adrenergic agents

Lady Ann L. Francisco

Objectives:

Steps of Biosynthesis of Catecholamine

Distribution of adrenergic receptors

Individual Functions of Adrenergic

receptors

All aspects of adrenaline – Dale`s

Phenomenon

Neurotransmission in ANS

Noradrenergic transmission

Nor-adrenaline is the major neurotransmitter of the Sympathetic system

Noradrenergic neurons are postganglionic sympathetic neurons with cell bodies in the sympathetic ganglia

They have long axons which end in varicosities where NA is synthesized and stored

Adrenergic transmission

Catecholamines:

Natural: Adrenaline, Noradrenaline,

Dopamine

Synthetic: Isoprenaline, Dobutamine

Non-Catecholamines:

Ephedrine, Amphetamines, Phenylepherine,

Methoxamine, Mephentermine

Also called sympathomimetic amines as most of

them contain an intact or partially substituted

amino (NH2) group

• Catecholamines:

Compounds containing

a catechol nucleus

(Benzene ring with 2

adjacent OH groups)

and an amine

containing side chain

• Non-catecholamines

lack hydroxyl (OH)

group

Biosynthesis of Catecholamines

Phenylalanine

PH

Rate limiting Enzyme

5-HT, alpha Methyldopa

Alpha-methyl-p-

tyrosine

Storage of Noradrenaline

Release of NA – Feedback Control

Regulators of NA release

Uptake of Catecholamines

Reuptake

Sympathetic nerves take up amines and release them as neurotransmitters

Uptake I is a high efficiency system more specific for NA

Located in neuronal membrane

Inhibited by Cocaine, TCAD, Amphetamines

Uptake 2 is less specific for NALocated in smooth muscle/ cardiac muscle

Inhibited by steroids/ phenoxybenzamine

No Physiological or Pharmacological importance

Metabolism of CAs

Mono Amine Oxidase (MAO)

Intracellular bound to mitochondrial membrane

Present in NA terminals and liver/ intestine

MAO inhibitors are used as antidepressants

Catechol-o-methyl-transferase (COMT)

Neuronal and non-neuronal tissue

Acts on catecholamines and byproducts

VMA levels are diagnostic for tumours

Metabolism of CAs

(Homovanillic acid) (Vanillylmandelic acid)

Adrenergic neurotransmission

Adrenergic Receptors

Adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors that are the target of catecholamines

Adrenergic receptors specifically bind their endogenous ligands – catecholamines (adrenaline and noradrenline)

Increase or decrease of 2nd messengers cAMP or IP3/DAG

Many cells possess these receptors, and the binding of an agonist will generally cause the cell to respond in a flight-fight manner.

For instance, the heart will start beating quicker and the pupils will dilate

How Many of them ????

Alpha (α) Beta (β)

Adenoreceptors

α 1 β3β 2β1α 2

α 2B α 2Cα 2A

α 1A α 1B α 1D

Differences - Adrenergic

Receptors (α and β) !

Alpha (α) and Beta (β)

Agonist affinity of alpha (α):

adrenaline > noradrenaline > isoprenaline

Antagonist: Phenoxybenzamine

IP3/DAG, cAMP and K+ channel opening

Agonist affinity of beta (β):

isoprenaline > adrenaline > noradrenaline

Propranolol

cAMP and Ca+ channel opening

Potency of catecholamines on

Adrenergic Receptors

Adr NA

Iso

Iso Adr

NA

Log Concentration

Aortic strip contraction Bronchial relaxation

α β

Molecular Effector Differences -

α Vs β

α Receptors:○ IP3/DAG

○ cAMP

○ K+ channel opening

β Receptors:○ cAMP

○ Ca+ channel opening

Recall: Adenylyl cyclase: cAMP pathway

PKA Phospholamban

Increased Interaction with Ca++

Faster relaxation

Troponin

Cardiac contractility

OtherFunctionalproteins

PKA alters the functions of many

Enzymes, ion channels,

transporters

and structural proteins.

Faster sequestration of

Ca++ in SR

PKc

Also Recall: Phospholipase C:

IP3-DAG pathway

Differences between β1, β2 and β3

Beta-1 Beta-2 Beta-3

Location Heart and JG cells Bronchi, uterus,

Blood vessels,

liver, urinary tract,

eye

Adipose

tissue

Agonist Dobutamine Salbutamol -

Antagonist Metoprolol, Atenolol Alpha-methyl

propranolol

-

Action on

NA

Moderate Weak Strong

Clinical Effects of β-receptor

stimulationβ1: Adrenaline, NA and Isoprenaline:

Tachycardia

Increased myocardial contractility

Increased Lipolysis

Increased Renin Release

β2: Adrenaline and Isoprenaline (not NA)

Bronchi – Relaxation

SM of Arterioles (skeletal Muscle) – Dilatation

Uterus – Relaxation

Skeletal Muscle – Tremor

Hypokalaemia

Hepatic Glycogenolysis and hyperlactiacidemia

β3: Increased Plasma free fatty acid – increased O2 consumption -

increased heat production

Differences between α1 and

α2

Alpha-1 Alpha-2

Location Post junctional – blood vessels

of skin and mucous

membrane, Pilomotor muscle

& sweat gland, radial muscles

of Iris

Prejunctional

Function Stimulatory – GU,

Vasoconstriction, gland

secretion, Gut relaxation,

Glycogenolysis

Inhibition of transmitter

release, vasoconstriction,

decreased central symp.

Outflow, platelet

aggregation

Agonist Phenylephrine, Methoxamine Clonidine

Antagonist Prazosin Yohimbine

α1 adrenoceptors

Clinical effectsEye -- Mydriasis

Arterioles – Constriction (rise in BP)

Uterus -- Contraction

Skin -- Sweat

Platelet - Aggregation

Male ejaculation

Hyperkalaemia

Bladder Contraction

α2 adrenoceptors on nerve endings mediate negative feedback which inhibits noradrenaline release

Molecular Basis of Adrenergic

Receptors

Also glycogenolysis

in liver

Inhibition of

Insulin

release and

Platelet

aggregation

Gluconeogen

esis

Dopamine receptors

D1-receptors are post synaptic

receptors located in blood vessels and

CNS

D2-receptors are presynaptic present in

CNS, ganglia, renal cortex

Summary of agents modifying

adrenergic transmissionStep Actions Drug

Synthesis of NA Inhibition α - methyl-p-tyrosine

Axonal uptake Block Cocaine, guanethidine,

ephedrine

Vesicular uptake Block Reserpine

Vesicular NA Displacement Guanethidine

Membrane NA pool Exchange diffusion Tyramine, Ephedrine

Metabolism MAO-A inhibition

MAO-B inhibition

COMT inhibition

Moclobemide

Selegiline

Tolcapone

Receptors α 1

α 2

β1 + β2

β1

Prazosin

Yohimbine

Propranolol

Metoprolol

Adrenaline as prototype

Potent stimulant of alpha and beta

receptors

Complex actions on targets: Heart,

Blood vessel, Blood pressure(dale’s

phenomenon)

Dale`s Vasomotor Reversal

Phenomenon

Actions of Adrenaline

Respiratory

GIT

Bladder

Uterus

Skeletal Muscle

CNS

Metabolic effects

Increases concentration of glucose and lactic acid

Calorigenesis (β-2 and β-3)

Inhibits insulin secretion (α-2)

Decreases uptake of glucose by peripheral tissue

Simulates glycogenolysis - Beta effect

Increases free fatty acid concentration in blood

Hypokalaemia – initial hyperkalaemia

ADME

All Catecholamines are ineffective orally

Absorbed slowly from subcutaneous

tissue

Faster from IM site

Inhalation is locally effective

Not usually given IV

Rapidly inactivated in Liver by MAO and

COMT

ADRs

Restlessness, Throbbing headache,

Tremor, Palpitations

Cerebral hemorrhage, cardiac

arrhythmias

Contraindicated in hypertensives,

hyperthyroid and angina poctoris

Halothane and beta-blockers – not

indicated