Adrenergic Agents, Agonists & Antagonists PDF

Adrenergic Agents Agonists and Antagonists. Professor L M Pinto Pereira p.67 lippin 3rd ed  - interfere with the synthesis, storage, or release of norepinephrine (NE) from sympathetic nerve terminals. Classification of sympatholytics Adrenergic neuron blockers ▪Format...

Adrenergic Agents Agonists and Antagonists. Professor L M Pinto Pereira p.67 lippin 3rd ed  - interfere with the synthesis, storage, or release of norepinephrine (NE) from sympathetic nerve terminals. Classification of sympatholytics Adrenergic neuron blockers ▪Formation of False Transmitters - turned into alpharmethyl NE which is stored in vesicles and released e.g. -αMethyl dopa instead of NE, lower affinity for alpha-1 and beta receptors...reduced sympathetic activity - converted ▪Depletion of storage sites e.g. into -methyl norepinephrin e, a false transmitter - depletes catecholamines by inhibiting VMAT reserpine stored in adrenergic vesicles, ▪ Inhibition of release & enhance released instead of norepinephrin e - lower affinity uptake e.g. guanethidine for and receptors, ▪Stimulation of presynaptic α2 leading to reduced sympathetic activity. receptors e.g. Clonidine and - activate presynaptic alpha-1 adrenergic receptors in brain, leading to α-Methyl dopa inhibition of NE release...reduces sympathetic outflow...results in lower blood pressure  α2 SELECTIVE AGONISTS Also known as sympatholytics - decrease central sympathetic outflow through Also Decrease sympathetic tone centrally. stim.. of presynaptic alpha-2 adrenergic receptors in CNS...reduces release of NE, leading to decreased sympathetic tone and lower BP Clonidine - used for hypertension, opioid withdrawal, ADHD and hot flashes Methyldopa - hypertension during pregnancy guanabenz - similar to clonidine mechanism of action...hypertension guanfacine - hypertension, ADHD Major side-effect –drowsiness/sedation indication – hypertension  Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in Humans Indirect sympathomimetics -1 Amphetamine like agents- enter the neuron, interact with the vesicular monoamine transporter type 2 VMAT(2) esp in CNS, promoting the release of intravesicular neurotransmitter and an increase in cytoplasmic neurotransmitter. ( Dopamine , NE) - stimulate release of neurotransmitters by entering neurons and disrupting vesicular storage mechanisms, resulting in increased synaptic conc. of these neurotransmitters amphetamine - ADHD, narcolepsy methamphetamine - more potent CNS effects, abused recreationally methylphenidate [ADHD] modafinil - enhances wakefulness, narcolepsy, shift work disorder - contradicted with MAO inhibitors because they can cause excessive neurotransmitter...patients taking MAO inhibitors should avoid tyramine rich foods tyramine—present in aged cheese, wine, cured meats Watch for drug interaction with MAO inhibitors!!!  Indirect sympathomimetics- 2 NET inhibitors - block NET, preventing the reuptake of NE from synaptic cleft back into presynaptic neurons...increased conc. of NE enhancing adrenergic signalling Cocaine- inhibits NET, DAT, increasing levels of NE, D...euphoria, increased alertness, vasoconstriction, local anaesthetic action...high abuse protential and can cause hypertension, tachycardia, and arrhythmias Duloxetine- NE and Serotonin reuptake inhibitor- Antidepressant Atomexetine– [ADHD] - selective NET inhibitor Reboxetine – SNRI-- Antidepressant - selective NET inhibitor  Clinical use of Amphetamine-like drugs In ADHD “Attention Deficit Hyperactivity Disease: (Methylphenidate, Dexamfetamine) In narcolepsy Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night Amphetamine-like drugs stimulates the CNS & make the patient awake (Dexamfetamine and Modafinil) To suppress appetite (Not in current use) In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite (An obsolete use) Amphetamine - facilitates adrenergic effects via these neurotransmitters It is non-selective adrenergic agonist, non-catecholamine Acts mainly, indirectly via enhancing NE release and DA. - from presynaptic neurons and inhibits their reuptake Since it is a non-catecholamine, it can be given orally It is lipid–soluble enough to be absorbed from intestines and enters CNS (This leads to CNS stimulation like Restlessness and Insomnia). t1/2 = 45 – 60 min (long duration of action) It is metabolized in the Liver Amphetamines - Side effects The side effects are due to chronic use These include : Tolerance (gradual reduction in effect, requiring higher doses) tachyphylaxis (rapid decrease in response after repeated doses in a short period) Dependence (psychological and physical dependence with compulsive drug-seeking behaviour) Addiction Paranoia Psychosis(amphetamine induced psychosis) Hypertension (due to drug's stimulation of adrenergic pathways...increased release of NA...vasoconstriction and increased CO) Beta receptors on body Organs Eyes: Beta receptors are found in the ciliary epithelium in the eye. When stimulated Produces Aqueous Humor. When blocked, decreases Aqueous Humor production (useful in glaucoma) CVS: Beta 1 receptors are found in the heart. When stimulated Increase in Heart rate (contractility + conduction velocity) Pulmonary: Beta 2 receptors Bronchodilation (in bronchial smooth muscle...helpful in conditions like asthma or COPD) On JGA of the kidney, promotes renin release, adding to the control of hypertension be Beta blockade. (juxtaglomerular apparatus- increases angiotensin II and contributes to BP reg.)  In the heart. β 1 stimulation causes In S.A node : increase HR (+ve chronotropic) In Myocardium tissue : increase contractility (+ve inotropic) Adrenoceptors In Conducting system : increase conduction velocity (+ve β 1 – adrenoceptors dromotropic) Site of β 1 – adrenoceptors & (increase risk of Increase ectopic beats arrhythmias) the effects of their stimulation In the Juxtaglomerular Apparatus of the kidney. β 1 stimulation cause increased renin release. Then causes increase in BP In fat cells (with α1, α2 & β 3) β 1 stimulation causes increased Lipolysis (breaking down triglycerides into free fatty acids and glycerol) In fat cells (with α1, α2 & β 3)  Beta receptors All β receptors activate adenylate cyclase, raising the intracellular cAMP concentration Type β1: These are present in heart tissue, and increase heart rate by acting on the cardiac pacemaker cells Type β2: These are in the vessels of skeletal muscle, and cause vasodilatation, which allows more blood to flow to the muscles, and reduce total peripheral resistance Beta-2 receptors are also present in bronchial smooth muscle, and cause bronchodilation when activated Stimulated by adrenaline, but not noradrenaline Bronchodilator salbutamol works by binding to and stimulating the β2 receptors - salbutamol is short acting beta-2 receptor agonist Type β3: Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism  Clinical Effects of β-receptor stimulation β1: Adrenaline, NA and Isoprenaline: Tachycardia Increased myocardial contractility Increased Lipolysis Increased Renin Release β2: Adrenaline and Isoprenaline (not NA) Bronchi – Relaxation SM of Arterioles (skeletal Muscle) – Dilatation Uterus – Relaxation Skeletal Muscle – Tremor Hypokalemia Hepatic Glycogenolysis and hyperlactiacidemia β3: Increased Plasma free fatty acid – increased O2 consumption - increased heat production - free fatty acids are used as fuel...enhance mitochondrial activity and increase O2 consumption - activates non-shivering thermogenesis in brown adipose tissue via uncoupling protein-1 in mitochondria...produce heat instead of ATP β 1 – adrenoceptor agonists and antagonists β 1 selective agonists E.g. Dobutamine β 1 selective antagonists E.g. Atenolol Esmolol Metoprolol  Beta 1 Adrenoreceptor Agonist Dobutamine: It is a synthetic direct acting β 1 – selective agonist (only) T1/2 = 10 – 15 min It is metabolized in the liver by oxidative deamination There is tolerance to its action Given only parenterally (not orally) It increases CO with minimal effect on HR. It has less arrhythmogenic effects than dopamine Uses: Inotropic agent for Heart Failure; in septic and cardiogenic shock.  Sympathomimetic Agents - drugs that mimic effects of the symp. NS by stimulating adrenergic receptors or increasing levels of catecholamines Endogenous Catecholamines Norepinephrine Epinephrine Dopamine Synthetic (exogenous) Isoprenaline α1 Sympathomimetic agents Midodrine- a prodrug selective α1 Agonist used esp in orthostatic hypotension (increasing vascular tone + raising BP) Phenylephrine selective α1 Agonist for decongestion,, mydriasis and BP rise. Active orally, Not metabolized by COMT. (reduces nasal mucosal swelling, induces pupil dilation for eye exams, increases BP in hypotensive states (e.g., during surgery)) Oxymetazoline- direct α agonist- topical decongestant (in colds / allergic rhinitis) Adrenoreceptor Agonists Side – effects of sympathomimetic drugs: On the CVS Hypertension Cardiac arrhythmia Myocardial infarction (chest pain) Increased severity of angina pectoris and of myocardial infarction On the eye Increased I.O.P leading to Glaucoma Adrenoreceptor Antagonists α– blockers Non selective Selective β– blockers Non selective Selective With intrinsic sympathomimetic activity Alpha Blockers (non-selective) ◆ Phenoxybenzamine (non competitive,irreversible) ◆ Phentolamine (competitive, reversible) on-competitive) ◆ Phenoxybenzamine (irreversibly binds to alpha-1 and 2 receptors) Non-competitive non-selective alpha adrenergic antagonist. Net effect: α 1 blockage > α 2 blockage (primary action is on alpha-1 in vascular smooth muscle leading to vasodilation and reduced BP) Uses: malignant HTN, Pheochromocytoma, HTN 2° to Clonidine Withdrawal, Cheese Reaction, Cocaine induced HTN. Decreases the workload of the heart, and decreases the risk of MI (also block alpha-2...leading to increased release of NE from symp neurons, but overall effect is vasodilation) Competitve Antagonist Vs. Non-competitive Antagonist  α 1 selective: (ends with –sin or –cin) Prazosin, Terazosin Alpha selective Doxazocin, Blockers Tamsulocin  Effects: Blocks vaso- and aterioconstriction vasodilation and arteriodilaton Decrease in Blood pressure. (management of hypertension) Alpha 1 Blocks alpha receptors in the eye blockers (pupillary dilator muscle) Miosis (vascular smooth muscle, bladder, eye) (constriction of pupil) Reduces Bladder tone and allows relief of urinary retention in patients (relaxes smooth muscle of bladder neck and with BPH prostate reducing bladder tone and urethral resistance...improving urine flow and relieving (benign prostatic hyperpasia) urinary tension) Alpha 1 blockers Uses/Side effects Drugs Arteriodilation, used in Raynaud’s Phenomenon Increase Urinary Motility, used in Urinary retention or BPH (Terazosin/Tamsulosin is most commonly used in BPH) Side effects: Nasal Congestion, Hypotension - Raynaud's phenomenon: vasoconstriction in fingers and toes causing episodes of colour change and pain...alpha-1 blockers promotes arterial dilation, improving blood flow - vasodilation...nasal congestion due to dilation of blood vessels in nasal passages Beta blockers (β1 selective) ◆ Also known as Cardioselective Beta Blockers, decreases HR ◆ Atenolol ◆ Betaxolol ◆ Esmolol (short half life) ◆ Acebutalol ◆ Metoprolol ◆ Bisoprolol ◆ Nebivolol Beta Non-selective ◆ Non Selective Beta blockers ◆ Propranolol ◆ Timolol - beta-1 reduces heart rate and decreases contractility, reducing myocardial oxygen ◆ demand Nadolol - beta-2 inhibit bronchodilation leading to potential bronchospasms...also reduce ◆ Pindolol glycogenolysis and lipolysis ◆ Blocks beta 1 and beta 2 receptors Bronchospasms and Decrease in HR ◆ Contraindicated in Asthmatics (bronchospasms can worsen asthma and other resp. conditions) ◆ Decreases aqueous humor production used in Open Angle glaucoma (Timolol) (lowers I.O.P. in open angle glaucoma) Uses of Beta Blockers ◆ Hypertension - mild to moderate HTN ◆ Angina pectoris -decreases cardiac work load ◆ Cardiac arrhythmias-slow heart rate and conduction at the AV node ◆ Myocardial infarction- prevents reinfarction, prevents the development of ventricular fibrillation (life-threatening arrhythmia that occurs when ventricles of heart experience rapid, erratic electrical activity) Uses of Beta Blockers ◆ Glaucoma. Timolol and Betaxolol are used topically ◆ Migraine. Used for prophylaxis ◆ Thyrotoxicosis (hyperthyroidism...tachycardia, palpitations, tremors...block effects of excess thyroid hormone on heart) ◆ Essential tremors (common neurological condition) ◆ Congestive cardiac failure (carvedilol and labetolol) (improvement in CO, reduce afterload...decrease HR and myocardial O2 demand) Side effects of Beta blockers Beta 2 Exacerbation of Asthma Masks the sign of a hypoglycemic episode (symptoms of hypoglycemia like tachycardia, shaking and sweating) Bradycardia (esp. in high doses) Beta blockers with intrinsic sympathomimetic activity (ISA) Acebutolol, Pindolol (partially stim. beta receptors while blocking them) Beta blockers with ISA are a class of drugs that lower blood pressure while maintaining heart rate. They stimulate beta-adrenergic receptors, which releases epinephrine and oppose its effects. Consequently BP is decreased while heart rate and cardiac output at rest are maintained. Beta blockers with ISA have some beta-blocking effects, but not to the same degree as beta blockers without ISA Indications Hypertension (patients with excessive bradycardia) Angina Ventricular arrhythmias (stabilise heart's rhythm w/o excessively slowing it) Alpha and Beta Antagonists (dual action meds that block both alpha and beta adrenergic receptors) Labetalol - considered safe during pregnancy (doesn’t cross Placenta, also used in hypertension of pregnancy) (causes vasodilation, decreased BP (alpha); decreased HR (beta) Carvedilol Blocks alpha1 receptors Decrease BP Blocks beta receptors Decreases HR Used in Severe HTN, Angina, Heart failure