ADRENERGIC RECEPTOR AGONIST,CLASSIFICATION AND MECHANISM OF ACTION.

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1 ADRENERGIC RECEPTOR AGONIST,CLASSIFICATION AND MECHANISM OF ACTION. LEARNING OBJECTIVES At the end of lecture students should be able to know, Adrenergic receptor agonist, Classification and mechanism of action. Sympathetic or adrenergic drugs are the agents that activate the receptors stimulated by Adrenaline (Epinephrine) and Noradrenaline (Norepinephrine). CATECHOLAMINES The catecholamines act at postganglionic sympathetic nerve terminals except nerve endings supplying sweat glands. They also act as neurotransmitter in certain regions of brain. CATECHOLAMINE SYNTHESIS Catecholamines are synthesized within neuron from the amino acid phenylalanine. Phenylalanine Tyrosine DOPA Dopamine Noradrenaline Adrenaline. Synthesis of catecholamines is blocked by metyrosine. Adrenaline (Epinephrine) is mainly formed in adrenal medulla by methylation of noradrenaline.

2 Mechanism: Norepinephrine Release and Recycling Autonomic nerves: multiple transmitters, multiple effects STORAGE AND RELEASE Catecholamines are stored in vesicles in nerve terminal. Vesicular uptake of catecholamines is blocked by drugs like reserpine. Catecholamines are released from nerve terminal by neuronal stimuli. Catecholamine release is blocked by drugs like Beryllium and Guanethidine.

3 TERMINATION REUPTAKE-I Reuptake is blocked by cocaine, tricyclic antidepressants. DEGRADATION BY COMT DEGRADATION BY MAO Degradation is blocked by MAO inhibitors. RECEPTORS ADRENERGIC Alpha: α 1, α 2 Beta: Β 1, β 2. β 3 Dopamine: D 1 D 5 EFFECTS OF AUTONOMIC ACTIVITY

4

5 a1 stimulation: Constriction of blood vessels, Vascular smooth muscle activation Constriction of lung bronchioles, Constriction of bladder muscles u myocardial cardiac contractility, Relaxation of GI tract a2 stimulation: u central sympathetic outflow, u release of E & NE, a1 & b1 receptor activation, Constriction of lung bronchioles b1 stimulation: u in HR, u in myocardial contractility u in Renin secretion, u fluid retention b2 stimulation: Dilation of lung bronchioles Dilation of blood vessels CLASSIFICATION OF ADRENERGIC DRUGS

6 1. ACCORDING TO CHEMICAL NATURE: A. CATECHOLAMINES NATURAL: Adrenaline (Epinephrine). Noradrenaline (Norepinephrine). Dopamine. SYNTHETIC: Isoproterenol (Isoprenaline). Dobutamine. B. NON CATECHOLAMINES: EPHEDRINE. AMPHETAMINE. METHOXAMINE. PHENYLEPHRINE. METHYLDOPA. CLONIDINE. ALBUTEROL. TERBUTALINE. RITODRINE. METAPROTERENOL. ACCORDING TO MECHANISM OF ACTION DIRECTLY ACTING: ADRENALINE. NORADRENALINE. DOPAMINE. ISOPROTERENOL. DOBUTAMINE. METHOXAMINE. PHENYLEPHRINE. ALBUTEROL.

7 TERBUTALINE. RITODRINE. METAPROTERENOL. INDIRECTLY ACTING: AMPHETAMINE &TYRAMINE. MONOAMINE OXIDASE INHIBITORS (ISOCARBOXAZID AND PHENELZINE). IMIPRAMINE AND OTHER TRICYCLIC- ANTIDEPRESSANTS COCAINE. MIXED ACTING ACCORDING TO RECEPTOR AFFINITY ALPHA AGONISTS: 1 Agonists PHENYLEPHRINE. METHOXAMINE. 2 Agonists CLONIDINE. METHYLDOPA MIXED & AGONISTS: ADRENALINE. NORADRENALINE. EPHEDRINE. METARAMINOL -AGONISTS 1 & 2 Agonists: ISOPRENALINE. 2 Agonists: ALBUTEROL.

8 TERBUTALINE. RITODRINE. METAPROTERENOL SYMPATHETIC RECEPTORS: are divided into three groups 1. - ADRENERGIC RECEPTORS: These are further subdivided into 1 & 2 adrenergic receptors. 1- receptors are located on vascular smooth muscles, dilator pupillae muscle and urinary bladder. 2- receptors are located on presynaptic adrenergic and cholinergic nerve terminals, platelets, fat cells, pancreas, kidneys and postsynaptic adenoceptors in CNS ADRENERGIC RECEPTORS These are further subdivided into 1, 2 & 3 adrenergic receptors. 1 receptors are located mainly on heart and are also present on kidneys. 2 receptors are located on smooth muscles of blood vessels of skeletal muscles, bronchial and uterine smooth muscles, pancreas and liver. 3 receptors are located on fat cells. DOPAMINE RECEPTORS (D): Dopamine receptors are mainly located in brain, and in splanchnic and renal blood vessels.

9 They are complexly divided into D1, D2, D3, D4, & D5 receptor subtypes AFFINITY FOR RECEPTORS -ADRENERGIC RECEPTORS: EPI N.E ISP -ADRENERGIC RECEPTORS ISP EPI N.E 1 = ISP EPI = N.E 2 = ISP EPI N.E EPINEPHRINE: 1 = 2 1 = 2 NOREPINEPHRINE: 1 = 2 ISOPRENALINE: = 2 = More than Epinephrine has equal affinity for both 1 & 2 receptors; it also has equal affinity for both 1 & 2 receptors. Norepinephrine has equal affinity for both 1 & 2 receptors, but has high affinity for 1 than 2 receptors.

10 Isoprenaline has equal affinity for both 1 & 2 receptors. Dobutamine has more affinity for 1 than 2 receptors, and dopamine has high affinity for D-receptors than 1 that has more affinity than 1 receptors, dopamine binds equally to D1 and D2 receptors. Albuterol, Terbutaline, and Ritodrine are 2 agonists; they have low affinity for 1 receptors. DISTRIBUTION AND ACTIONS OF SYMPATHETIC RECEPTOR SUBTYPES Alpha1 Most vascular smooth muscles. Pupillary dilator muscle. Heart. Urinary bladder and prostate. Ductus deferens, seminal vesicles and prostate. ACTIONS Contraction. Contraction (dilatation of pupil). Increase force of contraction. Contraction of trigone

11 and sphincter (urinary retention). Ejaculation. Alpha-2 Presynaptic adrenergic& cholinergic nerve terminals. Platelets. Fat cell. Pancreas. Kidneys. Postsynaptic CNS `adrenoceptors. Inhibition of neurotransmitter release. Aggregation. Inhibition of lipolysis Inhibition of insulin release. Inhibition of renin secretion. Multiple effects. DISTRIBUTION AND ACTIONS OF SYMPATHETIC RECEPTOR SUBTYPES Beta1 Heart. Increase force and rate of contraction. Kidneys Stimulation of renin secretion. Beta2 Respiratory, uterine and vascular smooth muscles (BV supplying skeletal muscles). Liver. Pancreas. Promote smooth muscle relaxation. Activation of glycogenolysis. Stimulation of insulin secretion. DISTRIBUTION AND ACTIONS OF SYMPATHETIC RECEPTOR SUBTYPES

12 Type Tissue Actions Beta3 Fat cells. Activation of lipolysis D1 Smooth muscle Dilatation of renal blood vessels. D2 Nerve ending Modulate transmitter release. NOREPINEPHRINE It is hydroxylated dopamine. It is mainly synthesized and secreted at adrenergic neurons. It has activity on α & β1 receptors, but has insignificant activity on β2 receptors. It increases both systolic and diastolic BP

13 It produces reflex bradycardia. It has no bronchodilator effect. EPINEPHRINE It is methylated norepinephrine. It is mainly synthesized and secreted at adrenal medulla. It has activity on α, β1 & β2 receptors. EPINEPHRINE It increases systolic BP and decreases diastolic BP.

14 It produces tachycardia. It produces bronchodilatation.. DOPAMINE Natural. Act as a neurotransmitter in body. It has affinity for D, β1 & α1 receptors. Increases myocardial O2 consumption and demand. DOBUTAMINE Synthetic.

15 It is not a Neurotransmitter It is relatively β1 selective. It has little effect on myocardial O2 consumption and demand. EPINEPHRINE It is naturally occurring catecholamine present in human body. Acts as a neurotransmitter It acts directly. Does not cross BBB. Degraded by COMT & MAO. Has short duration of action. More potent. EPHEDRINE

16 It is naturally occurring non-catecholamine, derived from plants. It does not act as a neurotransmitter It acts directly & indirectly. Crosses BBB. It is not degraded by COMT & MAO. Has long duration of action. Less potent. THANKYOU.

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