ADRENERGIC RECEPTORS AND MODULATORS

Dr Imran Zaheer

JNMCH, AMU

Aligarh

INTRODUCTION

Sympathetic System

Preganglionic fibers originate from

• Thoracic (T1-T12) segments of the cord

• Lumbar (L1-L3) segments of the cord

Most of the ganglia are located in paravertebral chains that lie along the spinal cord

Few (prevertebral) on the anterior aspect of the aorta

Preganglionic fibers are short and the postganglionic fibers are long

NEUROTRANSMITTERS

• 3 types Collectively called catecholamines

1. Noradrenaline(NA)at postganglionic sympathetic sites(except sweat glands, hair follicles) & in certain areas of brain.

2. Adrenaline(Adr)secreted by adrenal medulla

3. Dopamine(DA)transmitter in basal ganglia, limbic system, CTZ, anterior pituitary.

occurs in adrenergic neuronal

cytoplasm

occurs inside granules

occurs in adrenal medulla

STORAGE OF TRANSMITTER

• Stored in synaptic vesicles or granules within adrenergic nerve terminal.

• Vesicular membrane actively takes DA from cytoplasm & synthesize NA inside vesicle with help of DA β-hydroxylase.

• NA stored in a complex with ATP(4:1) adsorbed on protein chromogranin A.

• In adrenal medulla, NA thus formed is diffuses into cytoplasm where it is methylated to Adr.

• Adr so formed is stored in separate granule Chromaffin granule.

RELEASE OF TRANSMITTER

• Depolarisation of nerve terminal membrane opens calcium channels in nerve terminal membrane & resulting entry of Ca2+ promoting fusion and discharge of synaptic vesicles

REGULATION OF TRANSMITTER RELEASE

• Release of cotransmitters can be modulated by prejunctionalautoreceptors and heteroreceptors.

• Following their release from sympathetic terminals, all three cotransmitter norepinephrine, neuropeptide Y (NPY), and ATP can feedback on prejunctionalreceptors to inhibit the release of each other.

• Enhancement of sympathetic neurotransmitter release can be produced by activation of b2

adrenergic receptors

UPTAKE OF NEUROTRANSMITTER

Transport of noradrenaline

Uptake 1(NorepinephrineTransporter)

Uptake 2(Extraneuronalamine Transporter)

Vasicular Transporter(VMAT- 2)

Specificity NA > A A > NA NA = A

Location Neuronal membrane Non-neuronal cell membrane (smooth muscle, cardiac muscle, endothelium)

Synaptic vesicle membrane

Other substrates Tyramineguanethidine

(+)-NoradrenalineHistamine

Dopamine5-HT

Inhibitors CocaineTricyclic Antidepressants (e.g. desipramine

Steroid hormones (e.g. corticosterone)Phenoxybenzamine

Reserpine

Metabolism of neurotransmitter

• Endogenous & exogenous catecholamines are metabolised mainly by two enzymes, monoamine oxidase & catechol-O-methyl transferase (COMT).

• MAO occurs within cells bound to surface membrane of mitochondria, abundant in noradrenergic nerve terminals.

• COMT a widespread enzyme that occurs in both neuronal and non-neuronal tissues, acts on both catecholamines & its deaminatedproducts, produced by action of MAO.

• Main final metabolite of adrenaline & noradrenaline is 3-methoxy-4-hydroxymandelic acid (VMA).

ALDEHYDE DEHYROGENASE

ALDEHYDE REDUCTASE

ALCOHOL DEHYROGENASE

ALDEHYDE DEHYROGENASE

3,4-DIHYDROXYPHENYL GLYCOL 3,4-DIHYDROXYMANDELIC ACID

VANILLYL MANDELIC ACID

3-METHYL,4-HYDROXYPHENYLGLYCOL

DEAMINATION DEAMINATION

ADRENERGIC RECEPTORS

• All belong to superfamily of G-protein-coupled receptors

α1 α2 β1 β2 β3

Second messengers and effectors

PLC activation ↓cAMP ↑cAMP ↑cAMP ↑cAMP

↑ IP3

↑DAG

↑Ca2+

Selective agonists

Phenylephrine, methoxamine

Clonidine, clenbuterol

Dobutamine, xamoterol

Salbutamol, terbutaline, salmeterol, formoterol

BRL 37344

Selective antagonists

Prazosin, doxazocin

Yohimbine, idazoxan

Atenolol, metoprolol

Butoxamine

Effects of receptor activation

Tissues and effects α1 α2 β1 β2 β3

Blood vessels Constrict Constrict Dilate

Bronchi Constrict Dilate

GI tract Relax Relax (presynaptic effect)

Relax

GI sphincters Contract

Uterus Contract Relax

Bladder detrusor

Relax

α1 α2 Β1 Β2 β3

Bladder sphincter

Contract

Seminal tract Contract Relax

Iris (radial muscle)

Contract

Ciliarymuscle

Relax

Heart:

Rate Increase

Force of contraction

Increase

α1 α2 β1 β2 β3

Liver Glycogenolysis Glycogenolysis

Fat LipolysisThermogenesis

Pancreatic islets

Decrease insulin secretion

α1 α2 β1 β2 β3

Nerve Terminal:

Adrenergic Decrease release

Increase release

Cholinergic Decrease release

Salivary gland

K+ release and watery secretion

Amylase secretion

Mast cells Inhibition of histamine release

Receptor Regulation

• Responses mediated by adrenoceptors are not constantly same.

• Three processes have considerable clinical significances.

1. Desensitisation

2. Up – Down regulation

3. supersensitivity

DRUGS THAT AFFECT ADRENERGIC RECEPTOR

DRUGS THAT AFFECT ADRENERGIC NEURONS

Therapeutic Classification of Adrenergic Drugs

• Pressure agentsNoradrenaline Ephedrin Dopamine Phenylephrine Methoxamine

• Cardiac stimulantsAdrenalin Dobutamine Isoprenaline

• BronchodilatorsIsoprenal Salbutamol Salmeterol Formoterol

• Nasal DecongestantsPhenylephrine Xylometazoline Oxymetazoline Naphazoline

• CNS StimulantsAmphetamine Methamphetamine Dexamphetamine

• AnorecticsFenfluramine Sibutramine Dexfluramine

• Uterine relanxant & vasodilatorsRitodrine Isoxsuprine Salbutamol Terbutaline

Clinical uses of adrenoceptor agonists

• Cardiovascular system – cardiac arrest: adrenaline– cardiogenic shock: dobutamine (β1-agonist) – heart block: β-agonists (e.g. isoprenaline) can be used temporarily

while electrical pacing is being arrange

• Anaphylactic shock (acute hypersensitivity) – adrenaline is the first-line treatment along with steroids &

antihistaminics

• Respiratory system – Asthma : selective β2-receptor agonists (salbutamol, terbutaline,

salmeterol, formoterol) – nasal decongestion: drops containing oxymetazoline or ephedrine for

short-term use

• Miscellaneous indications – adrenaline can be used to prolong local anaesthetic action

– miscellaneous indication for α2-agonists (e.g. clonidine) include hypertension , menopausal flushing, lowering intraocular pressure & migraine prophylaxis

– Obesity

– CNS uses• Hyperkinetic children

• Narcolepsy

TOXICITY OF ADRENERGIC DRUGS

• Restlessness, palpitation, anxiety, tremor, may occur after s.c. /i.m. injection of Adr.

• Marked rise in BP leading to cerebral haemorrhage.

• Ventricular tachycardia/fibrillation, angina, myocardial infarction are the hazards of large doses of Adr.

• CNS toxicity is rarely observed with adr. drugs

– In moderate doses, amphetamines commonly cause

restlessness, tremor, insomnia, & anxiety; in high doses, a

paranoid state may be induced.

ADRENERGIC ANTAGONISTS

• These are drugs which antagonize the receptor action of adrenaline and related drugs.

• They are competitive antagonists at α or β or both α and β.

1. α ADRENERGIC BLOCKING DRUGS

2. β ADRENERGIC BLOCKING DRUGS

α ADRENERGIC BLOCKING DRUGS

I. Nonequilibrium type

B-Haloalkylamines - Phenoxybenzamine.

ll. Equilibrium type

A. Nonselective

(i) Ergot alkaloids-Ergotamine, Ergotoxine

(ii) Hydrogenated ergot alkalolds-Dihydroergotamine(DHE), Dihydroergotoxine

(iii) Imidazolines-- Phentolamine

(iv) Miscellaneous - Chlorpromazine

B. α1 selective- Prazosin, Terazosin, Doxazosin, Tamsulosin

C. α2 selective- Yohimbine

Pharmacological properties

Cardiovascular effect

• Blockade of α receptors → vasodilatation → decrease in peripheral

vascular resistance → fall in BP → Hypotension.

• Resultant fall in BP → baroreceptor reflex → sympathetic discharge since

α receptors are blocked, stimulates β1 receptor in heart → tachycardia

• α receptors blocked → absence of efficient peripheral vasoconstriction in

erect posture → peripheral pooling of blood → cerebral hypoxia , vertigo

and fainting → postural hypotension

• Nasal stuffiness due to blocked of α receptor in nasal blood vessels.

• Miosis due to loss of tone of radial muscles of iris.

• Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α1 receptor → urine flow in patients with benign hypertrophy of prostate (BHP) is improved.

• Inhibition of contractions of vas deferens and ejaculatory duct → failure of ejaculation → impotence

• Intestinal motility is increased due to partial inhibition of relaxant sympathetic influences → diarrhoea

β ADRENERGIC BLOCKING DRUGS

Nonselective (β1 and β2 )

a. Without intrinsic sympathomimetic activity

Propranolol, Sotalol, Timolol.

b. With intrinsic sympathomimetic activity

Pindolol

c. With additional α blocking property

Labetalol, Carvedilol

Cardioselective (β1)

Metoprolol, Atenolol, Acebutolol, Bisoprolol

Esmolol, Betaxolol, Celiprolol, Nebivolol

Classifying B blockers into 3 generations

Pharmacological properties

Cardiovascular system

• ↓ heart rate, ↓ myocardial contractility, ↓ conduction velocity,↓myocardial oxygen demand

Though β1 receptor blockade is the main mechanism responsible for antihypertensive effect :

- ↓ renin release

- ↓ decrease in central sympathetic outflow

- Chronic ↓ in c.o

- Blockade of facilitatory effect of presynaptic β2 receptor on NE release.

Pulmonary system

– Least affect on bronchial muscle of normal individuals.

– In asthmatic or COPD pts→ severe bronchoconstriction.

Metabolic effects

– Inhibits stress or adrenaline induced glycogenolysis in type 1 DM to overcome episodes of hypoglycaemia.

– Masks the sympathetic manifestation (tremor, tachycardia, sweating) of hypoglycemia.

– Adverse effect on lipid profile : ↓ HDL,↑ LDL & Triglycerides.

CNS effects

– ↓ decrease in central sympathetic outflow

– Chronic use leads to sedation, lethargy and disturbances in sleep.

Ocular effects

– decreases formation of aqueous humour ↓ intraocular pressure

Therapeutic uses

Cardiovascular use

– Hypertension

– Congestive heart failure

– Angina pectoris : C/I in prinzmetals angina.

– Cardiac arrythmias.

– Myocardial infarction: ↓ incidence ,recurrence and mortality after long term use

Non cardiovascular use :

– Migraine prophylaxis

– Anxiety provoking situations

– Glaucoma

– Hyperthyroidism

– Pheochromocytoma

– Bleeding oesophageal varices associated with portal hypertension

Adverse effects

– Bronchoconstriction

– Bradycardia

– Cold extremities

– CNS side effects: fatigue ,sleep disturbance and depression

– Heart failure

– Hypoglycemia

– Adverse serum lipid profile

THANK YOU

REGULATION OF TRANSMITTER RELEASE

• The release of cotransmitters can be modulated by prejunctionalautoreceptors and heteroreceptors.

• Following their release from sympathetic terminals, all three cotransmitter norepinephrine, neuropeptide Y (NPY), and ATP can feedback on prejunctionalreceptors to inhibit the release of each other.

• Enhancement of sympathetic neurotransmitter release can be produced by activation of b2

adrenergic receptors

DRUGS THAT AFFECT ADRENERGIC NEURONS