Drugs Acting on Adrenergic System PDF

Adrenergic (Sympathetic) Nervous system Dr/ Esraa Mostafa Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine Ain Shams University The sympathetic system is an important regulator of activities of the heart & peripheral vasculature especially in resp...

Adrenergic (Sympathetic) Nervous system Dr/ Esraa Mostafa Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine Ain Shams University The sympathetic system is an important regulator of activities of the heart & peripheral vasculature especially in response to stress.  Adrenergic Neurotransmitters (Endogenous catecholamines) 1. Norepinephrine (NE) / Noradrenaline Postganglionic sympathetic fibers & of some tracts in CNS 2. Epinephrine (Ep) / Adrenaline Major hormone of adrenal medulla. 3. Dopamine (DA) Central transmitter & peripheral transmitter. Regulation of CA release  Adrenergic Receptors (Adrenoceptors) Belongs to G-protein family of receptors I. Alpha adrenergic receptors II. Beta-adrenergic receptors α1 β1 α2 β2 β3 III. Dopaminergic receptors D1 D2  α1 I. Alpha adrenergic receptors Linked to Gq protein >> stimulatory except on GIT & urinary walls Presents mainly in smooth muscles 1-Blood vessels Vasoconstriction (Blood Pressure) 2-GIT & urinary bladder Wall >>> Relaxation Sphincter >>> contraction 3-Eye Stimulate dilator pupillae muscle→ active mydriasis 4- Liver glycogenolysis (weak) & K+ release  α2 I. Alpha adrenergic receptors Linked to Gi protein Inhibitory Postsynaptic Presents mainly in neuronal sites 1. ↓ Central sympathetic outflow → ↓ BP. 2.  lipolysis. 3.  insulin secretion (predominant). 4. Inhibit renin release (weak). 5. Stimulate platelet aggregation & vasoconstriction α2 I. Alpha adrenergic receptors Presynaptic 1. Inhibit NE release from sympathetic nerves. 2. ↓ Ach release in the heart and intestine.  II. Beta-adrenergic receptors β1 Linked to Gs protein >> excitatory. Presents mainly in cardiac muscles 1. Cardiac stimulation >>> ↑ all cardiac properties (HR, Contraction & conduction)  ↑ COP & ↑ BP 2. Lipolysis 3. ↑Renin secretion >> Angiotensin II  VC   PR   BP.  II. Beta-adrenergic receptors β2 Linked to Gs protein (inhibitory to smooth muscles) 2. Vasodilation of skeletal & coronary blood vessels >> PR   BP. 2. Bronchodilation & mast cell stabilization. 3. (+) insulin release (weak effect). 4. Liver & muscle glycogenolysis (predominant)   blood glucose. 5. Skeletal muscle tremors 6. 3. Uterine (pregnant uterus after the 20th week) and intestinal relaxation Effect on blood vessels  II. Beta-adrenergic receptors β3 Lipolysis & relax detrusor smooth muscle of urinary bladder III. dopaminergic receptors D1: vasodilation of renal, coronary, cerebral & mesenteric blood vessels. D 2: Presynaptic: ↓ DA & NE release from nerve endings.  Sympathomimetic Drugs (Adrenergic Agonist) Classification According to Mechanism of Action 1. Direct Acting >>> Directly acting on receptors 2. Indirect Acting >>>  Reuptake or ↑↑ Release 3. Dual (mixed) Acting  Direct Acting Adrenergic Agonists Non-selective sympathomimetics 1.Epinephrine  ++ (α1, α2, β1, β2) 2.Norepinephrine  ++ (α1, α2, β1) Epinephrine (α1, α2, β1, β2)  Epinephrine / Adrenaline Cardiovascular (β1): +ve Inotropic (↑ force of contraction) +ve Chronotropic (↑ HR) +ve Dromotropic (↑ conductive velocity) ↑↑ automaticity& causes arrhythmias (Large dose). Vascular effects: VC of cutaneous & visceral blood vessels (α1). Vasodilatation of skeletal & coronary vessels (β2).  Epinephrine / Adrenaline Epinephrine affects blood pressure by a dual mechanism: A dominant hypertensive effect through α1 & β1 receptors   BP. At therapeutic doses , the hypertensive effect masks the hypotensive one A weak hypotensive effect through β2 receptors   BP (Epinephrine reversal: In experimental studies, dt. α-receptor blockade).  Respiratory System Bronchodilation (β2). Decongestion of BVs of mucous membrane of upper respiratory tract (α1).  3-Eye 1. Contraction of dilator pupillae muscle of iris (α1) → active mydriasis without cycloplegia. 2.  IOP by decreasing formation of aqueous humor. Effect on other smooth muscles Relaxation of GIT wall Contraction of sphincters of GIT & bladder Metabolic actions: ↑Hepatic glycogenolysis (↑blood Glucose) (β2&α1) Insulin release ( by α2 &  by β2) Lipolysis (β2& β3) &  by α2 Renin release (β1) Skeletal muscles  tremors (β2)  Preparations and Dosage of EP ▪ SC or IM 1:1,000 in mild anaphylactic shock. ▪ IV 1:10,000: severe anaphylactic shock - cardiac arrest (intra-cardiac). ▪ Inhalation 1:100 in asthma. ▪ Topical: 1:100 in bleeding states - 1% solution for ophthalmic use.  Therapeutic uses of EP 1. Anaphylactic shock (reverses bronchospasm & hypotension → life saving). 2. Asthma 3. Cardiac Arrest. 4. Bleeding (topical hemostatic →on bleeding surfaces during surgeryor bleeding (epistaxis) → VC and reduce bleeding). 5. Added to local Anesthetics to prolong their action by inducing local VC  delaying absorption of local anesthetics. 6. Open Angle glaucoma (↓ IOP): dipivefrine (pro-epinephrine) is used instead of epinephrine (since epinephrine is destroyed in alkaline medium).  Norepinephrine (noradrenaline)  (α1, α2, β1) α1 effect → marked vasoconstriction →↑ BP or gangrene. β1 effect → positive inotropic & chronotropic effect.  Therapeutic uses of NE Shock (mainly due to its α1 action)  Therapeutic uses of NE Shock (mainly due to its α1 action Vasoconstriction →↑ BP - Septic shock - Cardiogenic shock (if BP < 70mmHg). Dopamine (Non-selective α1, β1, D1) Dobutamine (Selective β1) Natural Synthetic Low dose: Stimulate D1-receptor ----------------- Renal VD   renal blood flow Moderate dose: Stimulate β1-receptor Stimulate β1-receptor (inotrope > +ve chronotrpe & inotrope Anginal Pain chronotrope)  less arrhythmia & Arrhythmia High dose: Stimulate α1-receptor -------------------- VC  hypertension, gangrene Uses Used for severe acute or chronic refractory HF Same as dopamine Preferred in shock/ hypotension (α1 action) or in But preferred in normotensive patient with normal renal impairment (D1 action) kidney functions Dose: IV infusion (low dose & increase gradually to a maximum) Start 2 ug/Kg/min (max. 50 ug/Kg/min) Start 2.5 ug/Kg/min (max. 10 ug/Kg/min)  Adverse effects Dopamine & Dobutamine (Avoided by gradual titration of infusion) 1. Palpitation- anginal pain- arrhythmia (less with dobutamine). 2. Hypertension (with dopamine). 3. Headache, nausea, vomiting (with dopamine).  Isoprenaline (Synthetic catecholamine) β1 &β2 receptor agonist β1 effect → +ve chronotropic & inotropic→ marked ↑ in cardiac output. β2 effect → Bronchodilatation and vasodilation →↓BP→ reflex ↑ in HR. Uses: Bradycardia 2ry to heart block (rarely). Adverse effect: Marked ↑↑ in HR (direct and reflex) → anginal attack & sudden death.  Selective α1-Agonists: Phenylephrine - Long acting (not inactivated by COMT). ❖Therapeutic uses 1. Hypotensive states to ↑ BP. 2. Mydriatic for fundus examination (no cycloplegia; preferred to atropine substitutes especially in patients with glaucoma). 3. Eye & nasal decongestant. 4. Local treatment for hemorrhoids.  Selective α1-Agonists: Midodrine Prodrug that is hydrolyzed to active form (desglymidodrine). ❖ Therapeutic uses Postural hypotension Adverse effects of α1 agonists 1. Hypertension & bradycardia. 2. Rebound nasal congestion & atrophic rhinitis (with local application).  Selective β1-Agonists Dobutamine: see before Selective β2-Agonists ❖ Advantages over non-selective β agonists 1. No cardiac complications in regular doses. 2. Longer acting (not metabolized by MAO or COMT). 3. May be given by many routes (oral, inhalation, parenteral).  Selective β2-Agonists ❖Therapeutic uses 1. Bronchial asthma (inhalation) 2. Prevent premature labor & threatened abortion ❖Adverse effects (less with inhalation therapy): 1. Anxiety, restlessness and headache. 2. Tremors of skeletal muscle. 3. Tachycardia (at high concentration they stimulate β1 receptors). 4. Tolerance on long term systemic use (β receptor downregulation) 5. Hypokalemia and muscle cramps.  Selective D1 agonist: Fenoldopam Peripheral VD in some vascular beds. ❑ It is used mainly IV for the treatment of severe hypertension (emergency).  Indirectly Acting Sympathomimetics Amphetamine - Tyramine ❑ Act mainly by increasing NE release (once NE stores are depleted → tolerance & tachyphylaxis). ❑ Act to Lesser extent by  NE uptake by adrenergic neurons ❖ Therapeutic uses: Attention deficit hyperactivity disorder (ADHD)  Mixed- or Dual-acting Sympathomimetic Drugs Ephedrine - Pseudoephedrine Act both by release of NE with some direct action on the receptors. ❖Uses 1. Epistaxis: topical ephedrine. 2. Oral nasal decongestants : pseudoephedrine. 3. Spinal shock: ephedrine IMI (releases NE from anaesthetized sympathetic nerves). 4. Nocturnal enuresis (in children). 5. Urine incontinence (in adults). Drugs which block the sympathetic actions 1. Cardiac stimulation >>> ↑ all cardiac properties (HR, Contraction & conduction)  ↑ COP & ↑ BP. 2. ↑Renin secretion >> ↑ Angiotensin II  VC   PR   BP.  Pharmacological action of non-selective βBs I. Cardiovascular actions ▪ Β1 –Blockers: Decrease all cardiac properties  Heart Rate,  Force of contraction &  Oxygen consumption  Cardiac output & blood pressure  SA node rate & A-V conduction (Block intrinsic sympathetic activity)  Renin release ❖ Therapeutic Uses: Anti-hypertensive - Anti-anginal (Ischemic heart ds. – Anti-arrhythmic  Pharmacological action of non-selective βBs ▪ Β2-Blockers >> Vasoconstriction (unopposed α1 actions) ▪ βBs with α-blockade activity >>> Vasodilatation ❖ Uses: Prophylactic in esophageal varices Non-selective ßBs reduce portal blood flow by: Splanchnic vasoconstriction (β2 block) - ↓COP (β1 block).  II. Non - Cardiovascular actions 1. β2Blockers: -  Skeletal muscle tremors (uses: Essential tremors, propranolol is of choice). - Bronchoconstriction 2. Metabolic effects : - ↓glycogenolysis - ↓ Insulin release → glucose intolerance - ↓ conversion of T4 → T3. 3. CNS Depression (lipophilic βBs) Adverse effects, contraindications & precautions  1. Due to β1 blockade - Bradycardia - heart block. - Heart failure - Hypotension (more severe with vasodilator β-Blockers). 2. Due to β2 blockade - Cold extremities, fatigue & claudication pain (unopposed α1 actions; CI in peripheral vascular disease). - Bronchospasm (CI in asthma). - Prolongation of insulin-induced hypoglycemia. - Glucose intolerance. - Hyperkalemia in susceptible patients (e.g. renal impairment & diabetes).  3. CNS effects: nightmares & depression. 4. Others - Rebound angina & arrhythmias in ischemic heart disease (due to sudden cessation of βBs → up regulation of β receptors) → should do gradual withdrawal. - Sexual dysfunction  β-Adrenergic receptor blockers “βBs” Mechanism of action β-adrenoceptors blockade βBs classification Cardio-Selective Non-Selective “β1 & “β1Bs” “β2Bs” Atenolol - Bisoprolol Propranolol - Pindolol Combined (α & β blockers) Labetalol - Carvedilol  Additional mechanism of action Not related to β-adrenoceptors blockade ❑ Membrane stabilizing effect (MSA): 2ry to Na+ channels blockade induces local anesthesia ❑ Intrinsic sympathomimetic activity (ISA): Induce less: Bradycardia, Bronchospasm and Vasospasm ❑ Vasodilator activity: 2ry to α-blockade >> VD >> Useful in hypertension  βBs Pharmacokinetics classification Lipophilic Hydrophilic Balanced (properties in between lipophilic & hydrophilic)  Lipophilic “Propranolol” Hydrophilic “Atenolol” Absorption Well absorbed Irregularly absorbed First pass effect Extensive Less Bioavailability Less More More CNS penetration more Less CNS penetration Distribution CNS side effects.  less CNS side effects. Mainly hepatic (suitable Mainly renal (suitable in Elimination in renal impairment). hepatic impairment) T1/2 Short ( 2-3 doses daily) Long (one dose daily) ❑Esmolol: - Hydrophilic βB - Has a very short duration of action (t1/2=8min.) due to hydrolysis by plasma esterase enzymes.  Therapeutic Uses ❖ Secondary to β1Blockade 1.Hypertension 2.Ischemic heart disease 3.Cardiac arrhythmias 4.Heart failure 5.Hyperthyroidism / Thyrotoxic crisis “propranolol” ❖ Secondary to β2 blockade Prophylaxis of migraine “propranolol” - Essential tremors “propranolol” ❖ Secondary to CNS effects: Social anxiety disorder “propranolol”  Q: Mention non-cardiac uses of propranolol? 1.Hyperthyroidism / Thyrotoxic crisis 3. Essential tremors 4. Social anxiety disorder/ Panic 2. Prophylaxis of migraine attacks 1. NSAIDs e.g. aspirin → ↓antihypertensive effects (due to inhibition of PGs synthesis with subsequent salt & water retention). 2. Non-selective β blockers mask the hypoglycemia of insulin and sulfonylurea (insulin secretagogues). 3. β blockers potentiate the vasopressor effects of non-selective sympathomimetics (After β blockade, sympathomimetics act unopposed on α1 receptors “VC” ).  Selective α1 blockers Prazosin, Doxazosin, Tamsulosin Other α blockers Labetalol, Carvedilol  Pharmacological actions of selective α1 blockers I. Cardiovascular actions 1. Mixed vasodilators: a. Arteriodilators→↓ peripheral resistance→ ↓blood pressure. b. Venodilators→↓ venous return→ postural hypotension. 2. Tachycardia (less than nonselective agents): nonselective agents block presynaptic α2 receptors→↑ NE release → stimulates cardiac β1 receptors. 3. Chronic use → compensatory ↑ in blood volume (fluid retention). II. Other actions Block α receptor → decrease tone of bladder neck muscles & prostate →↓ resistance to urine flow → used in urine retention due to benign prostatic hyperplasia (BPH). Relaxation of vas deferens→ inhibition of ejaculation. Miosis - nasal stuffiness.  ❖Therapeutic uses of α blockers 1. BPH: prazosin, doxazosin, tamsulosin 2. BPH with essential hypertension: prazosin (tolerance develops due to tachycardia & fluid retention). 3. Hypertension in pregnancy and labor (labetalol). 4. Most hypertensive emergencies (labetalol).  Adverse Effects of α blockers 1. 1st dose postural hypotension: ↓ by giving small dose (1 mg) at bedtime. 2. Tachycardia (marked with non- selective agents). 3. Impaired ejaculation and sexual dysfunction. 4. Nasal congestion, flushing, headache. 5. Drowsiness and nausea. ❖Tamsulosin & Alfuzosin Affinity for α1A receptors on prostate & bladder neck muscle is higher than for vascular α1B receptors → ↑efficacy in BPH with minimal change in BP → less postural hypotensive effect than other α blockers. Centrally-Acting Sympatholytics “Central α2 Agonists”  1. Methyldopa ❖Mechanism of action: Prodrug → metabolized in the brain to α-methyl NE which stimulates central α2 receptors in brainstem  ↓ central sympathetic outflow. ❖Uses Hypertension especially in pregnancy. ❖Adverse effects: (limit its use) 1. Sympatholytic: Sedation - dry mouth – Bradycardia - Diarrhea. 2. Hepatitis, hemolytic anemia, systemic lupus (immune- based, less common). 3. Salt and water retention → tolerance & weight gain. 4. Depression 5. Parkinsonism & hyperprolactinemia (↓ DA).  2. Clonidine ❖ Mechanism of action 1. Activates postsynaptic α2 receptors → ↓central sympathetic outflow → ↓ BP. 2. Acts on peripheral presynaptic α2 receptors on adrenergic neurons → ↓ NE release. 3. Stimulates postsynaptic α2 receptors → ↓ renin & aldosterone. ❖Uses 1. Morphine withdrawal 2. Menopausal hot flushes. 3. Migraine prophylaxis 4. Hypertensive urgencies. ❖Adverse effects 1. Sympatholytic: Sedation - dry mouth – Bradycardia - Sexual dysfunction. 2. Salt and water retention → tolerance & weight gain. Thank you