Adrenergics Lecture Notes PDF

Adrenergics Pranaya Mishra PhD [email protected] 1 Learning Objectives • Explain the mechanism of action of adrenergic drugs. • Describe the receptor affinities for various adrenergic drugs. • Explain the role of reflex homeostatic adjustments on the observed cardiovascular effects of adrenergic...

Adrenergics Pranaya Mishra PhD [email protected] 1 Learning Objectives • Explain the mechanism of action of adrenergic drugs. • Describe the receptor affinities for various adrenergic drugs. • Explain the role of reflex homeostatic adjustments on the observed cardiovascular effects of adrenergic drugs. • Describe the effects of endogenous sympathetic neurotransmitters on effector organs. • Describe the pharmacologic effects of the adrenergic drugs. • Describe the significant pharmacokinetic properties of the adrenergic drugs. Learning Objectives • Describe the adverse effects of the adrenergic drugs. • Describe clinically important drug interactions and contraindications of adrenergic drugs. • Describe the therapeutic uses of the adrenergic drugs. • Explain by referring to the mechanism of action the therapeutic uses of the adrenergic drugs. Drug List Adrenergic Agonists Direct Acting Selective Nonselective α/β-agonists Mixed Acting Indirect Acting α-agonists α1-agonists β-agonists Isoproterenol Epinephrine Phenylephrine Dobutamine Norepinephrine Amphetamine α2-agonists Albuterol Dopamine Methyldopa Clonidine Terbutaline Apraclonidine Mirabegron Ephedrine Cocaine Tyramine 3 Classification of Adrenergic Drugs • Direct acting adrenergic agonists • Indirect acting adrenergic agonists • Mixed acting adrenergic agonists 5 Adrenergic Drugs • Direct acting: o Epinephrine, Norepinephrine, Phenylephrine, Albuterol • Indirect acting: o acts by releasing NE o Tyramine, Amphetamine • Mixed acting: o Ephedrine, Phenylpropanolamine 6 Catecholamines • have catechol moiety and an ethylamine side chain • naturally occurring catecholamines includes – Epinephrine, Norepinephrine, Dopamine • rapidly inactivated by MAO & COMT - inactivation starts from the gut 7 Catecholamines Drug Receptors Epinephrine α1, α2, ß1, ß2 Norepinephrine Isoproterenol Dobutamine Dopamine α1, α2, ß1 ß1, ß2 ß1 D1 (ß1 & α1 at high doses) 8 Non-catecholamines Drug Receptors Oxymetazoline, Phenylephrine, Methoxamine α1 Albuterol, Pirbuterol, Terbutaline, Salmeterol, Formeterol ß2 Metaproterenol ß2>ß1 Ephedrine, Pseudoephedrine Clonidine, Apraclonidine α, ß α2 9 :- 10 :- 11 EPINEPHRINE • a potent activator of α and ß adrenergic receptors • has prominent cardiovascular effects 12 EPINEPHRINE PHARMACOLOGICAL ACTIONS CVS : (ß1) HEART: • powerful cardiac stimulant • increases the force of contraction of heart (+ve inotropic) • increases the rate of contraction of heart and increase heart rate (HR) (+ve chronotropic) • increase cardiac output, increase BP • increases the conduction through AV node (+ve dromotropic) 13 14 EPINEPHRINE CVS : (α1) BLOOD VESSELS: • Vasoconstriction (α1) : rise in BP at high dose (Vasopressor effect) • Vasodilatation of Vessels of Skeletal muscle: (ß2) – low dose (Vasodepressor effect) Biphasic Response - different effects based on dose 15 Epinephrine: Biphasic response α1 Blood pressure Epinephrine in high dose ß2 16 EPINEPHRINE • Dale's vasomotor reversal (Epinephrine Reversal): when α1 receptors are blocked, epinephrine will produce hypotension because of unmasking of ß2 receptors – activation 17 18 EPINEPHRINE Dose-dependant effects : • Low dose: ß1, ß2 stimulation • High dose: α1, ß1 (ß2 ) stimulation • ß2 is masked Remember: at low concentrations, Epinephrine has predominantly ß1 and ß2 effects. At higher concentrations, α1 effects become more pronounced. 19 Epinephrine: low dose :20 Epinephrine: high dose : 21 Epinephrine: high dose If ganglionic blocker given, won’t see this reflex bradycardia (ß2 effects masked) :- 23 Epinephrine Effects on respiratory system: • Bronchodilatation: ß2 24 Epinephrine 25 Epinephrine Metabolic effect • Hyperglycemia: • increases blood glucose level by: • • • • glycogenolysis in muscle and liver (ß2) gluconeogenesis (due to increased release of glucagon- ß2) insulin secretion (α2)*** insulin secretion (ß2 effect) (However, predominant effect on insulin secretion is inhibition thru α2)*** • Lipolysis (ß3): • increases cAMP level in adipose tissue, which stimulates a hormone-sensitive lipase, leading to hydrolysis of TGs to FFA and glycerol 26 Epinephrine Smooth Muscles • GIT: o relaxation (activation of α2 receptors on cholinergic terminals reduce ACh release; activation of ß2 receptors directly relaxes smooth muscle) o peristalsis is reduced and sphincters are constricted • BLADDER : o trigone and sphincter- constricted (α1 receptors) o detrusor relaxed (ß2 mediated) o Net effect: urinary retention • UTERUS: relaxation at term 27 Epinephrine Smooth Muscles • Eye o contraction of radial muscle of iris (mydriasis; α2) o decreased intraocular pressure ▪ The mechanism seems to involve mainly reduced aqueous humor production due both to vasoconstriction and α2-receptor activation. These actions override the increased production due to β2 receptor activation. 28 EYE: mydriasis 29 Epinephrine Skeletal Muscle • tremor (ß2 receptor activation accelerates the sequestration of cytosolic Ca++ and enhances the discharge of muscle spindles) • increased K+ uptake into the cells (due to ß2 receptor activation) Central Nervous System • does not enter the CNS, and so lacks direct central effect • restlessness, apprehension, and tremor are probably secondary to the effects on peripheral organ 30 Epinephrine Other effects • stimulation of renin secretion • inhibition of mast cells degranulation (due to activation of β-2 non-innervated receptors) which blocks the release of inflammatory mediators • stimulation of platelet aggregation (due to activation of α-2 non-innervated receptors) 31 Epinephrine: PHARMACOKINETICS • Epinephrine, Norepinephrine, and Dopamine – ORALLY INACTIVE • rapid onset but a brief duration of action (due to rapid degradation) • Epinephrine and Norepinephrine are degraded by MAO and COMT in the liver and adrenergic neuron 32 Epinephrine: PHARMACOKINETICS • in emergency situations, Epinephrine is given IV for the most rapid onset of action • may also be given SC, by endotracheal tube, by inhalation, or topically to the eye 33 Epinephrine: Therapeutic uses • Bronchospasm o primary drug used in an emergency due to acute attacks of asthma • Anaphylactic shock o drug of choice ▪ can increase BP in deadly hypotension (α1 effect) and increase respiratory exchange (ß2 effect) 34 Epinephrine: Therapeutic uses • With local anesthetics (Adjunct) o 1 in 100 000 parts o Increase duration of action of local anesthetic o e.g., Epinephrine+ Lidocaine • Glaucoma (open-angle) o decrease IOT due to decreased production of aqueous humor by vasoconstriction of ciliary body blood vessels (eye drop 2%) • Prodrug: Dipivefrin o rarely used 35 Epinephrine: Therapeutic uses • Cardiac arrest o to restore cardiac rhythm in patients with cardiac arrest or heart block, regardless of cause • Mydriasis for intraocular surgery 36 Epinephrine: Adverse effects • palpitation, increase in BP, arrhythmia, restlessness, tremors, throbbing headache • cerebral hemorrhage (due to marked elevation of BP) • contraindicated in angina pectoris 37 Epinephrine: Contraindications • Hypertension • Angina • Cardiac arrhythmias • Cerebrovascular disease • Hyperthyroidism • Pheochromocytoma 38 Epinephrine: Precautions • Hyperthyroidism • Cocaine users • Diabetes 39 Norepinephrine • activates α1, α2 and ß1 receptors • however, more α actions are seen----------Vasoconstriction • Baroreceptor reflex o increase in BP initiates baroreceptor reflex response and causes reflex bradycardia (decrease in HR), which will override the ß1 mediated direct effects on the heart Can you block this reflex bradycardia? 40 Norepinephrine CVS • no action on ß2 receptors • increase TPR due to vasoconstriction of most of the vascular beds • increase systolic and diastolic BP, so pulse pressure is not changed • decrease pulse rate (reflex bradycardia) (due to increase in BP--- reflex rise in vagal activity by stimulating baroreceptors--- decrease heart rate---- decrease pulse rate) 41 Norepinephrine :- 42 Norepinephrine Differentiation of high-dose epinephrine versus norepinephrine: • Epinephrine reversal: use of α1 blocker to reverse hypertension to hypotension in a patient receiving large dose of epinephrine • Hypertension was due to ?? (α1 and ß1- receptors) • Hypotension results from?? (ß2-receptors) 43 Norepinephrine: Therapeutic uses • Vasodilatory shock • Cardiogenic shock • With local anesthetics (in order to retard their absorption) 44 Isoproterenol - direct-acting synthetic CA - non-selective ß agonist (acts on ß1, ß2 and ß3 ) - no action on α receptors Isoproterenol • activation of cardiac ß1 receptors: increased contractility and heart rate • HR increases both by direct ß1 effect as well as reflex effect due to fall in BP through activation of ß2 receptors • activation of ß2 receptors: decrease in TPR, decrease in mean BP • systolic blood pressure does not fall significantly as diastolic due to ß1 receptor action, so the pulse pressure increases Isoproterenol Isoproterenol • Activation of ß2 receptors: o bronchial and GI smooth muscle relaxation o relaxation of the uterus (tocolytic effect) • Other effects: o causes less hyperglycemia than Epinephrine because there is no α2 mediated inhibition of insulin release Isoproterenol: Therapeutic Uses • Bronchospasm • Heart block • Bradyarrhythmias Dopamine • Acts on D1, D2, α and ß receptors o D1 in the renal and mesenteric blood vessels – dilates – most sensitive at low dose o Moderate high (intermediate) dose – positive inotropic action on the heart – ß1 receptors o High dose – vasoconstriction – α1 receptors As the dose increases, the binding of dopamine follows: D1 ß1 α1 Dopamine: Cardiovascular effects • Low dose • Vasodilation (renal ) (D1) • Moderate dose • ß1 • α1 • Higher dose D1 > b1 > a1 Dopamine Increases: • myocardial contractility • renal blood flow (RBF) • glomerular filtration rate (GFR) • sodium excretion • urine output Dopamine: Therapeutic uses In Cardiogenic shock • Drug of choiceo increases BP by stimulating heart (ß1) o increases perfusion to kidney and splanchnic areas (through D1 receptors) by vasodilatation---- increases blood flow to kidney---- increases GFR, increases Na+ diuresis--- prevents kidney shutdown Dopamine Agonists • FENOLDOPAM • DOPEXAMINE Dobutamine • selective ß1 agonist • increases the force of contraction of the heart (Inotropic effect), with little or no change in HR*** • used in CCF, MI with failure, because it increases CO without elevating the oxygen demand of myocardium - a major advantage over other sympathomimetic drugs (which work at the expense of oxygen) • R/A: IV α1-selective agents α1-selective agents • Phenylephrine • Methoxamine • Naphazoline • Xylometazoline Phenylephrine • selective α1 agonist • direct-acting, non-catecholamine • increases the mean blood pressure via vasoconstriction with minimal effect on pulse pressure (PP) • increase in BP can elicit reflex bradycardia (no direct effect on heart) • Contraction of radial muscle of eye : • What would happen if Phenylephrine is given along with Hexamethonium (a ganglionic blocker)? Phenylephrine: Therapeutic Applications • nasal decongestion • Mydriasis: to permit fundus examination (without cycloplegia) • to retard absorption of local anesthetics • postural hypotension (due to autonomic disorders, endocrine diseases, vascular insufficiency, etc.) • to raise BP Contraindications & Precautions • • • • • Hypertension Cardiac diseases (MI, Arrhythmias, Coronary diseases, etc.) CVD Hyperthyroidism Urinary retention Adverse effects • • • • Increased BP (Severe Hypertension) Anginal pain (in risk patients) Rebound congestion (when used as nasal decongestants) Photophobia (when used as mydriatics) α2-selective agonists • • • • • • Clonidine Apraclonidine Brimonidine Tizanidine Methyldopa Guanfacine Clonidine • α2-selective agonist, acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery • has multiple mechanisms of action which include: o activation of presynaptic α2-adrenoceptors located in the nucleus of tractus solitarius and in the rostral ventrolateral medulla (the main mechanism) o activation of non-adrenergic binding sites called imidazoline receptors located in the rostral ventrolateral medulla o these 2 mechanisms lead to decreased firing of the reticulospinal tract, that is a decrease in central adrenergic tone (main antihypertensive action) Clonidine • excellent oral bioavailability (100%) • transdermal patches also available Adverse effects: • sedation and drowsiness (20-50%) • Bradycardia • sexual dysfunction • rebound hypertension (following abrupt withdrawal of clonidine) • Xerostomia (40%), constipation (10%) 66 Clonidine: Therapeutic uses • used in hypertension (to lower BP because of its central actions) • also used to minimize the symptoms associated with opiates, benzodiazepines or tobacco withdrawal • open angle glaucoma (Apraclonidine) o decreases intraocular tension by decreasing the production of aqueous humor Apraclonidine: given as Ophthalmic preparation Other α2 Agonists • Guanfacine • Guanabenz • Methyldopa: HTN in pregnancy • Tizanidine: Spasmolytic (in spinal cord spasticity) Topical Sympathomimetics Direct-acting α-agonists • Naphazoline - used as topical vasoconstrictor – nasal decongestant • Oxymetazoline - to reduce congestion and swelling of the nasal mucosa- nasal decongestant • Xylometazoline - nasal decongestant Indirect Acting Adrenergic Drugs Indirect Acting Adrenergic Drugs • Amphetamine • Tyramine • Methyldopa • Ephedrine (mixed action) Amphetamine • non-catecholamine sympathomimetic drug • increases the release of monoamines (NE, dopamine, serotonin) in synaptic spaces, both peripherally and in the CNS (the main action) • blockade of catecholamine reuptake can occur • orally active • prominent CNS stimulatory action: increases BP and HR • increases alertness, increases concentration, and increases work capacity • reticular activating system is activated – wakefulness (insomnia) • details discussed under Drugs of Abuse NE NE NE Amphetamine: Therapeutic uses • as CNS stimulant in the treatment of children with attention deficit hyperactivity disorder (ADHD) • Narcolepsy (especially Modafinil, a new amphetamine substitute) Tyramine • releases large amounts of stored CA from nerve terminals • also is a false transmitter that is taken up by the adrenergic neurons where it is transformed into octopamine, a very weak adrenergic agonist o Octopamine is stored in the adrenergic vesicles, gradually displacing norepinephrine • not clinically used • found in fermented foods, such as aged/ripe cheese, meats, chicken liver, pickled or smoked fish such as anchovies or herrings, and red wines • inactivated by MAO in the gut; can precipitate “cheese reaction” if given along with MAO inhibitors Methyldopa • a false neurotransmitter, taken up by the adrenergic neurons where it is transformed into methylnorpinephrine, an α2-adrenergic agonist. • activation of central α2-adrenoceptors by methylnorepinephrine reduces central adrenegic tone (same as clonidine) • details will be discussed under “Antihypertensive drugs”. Cocaine • local anesthetic agent, having ability to block uptake of NE in the adrenergic neurons (both centrally and peripherally) • consequently, NE accumulates in the synaptic space, resulting in enhancement of sympathetic activity • a CNS stimulant and drug of abuse Indirect Acting Sympathomimetics -act by releasing NE Pharmacological Effects Applications • Vasoconstriction • Nasal decongestion • CNS effects: stimulation • Narcolepsy • Hyperkinetic Syndrome (ADHD) • anorexigenic • Obesity Mixed Acting Mixed Acting Ephedrine, Pseudoephedrine: • alkaloid from the plant – Ephedra vulgaris • acts directly on α and ß receptors and also indirectly by releasing stored NE from nerve endings. • repeated injections produce tachyphylaxis • effective orally - resistant to MAO and COMT • crosses the BBB – CNS stimulation (especially Ephedrine) • was used in bronchial asthma (not nowadays) and nasal congestion*** Other Adrenergic Drugs Phenylpropanolamine • α agonist • used as a nasal decongestant • may cause severe hypertension Phenylpropanolamine is `unsafe' according to a US FDA advisory committee Drugs Having Selective ß2 Action • • • • • • Albuterol Pirbuterol Salmeterol - long acting with late onset Formoterol - long acting with late onset Terbutaline Metaproterenol Drugs Having Selective ß2 Action • Respiratory System: o bronchodilation o enhanced mucociliary clearance o suppression of release of inflammatory mediators (leukotrienes, histamine etc.) from many inflammatory cells o reduction of microvascular permeability Drugs Having Selective ß2 Action Therapeutic uses: • • • • Asthma Chronic Obstructive Pulmonary Diseases (COPD) Hyperkalemia Premature labor (Tocolytics) Adverse effects: • • • • • tremor, muscle cramps sinus tachycardia, palpitations, flushing and hypotension arrhythmias, angina (in risk patients) Hypokalemia Hyperglycemia, increase in lactate in free fatty acids (with high doses) Drug Having Selective ß3 Action • Mirabegron o causes Detrusor muscle relaxation and increases bladder capacity o approved for the treatment of urge incontinence due to hyperactive (overactive) bladder ▪ R/A: Oral Tocolytic Agents • relax pregnant uterus and suppress premature labor • Ritodrine, Terbutaline (ß2 agonist) Adrenergic drugs Adrenergic (Sympathomimetic) Drugs: Therapeutic applications • PRESSOR AGENTS: Norepinephrine, Dopamine • CARDIAC STIMULANTS: Epinephrine, Isoproterenol, Dobutamine • BRONCHODILATORS: Epinephrine, Isoproterenol, Albuterol Adrenergic (Sympathomimetic) Drugs: Therapeutic applications • NASAL DECONGESTANTS: Ephedrine, Pseudoephedrine, Phenylpropanolamine, Oxymetazoline, Xylometazoline • CNS STIMULANTS: Amphetamine, Ephedrine • UTERINE RELAXANTS: Isoxsuprine, Terbutaline, Ritodrine Questions? 90 Thanks! 91