ADRENERGIC RECEPTORS AND MODULATORS

1. ADRENERGIC RECEPTORS AND
MODULATORS
Dr Imran Zaheer
JNMCH, AMU
Aligarh

2. INTRODUCTION

3. 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

4. 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.

5. occurs in
adrenergic
neuronal
cytoplasm
occurs inside
granules
occurs in
adrenal
medulla

6. 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.

7. 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

8. REGULATION OF TRANSMITTER RELEASE
• Release of cotransmitters can be
modulated by prejunctional
autoreceptors and
heteroreceptors.
• Following their release from
sympathetic terminals, all three
cotransmitter norepinephrine,
neuropeptide Y (NPY), and ATP
can feedback on prejunctional
receptors to inhibit the release of
each other.
• Enhancement of sympathetic
neurotransmitter release can be
produced by activation of b2
adrenergic receptors

9. UPTAKE OF NEUROTRANSMITTER
Transport of
noradrenaline
Uptake 1
(Norepinephrine
Transporter)
Uptake 2
(Extraneuronal
amine 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 Tyramine
guanethidine
(+)-Noradrenaline
Histamine
Dopamine
5-HT
Inhibitors Cocaine
Tricyclic
Antidepressants (e.g.
desipramine
Steroid hormones
(e.g. corticosterone)
Phenoxybenzamine
Reserpine

10. 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 deaminated
products, produced by action of MAO.
• Main final metabolite of adrenaline & noradrenaline is 3-methoxy-
4-hydroxymandelic acid (VMA).

11. DEAMINATION DEAMINATION
ALDEHYDE
DEHYROGENASE
ALDEHYDE
REDUCTASE
3,4-DIHYDROXYPHENYL GLYCOL 3,4-DIHYDROXYMANDELIC ACID
3-METHYL,4-HYDROXYPHENYLGLYCOL
ALCOHOL DEHYROGENASE
ALDEHYDE
DEHYROGENASE
VANILLYL MANDELIC ACID

12. ADRENERGIC RECEPTORS
• All belong to superfamily of G-protein-coupled receptors

13. 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

14. 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
Relax
detrusor

15. α1 α2 Β1 Β2 β3
Bladder
sphincter
Contract
Seminal tract Contract Relax
Iris (radial
muscle)
Contract
Ciliary
muscle
Relax
Heart:
Rate Increase
Force of
Increase
contraction

16. α1 α2 β1 β2 β3
Liver Glycogenolysis Glycogenolysis
Fat Lipolysis
Thermogenesis
Pancreatic
islets
Decrease
insulin
secretion

17. 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

18. Receptor Regulation
• Responses mediated by adrenoceptors are not constantly same.
• Three processes have considerable clinical significances.
1. Desensitisation
2. Up – Down regulation
3. supersensitivity

19. DRUGS THAT AFFECT ADRENERGIC RECEPTOR

20. DRUGS THAT AFFECT ADRENERGIC NEURONS

22. Therapeutic Classification of Adrenergic Drugs
• Pressure agents
Noradrenaline Ephedrin Dopamine Phenylephrine Methoxamine
• Cardiac stimulants
Adrenalin Dobutamine Isoprenaline
• Bronchodilators
Isoprenal Salbutamol Salmeterol Formoterol
• Nasal Decongestants
Phenylephrine Xylometazoline Oxymetazoline Naphazoline
• CNS Stimulants
Amphetamine Methamphetamine Dexamphetamine
• Anorectics
Fenfluramine Sibutramine Dexfluramine
• Uterine relanxant & vasodilators
Ritodrine Isoxsuprine Salbutamol Terbutaline

23. 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

24. • 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

25. 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.

26. 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

27. 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

28. 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

29. • 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

30. 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

31. Classifying B blockers into 3 generations

32. 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.

33. 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.

34. 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

35. 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

36. Non cardiovascular use :
– Migraine prophylaxis
– Anxiety provoking situations
– Glaucoma
– Hyperthyroidism
– Pheochromocytoma
– Bleeding oesophageal varices associated with portal
hypertension

37. Adverse effects
– Bronchoconstriction
– Bradycardia
– Cold extremities
– CNS side effects: fatigue ,sleep disturbance and depression
– Heart failure
– Hypoglycemia
– Adverse serum lipid profile

38. THANK YOU

39. REGULATION OF TRANSMITTER RELEASE
• The release of cotransmitters can
be modulated by prejunctional
autoreceptors and
heteroreceptors.
• Following their release from
sympathetic terminals, all three
cotransmitter norepinephrine,
neuropeptide Y (NPY), and ATP
can feedback on prejunctional
receptors to inhibit the release of
each other.
• Enhancement of sympathetic
neurotransmitter release can be
produced by activation of b2
adrenergic receptors

40. DRUGS THAT AFFECT ADRENERGIC NEURONS