Adrenergic system and drugs

sympathomimetics

1. Adrenergic Drugs/ Sympathomimetics These are the drugs that mimic the response of sympathetic or adrenergic system. Neurotramsmitters : Neurotransmitters are the chemical mediators released by the neurons to transmit the signals through synapse. Three major endogenous catecholamines are: Adrenaline ( Adr , Epinephrine) Noradrenaline (NA, Norepinephrine ) Dopamine Adrenergic Receptors α β α 1 α 2 β 1 β 2 β 3

2. Tyrosine Dopa Dopamine Noradrenaline Adrenaline Synthesis: Tyrosine hydroxylase Amino acid decarboxylase Dopamine β - Hydroxylase Phenylethanolamine N-methyl transferase

3. Adrenergic drugs acts through adrenergic receptors. Adrenergic Receptors/ Adenoreceptors are of 2 types: alpha ( α ) & beta ( β ). Receptor Tissue Response α 1 Vascular smooth muscle vasocontraction Genitourinary tract smooth muscle contraction Smooth muscle (Sphincter, radial muscle of iris, gland) Contraction (mydriasis, secretion) Intestinal smooth muscle Relaxation α 2 Prejunctional nerve ending NA release Vascular smooth muscle vasoconstriction Alpha receptors ( α )

4. Receptor Tissue Response β 1 Heart Rate, FOC, A-V conduction Juxtaglomerular cells Rennin release β 2 Smooth muscles (Bronchial, gastrointestinal, genitourinary, uterus) Relaxation Skeletal muscle Glycogenolysis K + uptake Liver Glycogenolysis Gluconeogenesis β 3 Adipose tissue Lipolysis Beta receptors ( β )

5. Adrenergic drugs/ Sympathomimetics 1.Direct sympathomimetics Adrenaline, NorAdrenaline , Isoprenaline , P henylephrine , X ylometazoline 2.Indirect sympathomimetics Amphetamine, Cocaine, Sellegilline , Entacapone 3.Mixed action sympathomimetics Ephedrine, Mephentermine

6. Pressor agents Dopamine, NA, Mephentermine , Ephedrine Cardiac stimulant Dobutamine, Adr, Iso Bronchodilators Salbutamol ( albuterol ), Salmeterol , Terbutaline , Iso , Adr Nasal decongestant Xylometazoline , Oxymetazoline , Phenylephrine Pseudoephedrine CNS stimulants Amphetamine, Dexamphetamine Anorectics Fenfluramine , Sibutramine Uterine relaxant Ritodrine , Isoxsuprine , salbutamol , Terbutaline Clinical classification of Adrenergic drugs

7. Adrenaline ( Adr ) α1+ α2 + β1+ β2+weak β3 action Noradrenaline (NA) α1+ α2+ β1+ β2 but no β3 action Isoprenaline ( Iso ) β1+ β2+ β3 action but no α action Pharmacological Actions: Epinephrine (adrenaline) is a potent stimulant of both α and β adrenergic receptors. Most of the responses are seen after injection of epinephrine, although the occurrence of sweating, piloerection , and mydriasis depends on the physiological state of the patient. Particularly prominent are the actions on the heart and on vascular and other smooth muscle. Norepinephrine ( Noradrenaline ) and epinephrine both are direct agonists on effector cells, and their actions differ mainly in the ratio of their effectiveness in stimulating α and β2 receptors. They are approximately equipotent in stimulating β1 receptors. Norepinephrine is a potent α agonist and has relatively little action on β2 receptors.

8. Heart Positive ionotropic effect (increase in force of contraction) Positive chronotropic effect (increase in heart rate) Positive dromotropic effect (increase in heart conduction) Respiration Bronchodilation , Nasal decongestion Blood vessels Vasoconstriction Blood pressure Increases GIT Relaxation but sphincter contracts so peristalsis decreases Eye Mydriasis (Dilation of pupils) Uterus Non-pregnant-Contraction; Pregnant-Relaxation Skeletal muscle Tremor, glycogenolysis Metabolic Hyperglycemia, Lipolysis , Hypokalemia

9. Adverse effects: Adr -sc/ i.m : restlessness, palpitation, anxiety, tremor, pallor Adr-i.v . high dose: cerebral haemorrhage , arrhythmias Contraindications: Hypertensive, Hyperthyroidism, Angina Pectoris Patient receiving β -blocker. During anesthesia by Halothane

10. Dopamine is the immediate metabolic precursor of norepinephrine and epinephrine. It is a central neurotransmitter particularly important in the regulation of movement and possesses important intrinsic pharmacological properties. In the periphery, it is synthesized in epithelial cells of the proximal tubule and is thought to exert local diuretic and natriuretic effects. Dopamine is a substrate for both MAO and COMT and thus is ineffective when administered orally. It doesn’t cross BBB. In moderate dose (0.2-1mg) it increases BP & urine flow. Mechanism of action: Dopamine can activate α- and β-adrenergic receptors. It acts on dopaminergic receptors (D1-D5) present on peripheral mesenteric and renal vascular beds. Binding of dopamine produces vasodilation . D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release.

11. Indication : Given as i.v . infusion to patients with cardiogenic & septic shock. Severe Congestive Heart Failure Dose regulated by monitoring BP & urine formation. At high concentrations, dopamine activates vascular a 1 receptors, leading to more general vasoconstriction. Adverse Effects : Nausea, vomiting, tachycardia, anginal pain, arrhythmias, headache, hypertension, and peripheral vasoconstriction may be encountered during dopamine infusion. Contraindication : Hypovolemic shock, depression (patients receiving MAO inhibitors or tricyclic antidepressants)

12. Dobutamine Mechanism of Action: Dobutamine is a derivative of dopamine that directly acts on adrenergic receptors( β 1 ). Indications: Dobutamine is used to increase cardiac output in acute congestive heart failure as well as for inotropic support after cardiac surgery. It increases cardiac output and does not significantly elevate oxygen demands of the myocardium, a major advantage over other sympathomimetic drugs. It is used in pump failure (Myocardial Infarction, Cardiac surgery, CHF) Contraindication: Atrial fibrillation May cause tolerance

13. Ephedrine Mixed action adrenergic drugs Orally effective & long acting than Adr Crosses BBB so stimulation Used in mild chronic bronchial asthma & hypotension during spinal anaesthesia Amphetamine Synthetic compound similar to ephedrine but have more CNS action Improves alertness, attention, concentration & performance Included in dope test (drug for abuse) Used in attention deficit hyperactive disorder (ADHD) Phenylephrine alpha1 agonist used as mydriatics , decreases ocular tension Oral or nasal decongestant

14. Nasal Decongestants Topical : Oxymetazoline , Xylometazoline , Naphazoline alpha2 agonist, long duration of action Use cautiously in hypertensive patients Oral : Phenylephrine , Pseudoephedrine, Phenylpropanolamine (PPA) Produce vasoconstriction in mucosa & skin Used orally as decongestant of upper respiratory tract, nose & eustachian tubes Avoided in hypertensive patients PPA banned in Nepal (risk of haemorrhagic stroke)

15. Indications: 1.Vascular Uses: Hypotensive states (shock, spinal anaesthesia, hypotensive drugs) Along with local anaesthetics Control of local bleeding Nasal Decongestants 2. Cardiac Use Cardiac arrest (drowning, electrocution, etc.) – In combination with external cardiac massage Partial or complete A-V block – Isoprenaline as temporary measure Congestive Heart Failure 3. Bronchial asthma 4. Allergic disorders (histamine mediated) 5. Mydriatic Fundus examination Wide angle glaucoma

16. 6. Insulin Hypoglycaemia 7. Nocturnal enuresis in children and urinary incontinence – Amphetamine 8. Uterine relaxant – Ritoridine : to postpone labour – Isosuxprine : threatened abortion and dysmenorrhoea 9. Central Uses Attention Deficit Hyperkinetic Disorders – Amphetamine Narcolepsy – Amphetamine, Modafinil – Imipramine like drugs Epilepsy – Amphetamines Parkinsonism – Amphetamine Obesity – Considered in severe obesity