Adrenergic Sympathomimetic Drugs PDF

Adrenergic (Sympathetic) Nervous system Dr/ Esraa Mostafa Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine Ain Shams University  Nervous System Central Nervous System Peripheral Nervous System...

Adrenergic (Sympathetic) Nervous system Dr/ Esraa Mostafa Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine Ain Shams University  Nervous System Central Nervous System Peripheral Nervous System Somatic Nervous Autonomic Brain Spinal Cord System Nervous System Sympathetic Parasympathetic The sympathetic system is an important regulator of activities of the heart & peripheral vasculature especially in response to stress such as trauma, fear, hypoglycemia, cold, and exercise.  Neuronal Communication Action Potential Neurotransmitter Electrical signal along Chemical signals between neuron membrane neuron and other cells  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 & peripheral transmitter.  Regulation of CA release M2 (-) ❑Homotropic regulation (A transmitter regulates its own release) ❑Heterotropicregulation (A transmitter regulates release of another transmitter) ❖NE Release by Nn & β2  by α2& M2  Enzymatic Degradation of catecholamines ❑ Ep, NE & DA (catecholamines) and serotonin are degraded mainly by monoamine oxidase (MAO) & to a lesser extent by catechol-o-methyl transferase (COMT). ❑ The end product: Vanilylmandelic acid (VMA) is excreted in urine → ↑ in pheochromocytoma (used in its diagnosis).  Adrenergic Receptors (Adrenoceptors) Belongs to G-protein family of receptors I. Alpha adrenergic receptors II. Beta-adrenergic receptors β1 α1 β2 α2 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) 1. Artery →↑PR→↑BP 2. Vein →↑Venous return→↑COP→↑BP  α1 I. Alpha adrenergic receptors Linked to Gq protein  stimulatory except on GIT & urinary walls Presents mainly in smooth muscles 2-GIT & urinary bladder Wall  Relaxation Sphincter  contraction 3- contraction of Prostate & vas deferens 4- Liver glycogenolysis (weak) & K+ release (Hyperkalemia) 4-Eye Stimulate (contraction) dilator pupillae muscle→ Active mydriasis α2 I. Alpha adrenergic receptors Linked to Gi protein Inhibitory Presynaptic Presents mainly in neuronal sites 1. Inhibit NE release from sympathetic nerves. 2. ↓ Ach release in the heart and intestine.  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  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. ↑Renin secretion  Angiotensin II  VC   PR   BP. 3. Lipolysis  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. Uterine (pregnant uterus after the 20th week) and intestinal relaxation  β3 II. Beta-adrenergic receptors Lipolysis Relax detrusor smooth muscle of urinary bladder III. dopaminergic receptors D1: Vasodilation of renal, coronary, cerebral & mesenteric blood vessels. D2: Presynaptic: ↓ DA & NE release from nerve endings. Sympathomimetic Drugs  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 Indirect Acting Dual (mixed) Norepinephrine (Non-selective) Amphetamine Ephedrine Epinephrine (Non-selective) Methylphenidate Pseudoephedrine Isoprenaline (Non-selective) Tyramine Dopamine (Non-selective) Dobutamine (Selective) Phenylephrine (Selective) Midodrine (Selective) Beta-2 agonist (Selective) Fenoldopam (Selective)  Direct Acting Adrenergic Agonists Non-selective sympathomimetics 1. Epinephrine  ++ (α1, α2, β1, β2) 2. Norepinephrine  ++ (α1, α2, β1) 3. Isoprenaline  ++ (β1 & β2): Used in Bradycardia 2ry to heart block 4. Dopamine & Dobutamine Epinephrine (α1, α2, β1, β2)  Epinephrine / Adrenaline Cardiovascular (β1): ↑ Systolic BP +ve Inotropic (↑ force of contraction) & ↑ Diastolic BP +ve Chronotropic (↑ HR) +ve Dromotropic (↑ conductive velocity) ↑↑ automaticity& causes arrhythmias (Large dose). Vascular effects: VC of arterioles of skin, mucosa, splanchnic & renal vessels (α1)  PR. Vasodilatation of skeletal & coronary vessels (β2).  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 (No effect on ciliary muscle). 2.  IOP by decreasing formation of aqueous humor (VC of ciliary BV (α1) Effect on other smooth muscles Relaxation of GIT wall Contraction of sphincters of GIT & bladder Inhibition of uterine tone & contractions in last months of pregnancy (β2) Metabolic actions: ↑Hepatic glycogenolysis (↑blood Glucose) (β2&α1) Insulin release ( by α2 /  by β2) Lipolysis ( β2& β3 /  by α2) Renin release ( β1 /  by α2) Skeletal muscles  tremors (β2)  Preparations and Dosage of EP Diluted ▪ 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 Anaphylactic shock (reverses bronchospasm & hypotension → life saving). Asthma (if associated with locked lung) Cardiac Arrest (intracardiac). Bleeding (topical hemostatic →on bleeding surfaces during surgery or bleeding (epistaxis) → VC and reduce bleeding). Added to local Anesthetics to prolong their action by inducing local VC  delaying absorption of local anesthetics. Open Angle glaucoma (↓ IOP): dipivefrine (pro-epinephrine) is used instead of epinephrine (since epinephrine is destroyed in alkaline medium).  Norepinephrine (Noradrenaline) ( α 1, 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 associated with hypotension (mainly due to its α1 action) Vasoconstriction →↑ BP - Septic shock - Cardiogenic shock (weak cardiac functions if BP < 70mmHg). - Shock after resection of pheochromocytoma. - Shock with pulmonary embolism  Dopamine (Non-selective α1, β1, D1) Dobutamine (Selective β1) Natural catecholamine Synthetic catecholamine Low dose: Stimulate D1-receptor: ----------------- Renal VD   renal blood flow Moderate dose: Stimulate β1-receptor: Stimulate β1-receptor (inotrope > +ve chronotrope & inotrope COP &HR chronotrope)  less arrhythmia (Anginal Pain & Arrhythmia) High dose: Stimulate α1-receptor: -------------------- VC  hypertension, gangrene Uses Used for severe acute or chronic refractory HF Same as dopamine Preferred in shock with hypotension (α1 action) or in But preferred in normotensive patient with renal impairment (D1 action) normal kidney functions Dose: IV infusion by titration (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 (VD), nausea, vomiting (with dopamine, D2 in CTZ).  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 Short acting Long acting Salbutamol, albuterol, Salmeterol ❖Therapeutic uses 1. Bronchial asthma (inhalation) 2. Prevent premature labor & threatened abortion  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 –Methylphenidate - Tyramine They are non-catecholamines 1.Not destroyed by MAO in the GIT → Can be given orally 2.Not metabolized by neuronal MAO → Longer duration of action 3.Can penetrate the BBB →Act on the CNS Strong CNS stimulation Strong anorexigenic  Indirectly Acting Sympathomimetics Amphetamine –Methylphenidate - Tyramine ❑ Enter the nerve terminal and displace stored NE  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 (CNS stimulation): Attention deficit hyperactivity disorder (ADHD)  Tyramine ▪ Indirectly acting sympathomimetic → releases catecholamines. High concentration in fermented foods (cheese, beer, fava beans, chicken liver). ▪ Metabolized by MAO in GIT. ❑ Cheese reaction (Food drug interaction): Patients on MAOIs should avoid tyramine-rich food (e.g. old cheese) since tyramine will escape metabolism & reach systemic circulation → NE release from neurons which is studded with NE (due to MAOIs) → hypertensive crisis.  Mixed- or Dual-acting Sympathomimetic Drugs Ephedrine - Pseudoephedrine Act both by release of NE & direct action on the receptors. ❖Uses 1. Epistaxis: topical ephedrine. 2. Nasal decongestants (Oral) : pseudoephedrine. 3. Spinal shock: ephedrine IMI (releases NE from anaesthetized sympathetic nerves). 4. Nocturnal enuresis (in children). 5. Urine incontinence (in adults). Thank you