivity to a receptor depends on chemical structure and dose

MOA

Alpha blockers

Reversible: ex. phentolamine, prazosin, labetalol

Irreversible: covalent bond with receptor

Phenoxybenzamine

Beta blockers

Competitive antagonists

Well absorbed orally, but generally of low bioavailability

Extensive 1st pass effect in the liver

Affected by Cytochrome P450 inducers and inhibitors

Adrenoceptor Antagonists

Beta blockers

Average half life of 3-10 hours

Except esmolol = rapid effect and rapidly inactivated

(10min) = good for hypertensive crisis

Adrenoceptor Antagonists

Receptor Affinity

Alpha antagonists

Prazosin, terazosin, doxazosin α1 >>>>α2

Phenoxybenzamine α1 > α2

Phentolamine α1 = α2

Yohimbine, tolazoline α2 >> α1

Mixed antagonists

Labetalol, carvedilol β1 = β2 ≥ α1 > α2

Beta antagonists

Metoprolol, acebutolol, alprenolol

atenolol, esmolol, nevibolol, etc.

β1 >>> β2

Propanolol, carteolol, pindolol, timolol β1 = β2

Butoxamine β2 >>> β1

Adrenoceptor Antagonists = Opposite

effectType Tissue location Action

α1 Most vascular smooth muscle Contraction

Pupillary dilator muscle Contraction (dilates pupil)

Pilomotor smooth muscle Erects hair

Prostate Contraction

Heart inotropy

α2 Post synaptic CNS neurons Probably multiple (BP)

Platelets Aggregation

Adrenergic and cholinergic nerve

terminals

Inhibits transmitter release

Some vascular smooth muscle Contraction

Fat cells Inhibits lipolysis

Adrenoceptor Antagonists = Opposite

effectType Tissue location Action

β1 Heart, juxtaglomerular cells chronotropy and

inotropy

renin release

β2 Respiratory, uterine and vascular

smooth muscle

Smooth muscle

relaxation

Skeletal muscle Potassium uptake

Human liver Activates glycogenolysis

β3 Fat cells lipolysis

D1 Smooth muscle Dilates renal blood

vessels

D2 Nerve endings Modulates transmitter

release

Alpha Antagonists

Phenoxybenzamine

Irreversible alpha blocker

Also blocks histamine, Ach, and 5HT receptors

Reduces blood pressure when sympathetic tone is high

useful for pheochromocytoma

ADR

orthostatic hypotension and tachycardia

Nasal congestion and inhibition of ejaculation

Alpha Antagonists

Phentolamine

Competitive blocker of α1 and α2

Vasodilation with direct and reflex tachycardia (due to

antagonism to α2 receptors)

ADR: tachycardia, arrythmia

Used for tx of pheochromocytoma

Alpha Antagonists

Prazosin, Terazosin and Doxazosin

α1 blocker

Vasodilation with minimal effect on the heart

Relaxes prostate muscle (useful for BPH)

Half life

Half life (hours)

Prazosin 3

Terazosin 9-12

Doxazosin 22

Beta Antagonists

Propanolol

Non-selective beta blocker

Decreased chronotropy and inotropy

Mild bronchoconstriction

Metoprolol, atenolol

Selective beta1 blocker

Decreased chronotropy and inotropy

Mild hypoglycemia and vasodilation

Beta Antagonist

Nebivolol

Most selective beta1 inhibitor

Esmolol

Ultra short acting beta1 selective antagonist

Treatment for arrythmias, perioperative hypertension

and myocardial ischemia

Mixed Antagonists

Labetalol and carvedilol

β1 = β2 ≥ α1 > α2

Decreased blood pressure, but with less reflex

tachycardia due to low alpha antagonism

Uses – Alpha blockers

Treatment for

Pheochromocytoma

Urinary obstruction and BPH

Other uses (not drug of choice)

Hypertensive emergencies

Chronic hypertension

Peripheral vascular disease

Erectile dysfunction

Uses – Beta blockers

Treatment for

Angina and following myocardial infarction

Decrease work load and oxygen demand of heart

Heart arrythmias

Regulate heart rate and heart conduction speed

Chronic heart failure

Decrease cardiac remodeling

Glaucoma

Hypertension

Especially for patient with uncontrolled diabetes

In combination with a diuretic and a peripheral vasodilator

Uses – Beta blockers

Treatment for

Hyperthyroidism (for Propanolol)

Sympathetic antagonism and decreased peripheral

conversion of T4 to T3 (more active to less active)

Precautions

Beta blockers

Hypercholesterolemia

May increase LDL and decrease HDL

Congestive heart failure?

Beta2 blockers

Patients with asthma

Use another anti-hypertensive drug

Patients with diabetes and inadequate glucose reserves

Inhibits lipolysis and glycogenolysis = available blood glucose = may promote hypoglycemia