Adrenergic-drugs-Christian-James-B-Concepcion-RPh-CPS-PharmD
Chapter 9: Adrenoceptor Agonist & Sympathomimetic Drugs
Introduction
Effects of sympathetic stimulation mediated by release of NE from nerve terminals
Epinephrine acts as a hormone, NE acts as a neurotransmitter
Sympathomimetic Drugs
Grouped by mode of action and spectrum of receptors
Direct agonists: Norepinephrine and Epinephrine
Indirect agonists: enhance actions of endogenous catecholamines
Mechanisms of Indirect Agonists
Displace stored catecholamines from adrenergic nerve ending (tyramine)
Decrease clearance of released NE by inhibiting reuptake or preventing enzymatic metabolism
Adrenoceptor Types and Subtypes
Types: a, a2, B1, B2, B3, Dopamine
Agonists and antagonists for each subtype
Receptor Selectivity
Drugs may preferentially bind to one subgroup of receptors
Selectivity is not absolute and can interact with related classes of receptors at higher concentrations
Medical Chemistry of Sympathomimetic Drugs
Phenylethylamine is the parent compound
Substitutions can be made on the benzene ring, terminal amino group, and α & β carbons of the ethylamino chain
Substitution by -OH groups yields catecholamines
Absence of -OH groups increases bioavailability and distribution to the CNS
Size of alkyl substituents on the amino group increases β-receptor activity
Substitutions at the α carbon block oxidation by MAO and prolong drug action
Alpha-methyl compounds have resistance to oxidation by MAO and enhanced ability to displace catecholamines
Specific Sympathomimetic Drugs
Endogenous catecholamines: Epinephrine, Norepinephrine, Dopamine
Phenylephrine: longer duration of action, used as mydriatic and decongestant
Midodrine: selective α1-receptor agonist, indicated for orthostatic hypotension
Methoxamine: acts like phenylephrine, causes vasoconstriction and bradycardia
Direct-acting Sympathomimetics
Alpha2-selective agonists
Ability to decrease blood pressure through actions in the CNS
Direct application to a blood vessel may cause vasoconstriction
Examples: Clonidine, methyldopa, guanfacine, guanabenz
Dexmedetomidine
Sedation of initially intubated and mechanically ventilated patients in intensive care
Reduces requirements for opioids in pain control
Tizanidine
Used as a central muscle relaxant
Xylometazoline and oxymetazoline
Topical decongestants due to their ability to promote constriction of the nasal mucosa
Isoproterenol (Isoprenaline)
Very potent β-receptor agonist
Little effect on α receptors
Dobutamine
Increases cardiac output with less reflex tachycardia
Chemical structure resembles dopamine, but its actions are mediated mostly by activation of α and β receptors
Mixed acting Sympathomimetics
Ephedrine
First orally active sympathomimetic drug found in Ma huang
Popular herbal medication
Pseudoephedrine
Component of many decongestant mixtures
Phenylpropanolamine
Common component in OTC appetite suppressants
Removed from the market due to association with hemorrhagic strokes in young women
Can increase blood pressure in patients with impaired autonomic reflexes
Indirect-acting Sympathomimetics
Amphetamine-like
Enter the sympathetic nerve ending and displace stored catecholamine transmitter
Inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter (NET)
Examples: Amphetamine, methamphetamine, phenmetrazine, methylphenidate
Modafinil
Psychostimulant that differs from amphetamine
Used primarily to improve wakefulness in narcolepsy and other conditions
Tyramine
Byproduct of Tyrosine metabolism
Catecholamine Reuptake inhibitors
Atomoxetine
Selective inhibitor of the norepinephrine reuptake transporter
Used in the treatment of Attention Deficit Disorder
Reboxetine
Similar to atomoxetine
Sibutramine
Serotonin and norepinephrine reuptake inhibitor
Initially approved as an appetite suppressant for long-term treatment of obesity
Duloxetine
Widely used antidepressant with balanced serotonin and norepinephrine reuptake inhibitory effects
Increased cardiovascular risk has not been reported with duloxetine
Approved for treatment of pain in fibromyalgia
Cocaine
Local anesthetic with a peripheral sympathomimetic action
Inhibits dopamine reuptake into neurons in the CNS
Dopamine Agonist
Levodopa
Converted to dopamine in the body
Treatment of Parkinson's disease and prolactinemia
Fenoldopam
D1 receptor agonist that selectively leads to peripheral vasodilation in some vascular beds
Primary indication is in the treatment of severe hypertension
Therapeutic Uses
Treatment of Acute Hypotension
Chronic orthostatic hypotension
Cardiac stress test (Dobutamine injection)
Inducing local vasoconstriction
Pulmonary applications
Anaphylaxis
Ophthalmic applications
Genitourinary applications
CNS applications
Others: Tizanidine (muscle relaxant)
Adrenoceptor Antagonists Drugs
Introduction
Catecholamines play a role in many physiologic and pathophysiologic responses
Drugs that block their receptors have important effects
Effects vary according to the drug's selectivity for α and β receptors
Non-selective α antagonists
Used in the treatment of pheochromocytoma
Tumors that secrete catecholamines
α1-selective antagonists
Used in primary hypertension and benign prostatic hyperplasia
β-receptor antagonist drugs
Useful in a wide variety of clinical conditions
Established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, glaucoma, and other conditions
Pharmacology of the Alpha-Receptor Antagonist Drugs
Reversible antagonists dissociate from receptors and can be surmounted with high concentrations of agonists
Irreversible antagonists do not dissociate and cannot be surmounted
Specific Agents
Phenoxybenzamine
Binds covalently to α receptors, causing irreversible blockade
Inhibits reuptake of released norepinephrine
Used in the treatment of pheochromocytoma
Adverse effects: orthostatic hypotension, tachycardia, nasal stuffiness, inhibition of ejaculation
Phentolamine
Potent competitive antagonist at both α1 and α2 receptors
Used in pheochromocytoma
Sometimes used to reverse local anesthesia in soft tissue sites
Prazosin
Effective in the management of hypertension
Highly selective for α1 receptors
Relaxes both arterial and venous vascular smooth muscle
Extensively metabolized
50% of the drug is available after oral administration
Alpha-receptor blocking drugs
Terazosin
Reversible α1-selective antagonist
Effective in hypertension
Approved in men with urinary symptoms due to BPH
High bioavailability
Only a small fraction of unchanged drug excreted in the urine
Doxazosin
Treatment of hypertension and BPH
Long half-life compared to prazosin and terazosin
Tamsulosin
Competitive α1 antagonist
Higher affinity for α1A and α1D receptors
Effective in BPH by mediating prostate smooth muscle contraction
Alfuzosin
α1-selective quinazoline derivative approved for use in BPH
Increases risk of QT prolongation in susceptible individuals
Indoramin
α1-selective antagonist with antihypertensive efficacy
Urapidil
α1 antagonist with weak α2-agonist and 5-HT1A agonist actions
Weak antagonist action at β1 receptors
Used for hypertension and BPH
Labetalol
Has both α1-selective and β-antagonistic effects
Chlorpromazine and Haloperidol
Neuroleptic drugs that are potent dopamine receptor antagonists and antagonists at α receptors
Trazodone
Antidepressant with the capacity to block α1 receptors
Ergotamine & Dihydroergotamine
Ergot derivatives that cause reversible α-receptor blockade, possibly via a partial agonist action
Yohimbine
α2-selective antagonist
Used in the treatment of orthostatic hypotension by promoting norepinephrine release through blockade of α2 receptors
Clinical Pharmacology of Alpha-receptor blocking drugs
Pheochromocytoma
Tumor of the adrenal medulla or sympathetic ganglion cells
Phenoxybenzamine is used in the management of pheochromocytoma
Symptoms include intermittent or sustained hypertension, headache, palpitations, and increased sweating
Hypertensive emergencies
Limited application of α-adrenoceptor antagonist drugs
Labetalol has been used in this setting
Chronic Hypertension
Prazosin family of α1-selective antagonists are efficacious drugs in the treatment of mild to moderate systemic hypertension
Prazosin is associated with dizziness
Peripheral Vascular Disease
Prazosin or phenoxybenzamine may benefit individuals with Raynaud's phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation
Urinary Obstruction
Prazosin, Doxazosin, and Terazosin are efficacious in patients with BPH
Tamsulosin is also efficacious in BPH and has relatively minor effects on blood pressure at a low dose
Erectile dysfunction
Phentolamine combined with papaverine may cause erections in men with sexual dysfunction
Applications of Alpha2 Antagonists
Limited benefit in male erectile dysfunction
Potential use in the treatment of type 2 diabetes and psychiatric depression
Beta-Receptor Antagonist Drugs
Pharmacokinetic Properties
Peak concentrations occur 1-3 hours after ingestion
Propranolol undergoes extensive hepatic metabolism
Most β antagonists have half-lives in the range of 3-10 hours
Esmolol is rapidly hydrolyzed and has a half-life of approximately 10 minutes
Atenolol, Celiprolol, and Pindolol are less completely metabolized
Nadolol is excreted unchanged in the urine and has the longest half-life
Pharmacodynamics
Beta-blocking drugs lower blood pressure in patients with hypertension
Slowed atrioventricular conduction and increased PR interval
Antagonize the release of renin caused by the sympathetic nervous system
Fall in peripheral resistance in patients with hypertension
Effects on the Respiratory Tract
Blockade of β2 receptors in bronchial smooth muscle may increase airway resistance, particularly in patients with asthma
β1-receptor antagonists such as metoprolol and atenolol may have some advantage over nonselective β antagonists when blockade of β1 receptors in the heart is desired
Effects on the Eye
Reduce intraocular pressure, especially in glaucoma
Pharmacokinetic Properties of Beta-Receptor Antagonists (Page 69)
Chronic use of β-adrenoceptor antagonists is associated with:
Increased plasma concentrations of very-low-density lipoproteins (VLDL)
Decreased concentrations of HDL cholesterol
LDL cholesterol concentrations generally do not change
There is a variable decline in the HDL cholesterol/LDL cholesterol ratio, increasing the risk of coronary artery disease
β blockers with intrinsic sympathomimetic activity (partial agonists) are less likely to cause these effects
Pharmacodynamics of Beta-Receptor Antagonists (Page 70)
Sotalol is a nonselective Beta receptor antagonist
It lacks local anesthetic action
It has marked class III antiarrhythmic effects due to potassium channel blockade
Specific Agents (Page 71)
Propranolol is the prototypical β-blocking drug
Metoprolol and Atenolol are members of the β1-selective group
They are safer for patients who experience bronchoconstriction in response to propranolol
Nebivolol is the most highly selective β1-adrenergic receptor blocker
It elicits vasodilation and increases insulin sensitivity
Specific Agents (Page 72)
Nadolol has a very long duration of action
Timolol has no local anesthetic activity
It has excellent ocular hypotensive effects
Levobunolol and Betaxolol are used for topical ophthalmic application in glaucoma
Carteolol is a nonselective β-receptor antagonist
Specific Agents (Page 73)
Pindolol, Acebutolol, Carteolol, Bopindolol, Oxprenolol, Celiprolol, and Penbutolol have partial β agonist activity
They are effective in treating hypertension (HTN) and angina
Labetalol is available as a racemic mixture
The (S,R)-isomer is a potent α blocker
The (R,R)-isomer is a potent β blocker
Specific Agents (Page 74)
Esmolol is an ultra-short acting β-receptor antagonist
Butoxamine is a research drug selective for β2 receptors
Clinical Pharmacology of Beta-Receptor-Blocking Drugs (Page 75)
Beta-receptor-blocking drugs are used in the treatment of:
Hypertension
Ischemic Heart Disease
Long-term use of Timolol, Propranolol, and Metoprolol in patients with MI prolongs survival
Cardiac Arrhythmias
Heart failure
Metoprolol, Bisoprolol, and Carvedilol are effective in reducing mortality in selected patients with chronic heart failure
Clinical Pharmacology of Beta-Receptor-Blocking Drugs (Page 76)
Beta-receptor-blocking drugs are used in the treatment of glaucoma
Timolol is suitable for local use in the eye because it lacks local anesthetic properties
Betaxolol, Carteolol, Levobunolol, and Metipranolol are approved for the treatment of glaucoma
Clinical Pharmacology of Beta-Receptor-Blocking Drugs (Page 77)
Propranolol is used in the treatment of:
Hyperthyroidism, particularly in patients with thyroid storm
Neurologic Diseases
It reduces the frequency and intensity of migraine headaches
It reduces certain tremors (e.g., performance anxiety) and alcohol withdrawal symptoms