Sympathomimetics IMD Handout 2022-2023 PDF

Sympathomimetics Direct: adrenergic receptor agonist Indirect: increase release of catecholamines (tachyphylaxis) like amphetamine and tyramine Dual(ephedrine) Catecholamines : adrenaline , noradrenaline ,dopamine ,isoprenaline and doputam...

Sympathomimetics Direct: adrenergic receptor agonist Indirect: increase release of catecholamines (tachyphylaxis) like amphetamine and tyramine Dual(ephedrine) Catecholamines : adrenaline , noradrenaline ,dopamine ,isoprenaline and doputamine Non-catecholamines Orally Absorbed Pass BBB Slow onset Long duration Not destroyed by MAO ADRENALINE(α,β) Subcutaneous injection in dark ampules Therapeutic Uses:- 1-Antiallergic: anaphylactic shock, angioneurotic edema urticaria (physiological antagonism of histamine) 2-Prolongation of action of local anesthetics: given with them S.C. to delay absorption. 3-Hemostatic in epistaxis as nasal pack. It is used as eye drops in open angle glaucoma to decrease IOP – Dipivefrine is a prodrug, more effective (diffusible, lipophilic) & less toxic than adrenaline. 4-Acute bronchial asthma inhalation 5-hypoglycemic coma given S.C. (glucose IV is better) 6-intracardiac resuscitation Toxicity: Side Effects Contraindications Αlpha 1- Hypertension & cerebral hemorrhage. 1- Hypertension. 2- If given with local anesthesia in 2- with local anesthesia in fingers or fingers or toes or circumcision → toes or circumcision. gangrene. Βeta 3- Tachycardia, palpitation, arrhythmia. 3- Heart ischemia, arrhythmia 4- With general anesthesia (halothane) 4- With general anesthesia or or digitalis → arrhythmia. digitalis. α +β 5- Exaggerated with supersensitive 5- With sympatholytics, MAOI, receptors (with sympatholytics, ganglion blockers MAOI). Or: give smaller dose. 6- Irritability, tremors, insomnia. NORADRENALINE( α) ,β NB - IV infusion 1/1000 diluted in saline or glucose. - BP + ECG monitor are frequently done. - Don’t stop infusion suddenly to avoid sudden  of BP -Reflex brady cardia Therapeutic uses: Acute hypotensive state: during spinal anaesthesia, shock, sympathectomy. Toxicity: Side Effects Contraindications α: 1- Hypertension & cerebral hemorrhage. 1- Hypertension. 2- If given with local anesthesia in fingers or 2- with local anesthesia in toes or circumcision → gangrene. fingers, toes or circumcision. α+ β: 3- Exaggerated with supersensitive With sympatholytics, MAOI, receptors (with sympatholytics, MAOI). GB  4- Irritability, tremors, insomnia. Or: give smaller dose. * Drug interaction: NA after atropine – alpha blocker – ganglion blocker → leads to tachycardia (β1) ISOPRENALINE(β) Routes of administration:- - IV infusion. – Intracardiac - IM. – SC - Inhalation (Aerosol, metered). Therapeutic uses:- - Heart Block - Bronchial asthma by inhalation Toxicity: Side Effects Contraindications β: 1- Tachycardia, palpitation, 1- Heart ischemia, arrhythmia (e.g. arrhythmia & anginal pain. coronary heart disease, pulmonary embolism, Any beta effect thyrotoxicosis). DOPAMINE Dopaminergic + β1 + α Pharmacokinetics (ADME):- - Like adrenaline. - IV infusion (t1/2 is short: 2 minutes). Pharmacodynamics:- IV Dose Receptors Effect Blockers infusion Low rate 2-3 * D1 (in renal, -VD → decrease Haloperidol µ/kg/min coronary, PR  cerebral & -increase Renal mesenteric BV) blood flow & urine output Moderate 5-8 β-1 +ve inotropic Propranolol rate µ/kg/min >+ve chrono. (β- blocker) (increase CO and systolic BP) High rate 10-12 Αlpha Generalized VC Phentolamine µ/kg/min (α blocker) NB. IV infusion, slowly a. Decrease PR (helps tissue perfusion) Restore blood volume b. VD of renal & mesenteric (Fresh blood transfusion) before using dopamine ECG monitoring stop gradually decreasing the dose in patient taking MAOI Therapeutic uses:- - Shock: Cardiogenic, hemorrhagic, endotoxic - Heart Failure: especially if with hypotension Toxicity “Side Effects”:- 1- Ventricular arrhythmia. 2- Nausea & vomiting. 3- Interaction with MAO inhibitors → rise in BP → so reduce the dose. Fenoldopam : D1 agonist -  PR by VD of arterioles. Given by IV drip in emergency hypertension – t½ is 5 minutes. DOBUTAMINE (Selective B1 + Weak α) - Synthetic sympathomimetic catecholamine related to isoprenaline. Pharmacodynamics:- -Selective β-1 stimulant (+ weak α). -force of contraction without HR (more +ve inotropic than chronotropic effect). - No effect on Peripheral Resistance as it does not stimulate dopaminergic receptors. Pharmacotherapeutics:- Preparation & dose:- - IV infusion, 2.5-15 µ/kg/min. (same precautions as dopamine). -Take care: - ECG monitoring. - Stop gradually. - Measure BP & urine output. - Give fluid before dopamine. Therapeutic uses:- than - Shock: Cardiogenic (due to myocardial infarction). More Preferred dopamine -Heart Failure: especially if accompanied with hypotension. Toxicity “Side Effects”:- 1- CVS: tachycardia, palpitation, ventricular arrhythmia (but less than dopamine). 2- Nausea & vomiting. Comparison between Dopamine and Dobutamine Dopamine Dobutamine 1- Source & - Sympathomimetic - Sympathomimetic Chemistry - Precursor of N.A. in body - Synthetic - Chemical transmitter in C.N.S. 2- Action - Low rate of infusion β1 & weak α on Dopaminergic Receptors - Moderate rate: β1 - High rate: α 3- Peripheral Vasodilator ( PR) No effect resistance 4- Ventricular Inotropic > Chronotropic Inotropic > chronotropic action ( less ventricular arrhythmia ) CNS Stimulants Ephedrine – Amphetamine – Methamphetamine EPHEDRINE α + β(dual) Therapeutic uses:- - Local: hemostatic in epistaxis, nasal decongestant (better pseudoephedrine), mydriasis - Systemic: 1) Sympathomimetic: a. CVS: 1- Heart block. 2- before spinal anesthesia. 3- BP elevation in hypotension due to ganglion blockers or sympatholytics. b. Respiration: bronchial asthma (prophylaxis- orally) 2) Skeletal muscle: myasthenia gravis (together with neostigmine). 3) CNS: weaker than amphetamine 1- Nocturnal enuresis. 2-Narcolepsy. 3-Morphine toxicity to ++ RC, VMC (analeptic). Toxicity: Side effects: as adrenaline and: 1- CNS : marked insomnia, anxiety, tremors 2- Retention of urine in male patients with enlarged prostate. 3- Tolerance & tachyphylaxis (but no addiction) Contraindications: as adrenaline and in old prostatic patients Tyramine(tyramine cheese reaction) Indirectly acting sympathomimetic, which releases NA from NE. - Present in cheese, yoghurt. - Metabolized by MAO: in patients taking MAO inhibitors → hypertensive crisis (ttt: alpha blockers). - If stored are depleted by reserpine, tyramine has no more action.  AMPHETAMINE(more potent CNS stimulant than amphetamine ) α+β Pharmacotherapeutics:- orally, i.m. or i.v. - Not given in the late afternoon "3 p.m." Therapeutic uses:- - Psychic: - Lighten sleep & narcolepsy. - Calm hyperkinetic attention deficit syndrome in children but methylphenidate is more preferred as it has no peripheral action - Anorexigenic: in obesity. Side Effects:- As adrenaline + CNS: insomnia, anxiety, anorexia. Prolonged use → ADDICTION. Contraindication:- As adrenaline + patients with CNS symptoms (insomnia, anxiety, schizophrenia, anorexia). Drug Interaction:- MAOI + Amphetamine → severe hypertension. All sympathomimetics are contraindicated with MAO INHIBITORS SYMPATHOLYTICS HYPERTHYROIDISM Nasal Decongestants "α" Definition: group of drugs used as VC for nasal congestion. Given in: common cold, rhinitis, sinusitis. Forms: drops, spray, oral. Side effects: a. Rebound congestion after stopping the drug. b. Long use: atrophy of cilia with loss of smell. c. Drowsiness: especially in infants. Contraindicated in hypertensive & anginal patients. Old group: orally 1. Phenylephrine 2. Pseudoephedrine Newer group: locally longer duration and less rebound phenomenom a. Naphazoline b. Tetrahydrazoline c. Xylometazoline Vasodilator Sympathomimetics & Uterine Relaxants (Tocolytic) (β2-agonists) Members; Ritodrine Uses: 1- Vasodilators: in ttt of peripheral vascular disease (isoxuprine) 2- Uterine relaxant : - Contraction ring of uterus during labor. - Premature labor (to delay it). - Threatened abortion. 6- Anti-Asthmatic Sympathomimetics Selective β2-agonists:- Short Acting selective β-Agonists Long Acting selective β2 Agonists (SABA) (LABA) Salbutamol Salmeterol Formetrol Terbutaline Bambuterol Feneterol  I-ADRENERGIC RECEPTOR BLOCKERS A- ALPHA-BLOCKERS - α- Blockers block the pressor effect of noradrenaline on B.P. while they block and reverse the pressor effect of adrenaline on B.P. - α- Blockers include: A- Non-selective α blockers: phentolamine (reversible),phenoxybenzamine(irreversible) used in treatment of pheochromocytoma B- Selective α 1-blockers: prazosin, Tamsulusin , doxazosin. C- Selective α 2-blockers: yohimbin. SELECTIVE α1-BLOCKERS PRAZOSIN Actions:- Vasodilatation through: a) Post synaptic α1-blocker. b) Direct smooth muscle relaxation (phosphodiesterase inhibitor→↑ CAMP→↓ free Ca → V.D.) This V.D. action is not accompanied by reflex tachycardia since: 1- It is elective α1-blocker 2- Prazosin leads to ↑ cAMP (↑ H.R.) & ↑ cGMP (↓ H.R.) * The net result is constant H.R. VD action is on both arteries & veins: This is called mixed or balanced dilator →decrease both preload and after load. Side effects: 1) First dose phenomenon: postural Hypotension (with 1st dose) - 1st dose should be given at bed time. 2) Fluid retention (in chronic therapy). THERAPEUTIC USES OF ALPHA-BLOCKERS 1- Hypertension: due to excess catecholamines as pheochromocytoma. 2- Selective α–blocker: in primary hypertension. 3- Peripheral vascular diseases. 4- Reverse VC: caused by leakage of NA. during IV infusion 5- Benign prostatic hyperplasia (BPH): antagonize smooth muscle contraction in enlarged prostate by selective α–blocker as prazosin, doxazosin N.B: Tamsulosin (selective α1A-blocker) is more effective.  I- Non selective Beta Blockers PROPRANOLOL Propranolol will be taken as an example of this group (the most famous, having no ISA): Pharmacokinetics: 1- Absorption: complete ab. From GIT. 2- Distribution: lipophilic → pass BBB, has CNS action – 95% bound to plasma protection. 3- Metabolism: 2/3 in liver during its first passage and 1/3 reaches systemic circulation. 4- Excretion: in urine (glucuronide metabolite and free metabolites) * Atenolol, Nadolol, Sotalol are excreted unchanged in urine – (So contraindicated in renal disease) Pharmacodynamics: action of propranolol = general actions of Beta blockers Intrinsic sympathomimetic activity (ISA) ISA is absent with propranolol, and is prominent with pindolol Beta blockade: I- C.N.S: - Antianxiety - Antiparkinsonian - Prophylaxis against migraine. II- Eye: - Reduced the formation of aqeous humour →decrease I.O.P. (timolol – levobunolol – betaxolol) Ill- C.V.S: (Most important site of action):- A- Heart: Decreases all cardiac properties - Decreases contractility (-ve inotropic ). decrease cardiac output - Decreases H.R. (-ve chronotropic) - Delays A.V. conduction. - Reduction of heart work, and O2 Consumption. Decrease C.O.P - Decreases excitability. Antiarrhythmic action (class II) by B- B.V.: - Peripheral resistance is increased initially (peripheral VC) & blood flow to tissue is reduced (due to unopposed alpha VC (tone). C- B.P.: 1) Inhibit β presynaptic in CNS : decrease sympathetic flow – only with lipophilic BB. 2) Inhibit β presynaptic in NE: decrease release of NA 3) Inhibit β 1 in heart: decrease CO, bradycardia. 4) Inhibit β 1 in kidney: decrease renin secretion. 5) Baroreceptor action: rest their sensitivity. 6) Blood vessels action: - Increase prostacyclin level in vascular tissue. - Decrease PR (late – may initially). - VD properties of new BB classes. IV- Respiration Propranolol antagonizes bronchodilator effect of adrenaline; It may precipitate acute attack of bronchial asthma in asthmatics. V- Metabolism 1) Decrease glucose : block β2 in liver → inhibit glycogenolysis this causes hypoglycemia (which is severe in diabetic receiving insulin or oral hypoglycemic). 2) Decrease fatty acid: block β3 in fat cells & decrease plasma free fatty acid (FFA) However they enhance atherosclerosis by decrease HDL (protective lipoprotein against atherosclerosis) 3) Decrease renin 4) Hyperkalemia Uses of Beta-Blocker VERY IMPORTANT I-C.N.S.: 1- Antianxiety (antagonize somatic manifestation of anxiety). 2- Reduces tremors. BB can be used for tremors due to Parkinsonism or sympathetic overactivity. 3- Migraine prophylaxis II-Eye: - Open angle glaucoma: Timolol eye drops - decrease IOP (decrease aqueous humor without affecting pupil size) III-C.V.S.: Heart: 1- Angina pectoris prophylaxis (stable or atherosclerosis) (in between attacks): Reduce work of the heart and O2 consumption. Reduce exercise. Reduce BP. Reduce anxiety. BB are used in angina due to coronary atherosclerosis & not in vasospastic (variant, Prinzmetal) angina, since they worsen the condition (BB close β receptors leaving unopposed supersensitive a-receptors). 2- Acute phase of myocardial infarction - to: Reduce complications especially arrhythmia by antiarrhythmic action + Blockade of adrenaline induced hypokalemia. Reduce work of heart & size of infarction – Long term use: prolong survival 3- Arrhythmia: atrial and ventricular 2ry to sympathomimetics, thyrotoxicosis, digitalis 4- Hypertrophic obstructive cardiomyopathy: Reduce interventricular septal spasm. Blood Vessels: 1- Prevention & ttt of bleeding (varices) in liver cirrhosis: decrease CO, decrease splanchnic circulation. 2- Acute dissecting aortic aneurysm. Blood Pressure: 1- Essential hypertension (mild, moderate). 2- Pheochromocytoma (together with alpha-blocker). System Side Effects Contraindication 1- CNS Sedation, depression, night Severe depression (use mares,? Impotence hydrophilic B.B.). (only in lipophilic B.B. crossing BBB). 2- CVS a- Heart - Heart failure in cases of - Variant angina. inadequate myocardial function - Congestive HF. as M. infarction. - Heart block & sever - Heart block (atropine is bradycardia. antidote). - Not used with verapamil or diltiazem: -- contraction & conduction → HF & H. block. b- BV Cold extremities, Raynaud’s Raynaud’s phenomenon & phenomenon, intermittent other peripheral vascular claudication, numbness, tingling. diseases. c- BP Hypotension Hypotension 3- Precipitate acute attack of BA in Bronchial asthma (selective Respiration asthmatics. β1 are used)  4- - Hypoglycemia (severe in patients Hypoglycemia in insulin or Metabolism receiving insulin or oral oral hypoglycemic hypoglycemic) (Coma can occur treatment. without warning symptoms). - Atherosclerosis ( HDL) - Hyperkalemia especially in uremic patients. 5- Others - If given with supersensitive - With supersensitive receptors. (Sympatholytics, receptors. MAOI, …) → exaggerated [use B.B. without ISA] sympathomimetic action [only in BB with ISA] - Sudden discontinuation (withdrawal syndrome) → sympathetic overactivity & precipitation of anginal attack even myocardial infarction. II- Selective β1. Blockers They have some clinical advantages: 1- Less liable to produce Raynaud's phenomenon. 2- Less " " " bronchospasm. 3- Less " " " hypoglycemia. 4- Less " " " lipoprotein changes. 5- Less " " " K changes. However, it should be noted that cardioselectivity (beta 1selectivity is not absolute & is lost with high doses).  III- β-blocker with vasodilator properties These are B.B. with additional VD properties through alpha blocking effect like (CARVEDILOL, LABETALOL, or NO release like NEBIVOLOL) They are potent antihypertensives, and may be used in patients with: 1- Peripheral vascular disease. 2- Heart failure. Class1,2,3 Beta Blockers in Heart Failure They play a major role in ttt of HF esp. in ischemic H. disease & dilated cardiomyopathy. Used in: moderate HF (class II-III) not in severe (class IV) Values includes: 1- Prevent toxic effects of catecholamines on heart muscle (there is adrenergic activity in failing heart. 2- Partial blockade of RAS (renin – angiotensin system). 3- ↓incidence of sudden cardiac death & increase survival especially in post myocardial infarction patients. Members : Metoprolol – Bisoprolol – Carvedilol – Nebivolol C- βeta & Alpha -Blockers Labetalol,carvidolol Action: - It has both βeta and alpha-1 adrenergic blocking effect 3:1 - No selectivity on βeta receptors, does not affect cardiac output., No I.S.A. - Produces quick drop in B.P. due to : - α-blocking effect (reduce peripheral resistance).  - anti-renin action. - No tachycardia (selective α 1 blocker + Beta Blocker) Uses: 1) Hypertension: oral 100 mg t.d.s. or I.V., I.V. infusion. 2) Pheochromocytoma: very useful. II. Adrenergic Neurone Blockers – Antiadrenergic Drugs Act mainly by the following mechanisms: a- Drugs that primarily interfere or inhibit release of noradrenaline. e.g. guanethidine b- Drugs that primarily interfere or inhibit storage of noradrenaline e. g. reserpine c- Drugs that interfere or inhibit synthesis of noradrenaline e.g. alpha- methyldopa. Reserpine and alpha-methyldopa can produce depression III- Centrally Acting Drugs (alpha 2 agnosits = Depress VMC) Clonidine - α-methyldopa α2 agonists → ++presynaptic alpha2 receptor →↓ sympathetic flow from vasopressor centers →↓ NA release and ↓ renal vascular resistance so used in hypertension with renal insufficiency. Guanithidine 1- It inhibits the PERIPHERAL release of noradrenaline from sympathetic nerve endings leading to reduction of the sympathetic tone, vasodilatation and marked drop of blood pressure. 2- Causes Severe postural and exertional hypotension. Reserpine It depletes catecholamines BOTH centrally from the brain and peripherally from the sympathetic nerve 1- Casuse sedation, parkinsonism, night mares , psychic depression with suicidal attempts. Drugs that should be gradually withdrawn are Noradrenaline, dopamine, dobutamine Beta blockers clonidine