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Sympathetic Drugs. Stress and The Adrenal Glands.

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Presentation on theme: "Sympathetic Drugs. Stress and The Adrenal Glands."— Presentation transcript:

1 Sympathetic Drugs

2 Stress and The Adrenal Glands

3 Adrenal Medulla: A Modified Sympathetic Ganglion

4 Mechanism: Norepinephrine Release and Recycling

5 Review of Efferent Pathways: Motor and Autonomic

6 Catechalomines: Activity Stimulates the “fight or fight” reaction Increased plasma glucose levels Increased cardiovascular function Increased metabolic function Decreased gastrointestinal and genitourinary function

7 Activity of Epinephrine

8 Sympathomimetics Drugs that partially or completely mimic the actions or norepinephrine (NE) and epinephrine (Epi). Act either - directly on α- and/or β- adrenoceptors or indirectly on presynaptic terminals, usually by causing the release of NE. See Below

9 β 2 -Adrenoceptor Agonists – cause bronchial dilation - used for the treating asthma, prevent pre-term labor (relaxing uterine muscle). β 1 -Adrenoceptor Agonists – (e.g., dobutamine) sometimes used to increase the force of heart contraction in severe low- output heart failure. α 1 -Agonists – (e.g., phenylephrine) – used as mydriatics, decongestants. α 2 -Agonists – (e.g., clonidine, methyldopa) – centrally acting hypotensive drugs.

10 Sympathomimetics act mainly by causing release of NE (e.g., amphetamine) have the α 1 /α 2 selectivity of NE. β-Adrenoceptor antagonists (β-blockers) – used to treat hypertension, angina, cardiac arrhythmias, CHF, and glaucoma. α-Adrenoceptor antagonists (α-blockers) – limited clinical application – prazosin (selective α 1 - antagonist – used to treat hypertension. Adrenergic neuron blocking drugs – either deplete the nerve terminals of NE or prevent its release – used as hypotensive agents.

11 Metabolism of Norepinephrine

12 Reuptake Monoamine Oxidase Catechol-O-methytransferase (COMT) α 1 -Adrenoceptors – in several tissues (e.g., smooth muscle, salivary glands)  incr IP 3 and [Ca 2+ ] in  vasoconstriction or glandular secretion α 2 -Adrenoceptors – on noradrenergic nerve terminals. Activation by NE  inhibit AC, decr cAMP, Ca 2+ channels close  decr further nt release. β-Adrenoceptor – stim AC  incr [cAMP]  2 nd messenger intracellular signaling  physiol response.

13 Indirectly-Acting Sympathomimetics Transported into nerve terminals where they displace vesicular NE into the cytoplasm. Some is metabolized by MAO, but the remainder is released by carrier- mediated transport to activate adrenoceptors. Amphetamines – resistant to MAO. - Peripheral actions - tachycardia, hypertension - mainly caused by catecholamine release. - Dexamfetamine and methylphenidate used for hyperactive children. Cocaine – NE reuptake inhibitor (also dopamine) – Intense central stimulant  popular drug of abuse.

14 Acute and chronic effects of Indirectly acting sympathomimetics G = Guanethidine

15 Mechanism of action of cocaine and reserpine

16 Directly-Acting Sympathomimetics Effects in humans depends on their receptor specificity (α and/or β) and on the compensatory reflexes they evoke. Epi incr bp by stim the rate and force of the heart beat (β 1 effects). Stimulation of vascular α-receptors causes vasoconstriction (viscera, skin), whereas…, Stimulation of vascular β 2 -receptors vasodilation (skeletal muscle) … And the total peripheral resistance may actually decrease. NE has little-to-no effect on the vascular β 2 -receptors; thus, the α-mediated vasoconstriction is unopposed. The resulting rise in bp reflexively slows the heart, usually overcoming the direct β 1 -stimulant action on the heart rate.

17 β-Receptor-Selective Drugs Isoprenaline – stimulates all β-receptors  incr rate and force of heart beat and  vasodilation  full diastole and MAP, with little change in systolic pressure. β 2 -Adrenoceptor Agonists – relatively selective class of drugs that produce bronchodilation – used for asthma (resistant to MAO, not uptaken into neurons).

18 Adrenoceptor Antagonists α-Blockers Decr artiolar and venous tone  decr peripheral resistance  hypotension. Reverse the pressor effects of Epi, because its β 2 - mediated vasodilator effects are unopposed by α- mediated vasoconstriction  peripheral resistance falls (Epi reversal). Cause reflex tachycardia – this is greater with non-selective drugs that also block α 2 -presynaptic receptors on the heart, because the augmented release of NE further stimulates the cardiac β- receptors (e.g., prazosin).

19 Adrenoceptor Antagonists β-Blockers Vary in lipid solubility and cardioselectivity All block β 1 -receptors and decr bp and prevent angina. Higher K ow -drugs  more rapid absorption from GIT, 1 st -pass hepatic elimination  more rapidly eliminated. Also more likely to enter CNS and cause central effects (e.g., nightmares). Cardioselectivity diminishes with higher doses.

20 Adrenoceptor Antagonists β-Blockers (Cont’d) Nevertheless, selective β 1 -blockade  less peripheral vasoconstriction (cold hands and feet) and does not reduce the response to exercise- induced hypoglycemia (stim of gluconeogenesis in liver is mediated by β 2 -receptors). Cardioselective drugs may have sufficient β 2 - activity to ppt severe bronchospasms in patients with asthma – these patients should avoid β- blockers. Some possess intrinsic sympathomimetic activity (partial agonists), but this is debatable.

21 Catecholamine synthesis, storage, release, and reuptake pathways


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