Pharmacology

Adrenergic Agonist

Adrenergic system

  • The adrenergic drugs are activate the adrenergic receptor or adrenoreceptor by stimulating nor epinephrine (Nor adrenaline) or Epinephrine (Adrenaline).
  • It is also known as sympathomimetic.
  • The drugs that are blocks the activation of adrenergic receptor are named as sympatholytic.
  • The sympathomimetic acts on adrenergic receptor either directly (Direct-acting-agonist) or indirectly (Indirect-acting-agonist) by enhance release or blocking reuptake of NE (Indirect -acting-antagonist).
Direct acting agentsIndirect acting agentsDirect and indirect acting (Mixed action agents)
Albuterol
Clonidine
Dobutamine
Dopamine
Epinephrine
Formeterol
Fenoldopam
Isoproterenol
Mirabegron
Norepinephrine
Phenylephrine
Terbutaline  
Amphetamine
Cocaine
Ephedrine
Pseudoephedrine

Mechanism of adrenergic agonist

A. Adrenergic transmission

i. Synthesis of CAs

ii. Storage of CAs

iii. Release of CAs

iv. Binding of CAs

v. Uptake of CAs

vi. Metabolism of CAs

B.  Adrenergic receptor (Adrenoreceptor)

A.  Adrenergic transmission

i) Synthesis of NE

  • Catecholamines are synthesize from amino acid Phenylalanine.
  • Phenylalanine gets hydroxylation to form Tyrosine.
  • Tyrosine is transported by sodium linked carrier into the axoplasm of the adrenergic neuron.
  • Then it is hydroxylated to Dihydroxyphenyalanine (DOPA) by the enzyme tyrosine hydroxylase.
  • This step is the rate limiting step (Slowest step) in the formation of epinephrine.
  • Dopa is decarboxylated to form in presence of enzyme DOPA decarboxylase in the synaptic neurons.
  • The tyrosine hydroxylase enzyme is inhibited by α-methyl-p-tyrosine results in depletion of CAs.
  • That inhibitor can be used in “Pheochromocytoma” before surgery.

ii)  Storage of CAs

  • Dopamine is then transported into synaptic vesicles by an amine transport system.
  • Thus amine transport system is involved in reuptake of CAs.
  • This transport carrier is blocked by Reserpine.
  • Dopamine hydroxylated to for Nor epinephrine in presence of enzyme β-hydroxylase.
  • The CAs and other co-transmitters (DA, NE, ATP, β-hydroxylase etc.) are stored as a complex which is absorbed on a protein chromogranin.
  • Methylated to form epinephrine and CAs thus forced with in the cromaffin granules.
  • On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine direct into the circulation.

iii)  Release of CAs

  • Action potential arise at the nerve junction and trigger the Ca2+ ions into the cytoplasm of neuron.
  • Increase concentration of Ca2+ ion causes fuse cell membrane and to undergo exocytosis.
  • Guanithidine block this release.

iv)  Binding to receptor

  • NE released from the sympathetic vesicle diffuse into synaptic space and binds to post synaptic receptors.
  • Adrenergic receptors used both cyclic adenosine monophosphate (cAMP) as second messenger system and phosphatidylinositol cyclic to transduce the signal into an effect.

v)  Uptake of CAs

  • Uptake can be occur in two steps
    • a) Axonal Uptake: Take up NE is higher affinity than E and had be called as uptake-01. NET is present at neuronal membrane which transport NE by Na+ coupled mechanism. This uptake is most important mechanism for terminating the post junctional action of NA. About 75-90% of released NE is retaken. This pump is inhibited by Cocaine, Imipramine, Desipramine and others.
    • b) Vesicular Uptake: The membrane of intracellular vesicle has amine pump i.e. vesicular monoamine transporter (VMAT-2) which transport CAs from the cytoplasm to the interior of the storage vesicle.

vi)  Metabolism of CAs

  • Releasing of NE from vesicles into cytoplasm as well as taken up by axonal transport is attached with Mono amine oxidase (MAO) and Catechol-O-M-transferase (COMT) in liver and other tissue.

Adrenergic Receptor

α – Adrenergic receptor

  • Agonist affinity of α receptor: Adr > NA > Isoprenaline
  • Antagonist: Phenoxybenzamine
  • Pathways: IP3 / DAG, cAMP decrease and K+ channel opening.

α1 receptor

  • Location: Post junctional on effector organs.
  • Pathway: It acts by phospholipase ‘C’ and increased IP3 / DAG.
  • Coupling protein: “Gq
  • Effects:
    • Eye: Mydriasis
    • Arterioles: Constriction (increase in BP)
    • Uterus: Contraction
    • Skin: Sweat
    • Platelet: Aggregation
    • Male sex organ: Ejaculation
    • Bladder: Contraction
    • Splenic capsule: Contraction
    • Neurotransmitter: Increase release of Ach
    • Smooth muscle: Contraction (vasoconstriction)
    • Gland: Secretion
    • Gut: Relaxation
    • Liver: Glycogenolysis
    • Heart: Arrhythmia

α2 receptor

  • Location:
    • Pre-junctional nerve ending (α2A)
    • Post-junctional in brain
    • Pancreatic β cells and extra-junctional in certain blood vessels.
    • Platelets
  • Pathway:
    • Inactivation of Adenylate cyclase (AC)
    • Decrease cAMP
    • Increase K+ channel
    • Decrease Ca2+ channel or increase
    • Increase IP3 / DAG
  • Agonist: Clonidine
  • Antagonist: Yohimbine, Rauwolscine
  • Coupling protein: Gi / Go
  • Effect:
    • Inhibition of transmission release.
    • Vasoconstriction
    • Decrease central sympathetic flow.
    • Decrease insulin release.
    • Platelet aggregation

β receptor

  • Affinity: Isoprenaline > Adr > NA
  • All β receptor activate adenylate cyclase (AC), rising intracellular cAMP concentration.

β1 receptor

  • Location: Heart and JG cells
  • Agonist: Dobutamine
  • Antagonist: Metoprolol, Atenolol
  • Action on NA: Moderate
  • Effect:
    • Bronchi: relaxation
    • Smooth muscle of arterioles (skeletal muscle): Dilation
    • No effect on iris
    • Relaxation of ciliary muscle (less)
    • Intestinal relaxation
    • Detrusor (urinary muscle): Relaxation
    • Augmented insulin (mild) and glucagon secretion.
    • Liver: Glycogenolysis: hyperglycemia

β2 receptor

  • Β2 – agonist affinity Adrenaline and Isoprenaline (Not NA).
  • Location
    • Bronchi
    • Uterus
    • Blood vessels
    • Liver
    • Urinary tract
    • Eye
  • Agonist: Salbutamol
  • Antagonist: α-M-Propranolol.
  • Action on NA: weak
  • Effect:
    • Bronchi – Relaxation
    • Smooth muscle of Arterioles (skeletal muscle) – dilation
    • No effect on iris
    • Relaxation of ciliary muscle (less)
    • Detrusor (Urinary muscle) – Relaxation
    • Augmented insulin (Mild) and glucagon secretion.
    • Liver – Glycogenolysis – hyperglycemia. 

Adrenaline as a prototype

Heart

  • β1 – Cardiac stimulant (+ve chronotropic, +ve ionotropic)
  • act on β1 receptor in myocardium, pacemaker cells and conducting tissue.
  • Heart rate is increase by increasing slow diastolic depolarization of cells in SAN.
  • It activates latent pacemaker in A-V node and purkinje fibres.
  • In high dose arrhythmia can occur.
  • Cardiac output is enhanced and oxygen consumption is increased, cardiac efficiency is markedly decreased.
  • Reduce refractory period.

Blood vessel

  • Smaller vessel-arterioles – Vasoconstriction (α) and vasodilatation (β) depends on the drugs.
  • Decrease blood flow to skin and mucous membranes and renal beds (α effect 1 and 2).
  • Increased blood flow to the skeletal muscles coronary and liver vessels (β2 effect) counter balance by a vasoconstriction effect of α receptor.

Blood pressure

  • It depends on concentration of catecholamine present.
  • NA causes rise in systolic, diastolic and mean BP (no β2 action) – unopposed α action.
  • Isoprenaline causes rise in systolic but fall in diastolic BP (fall BP, β1 and β2).
  • Adr causes rise in systolic BP, but fall in diastolic BP means BP gradually rise (slow injection).
  • Decrease peripheral resistance at low concentration. β – Receptors are more sensitive to Adr than α – receptor.
  • Rapid i.v. injection of adrenalin marked rise in systolic and diastolic BP, but BP returns to normal in few minutes.

Respiration

  • Powerful bronchodilator.
  • Relax bronchial smooth muscle (not NA)
  • Β2 mediated effect.
  • Physiological antagonist to mediator to bronchoconstriction (e.g. Histamine).

GIT

  • Relaxation of gut muscle (α and β) and constricted sphincter – reduce peristalsis (not clinical importance).

Bladder

  • Relaxed detrusor muscle (β) but constriction of Trigone (smooth triangular region of the internal urinary bladder) – both are anti-voiding effect.

Uterus

  • Adrenaline contracts and relaxes (α and β action) but net effect depends on status of uterus and specific pregnant relaxes but non pregnant – contracts.

Skeletal muscle

  • Facilitation of Ach release in NM junction (α1).
  • β2 act directly on muscle fibers.
  • Abbreviate active state and less tension is slow conducting fibers and enhanced muscle spindle firing tremor.

CNS

  • No visible clinical effect in normal doses – as low penetration except restlessness, apprehension and tremor.
  • Activation of α2 in CNS decrease sympathetic out and reduction in BP and bradycardia (clonidine)

Metabolic effects

  • Increase contraction of glucose and lactic acid.
  • Calorigenesiss (β2 and β3)
  • Inhibit insulin secretion (α2).
  • Decrease uptake of glucose by peripheral tissue.
  • Stimulate Glycogenolysis β effect
  • Increase free fatty acid concentration in blood.
  • Hypokalemia – Initial hypokalemia

Pharmacokinetic

  • All Catecholamines are ineffective orally.
  • Absorbed slowly.
  • Faster from i.m. site
  • Inhalation is locally effective.
  • Not usually given i.v.
  • Rapidly inactivation on liver by MAO and COMT.

Clinical uses

  • Injectable preparation are available in dilutions 1:10000 and 1:00000
  • Dose 0.3-0.5 mg s.c. of 1:10000.
  • Used in
    • Anaphylactic shock
    • Prolonged action of local anaesthetic
    • Cardiac arrest
    • Topically, to stop bleeding
    • Hyperkinetic children (Psychomotor instability, learning disorder, emotional lability, immaturity etc.) – ADHD, minimal brain dysfunction Anorectic (an eating disorder characterized by markedly reduce appetite or total aversion to food.)

Adverse drug reaction

  • Restlessness, throbbing headache, tremor, palpitation.
  • Cerebral hemorrhage, cardiac arrhythmia.
  • Contraindicated in hypertensive, hyperthyroid and angina pectoris.
  • Halothane and β-blockers-not indicated.

Therapeutic classification of adrenergic drugs

  1. Pressor agents
    • NA
    • Ephedrine
    • Dopamine
    • Phenylephrine
    • Methoxamine
    • Mephentamine
  2. Cardiac stimulant
    • Adrenaline
    • Isoprenaline
    • Dobutamine
  3. Bronchodilators
    • Isoprenaline
    • Salbutamol
    • Terbutaline
    • Salmeterol
    • Bambuterol
  4. Nasal decongestants
    • Phenylephrine
    • Xylomethazoline
    • Oxymethazoline
    • Naphazoline
    • Pseudoephedrine
    • Phenyl propanolamine
  5. CNS stimulant
    • Amphetamine
    • Dexamphetamine
    • Methamphetamine
  6. Anorectics
    • Fenfluramine
    • Dexfenfluramine
    • Sibutramine
  7. Uterine relaxant and vasodilator
    • Ritodrine
    • Isoxsuprine
    • Salbutamol
    • Terbutaline

Hello! My name is Smrutiranjan Dash, a pharmacy professional. belonging from, Bargarh, Odisha. I have acquired Master degree in Pharmacy (Pharmacology) form B.P.U.T, Rourkela, Odisha. Currently I am working as an Assistant Professor at The pharmaceutical college, Barpali.

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