Post on 04-Jul-2015
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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