adrenergic agents
TRANSCRIPT
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