1. Adrenoceptor activating & Other Sympathomimetic drugs Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

2. Objectives o มีความรู้ความเข้าใจถึง Adrenoceptor และ Molecular mechanism ของการกระตุ้น adrenoceptor o มีความรู้ความเข้าใจถึงเภสัช วิทยา กลไกการออกฤทธิ์ เภสัช จลนศาสตร์ การใช้ประโยชน์ ทางคลินิก อาการไม่พึงประสงค์ ข้อควรระวังการใช้ยาที่ออกฤทธิ์ กระตุ้นระบบประสาทซิมพาเท ติก ทั้งชนิด direct acting และ indirect acting agents

3. Sympathetic nervous system CVS & Response to stress Essential control of CVS & Response to stress Neurotransmitters = Norepinephrine (NE) Adrenal medulla release NE & Epinephrine (Epi) … “ Hormone ” Act on RC called “ Adrenoceptor ” “ Sympathomimetic drugs (agents) ” Drugs causing sympathetic NS like action …. “ Sympathomimetic drugs (agents) ” Mimic = Like

4. The mode & spectrum of action of sympathomimetic drugs Direct Direct acting sympathomimetic drugs Binding to adrenoceptor >>> Adrenoceptor agonist Indirect Indirect acting sympathomimetic drugs Increase NE at synaptic cleft Replacement of NE at vesicle Uptake via uptake 1 into nerve terminal Increase NE release from vesicle Amphetamine, Tyramine, Ephedrine Inhibit NE reuptake Inhibit uptake 1 action Also inhibit action of the above group Cocaine, Tricyclic antidepressants (TCA)

5. Basic Pharmacology Adrenoceptor Beta (  )-adrenoceptor  1,  2,  3 adrenoceptor  1 Affinity … NE = Epi  2 Affinity … Epi >> NE Alpha (  )-adrenoceptor  1,  2 adrenoceptor  -1A,  -1B,  -1D  -2A,  -2B,  -2C  1 antagonist … Prazosin  2 antagonist … Yohimbine  1 &  2 antagonist (non-selective) … Dihydroergotamine Difference of adrenoceptor Affinity of selected agents Affinity of selected agents Molecular … Genes Molecular … Genes

6. Dopamine receptor Dopamine (DA) = Catecholamine Bind to Dopamine receptor & Adrenoceptor Important in CNS function & disease Psychosis … over DA Parkinson ’ s disease … lack of DA Some effects on splanchnic & renal vascular D1-like receptor D1-, D5-receptor D2-like receptor D2-, D3-, D4-receptor

7. Receptor selectivity

9. cAMP-dep. Protein kinase Gs Gi

10. Distribution of adrenoceptor subtypes TypeTissueActions Alpha1Most vascular smooth muscle (innervated) Contraction Pupillary dilator muscleContraction (dilates pupil) Pilomotor smooth muscleErects hair ProstateContraction HeartIncreases force of contraction Alpha2Postsynaptic CNS adrenoceptorsProbably multiple PlateletsAggregation Adrenergic and cholinergic nerve terminals Inhibition of transmitter release Some vascular smooth muscleContraction Fat cellsInhibition of lipolysis

11. Beta1HeartIncreases force and rate of contraction Beta2Respiratory, uterine, and vascular smooth muscle Promotes smooth muscle relaxation Skeletal musclePromotes potassium uptake Human liverActivates glycogenolysis Beta3Fat cellsActivates lipolysis D1Smooth muscleDilates renal blood vessels D2Nerve endingsModulates transmitter release

12. Central Nervous System (CNS) Catecholamine can not penetrate into CNS Amphetamine, Cocaine Non-catecholamine can penetrate into CNS … Amphetamine, Cocaine Alertness, Nervousness, Increased concentration of work, Insomnia, Euphoria, Anorexia, Paranoid Drug abuse Dopamine-mediated … increase pleasure … Drug addiction … Drug abuse

13. Clinical Pharmacology Factors considered before sympathomimetic use Factors considered before sympathomimetic use Intrinsic activity Receptor selectivity Duration of action Route of administration Bioavailability ADRs (esp. CVS)

14. Clinical uses H ypotension Shock Decreased local blood flow Decongestion Asthma Anaphylaxis Glaucoma Delay of labour CNS disorder>>> attention deficit, narcolepsy Others … Drug craving, hot flush

15. Toxicity of sympathomimetics CVS CVS Hypertension (hypertensive crisis) … cerebral hemorrhage, pulmonary edema, increase heart work load … angina, myocardial infarction (MI) Sinus tachycardia, Serious ventricular arrhythmia Use with caution in elderly, hypertensive patients, coronary artery disease patients Antagonised by Specific adrenoceptor antagonist CNS CNS … esp Amphetamine Restlessness, tremor, insomnia, anxiety, paranoid Cocaine may worsen convulsion or cerebral hemorrhage

16. Dobutamine HCl (Dobutrex ® )Vial 250 mg/ 20 ml Dopamine HCl (Dopaminex ® )Amp 50 mg/ 5ml, 200 mg/ 10 ml, 250 mg/ 10 ml Isoproterenol (Isuprel ® )Amp 0.2 mg/ ml Adrenaline (Epinephrine)Amp 1 mg/ ml Brimonidine (Alphagan ® )Ophth soln 0.2% Metaraminol bitartrate (Aramine ® )Vial 10 mg/ ml Methylphenidate (Rubifen ® )Tab 10 mg [children w/ attention def] Midodrine (Gutron ® )Tab 2.5 mg Naphazoline (Albalon ® )Ophth soln 0.1% Oxymetazoline (Iliadin ® )Nasal drop 0.025%, nasal spray 0.05% Phenylephrine [combined] Phenylpropanolamine [combined] Pseudoephedrine [combined] Norepinephrine [combined] Xylometazoline (Otrivin®)Metered dose nasal spray 0.1% Example of sympathomimetic drugs