Adrenergic Agents and Norepinephrine Overview

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Questions and Answers

What is the primary mechanism by which α2 selective agonists reduce sympathetic outflow?

Direct vasodilation of blood vessels.

Stimulation of presynaptic alpha-2 adrenergic receptors. (correct)

Inhibition of presynaptic alpha-2 receptors.

Activation of postsynaptic alpha-1 receptors.

Which condition is NOT commonly treated with clonidine?

Heart failure (correct)

Hypertension

ADHD

Opioid withdrawal

Which of the following agents is known for entering the neuron and disrupting vesicular storage mechanisms?

Clonidine

Norepinephrine

Methyldopa

Amphetamine (correct)

What is a major side effect associated with α2 selective agonists?

Drowsiness/Sedation Signup and view all the answers

Which of the following best describes the clinical use of guanabenz?

Treatment of hypertension Signup and view all the answers

What is the effect of presynaptic α2 receptor stimulation on norepinephrine release?

It prevents norepinephrine release. Signup and view all the answers

Which of the following is an indirect sympathomimetic agent?

Amphetamine Signup and view all the answers

What role does NET (norepinephrine transporter) inhibition play in adrenergic drug action?

Enhances the release of norepinephrine into the synaptic cleft. Signup and view all the answers

Which drug is a synthetic direct acting β1-selective agonist used primarily for heart failure?

Dobutamine Signup and view all the answers

What is a common side effect of sympathomimetic drugs on the cardiovascular system?

Cardiac arrhythmia Signup and view all the answers

Which α1 sympathomimetic agent is used in the treatment of orthostatic hypotension?

Midodrine Signup and view all the answers

What effect does Phenoxybenzamine predominantly exert in the body?

Vasodilation Signup and view all the answers

Which of the following is a β-blocker that can exhibit intrinsic sympathomimetic activity?

Pindolol Signup and view all the answers

What is a key therapeutic use of Phenylephrine?

To induce mydriasis Signup and view all the answers

Which of the following does NOT act as a direct agonist on adrenergic receptors?

Atenolol Signup and view all the answers

Which statement regarding Dobutamine's metabolism is correct?

It is metabolized via oxidative deamination in the liver Signup and view all the answers

What is the main action of adrenergic neuron blockers?

Inhibit the synthesis and release of norepinephrine Signup and view all the answers

Which compound is formed as a false transmitter in the presence of α-methyl dopa?

Alpha-methyl NE Signup and view all the answers

What is the role of reserpine in the context of adrenergic agents?

Inhibits VMAT to deplete catecholamines Signup and view all the answers

Which of the following best describes the effect of α2 selective agonists?

Inhibit the release of norepinephrine Signup and view all the answers

Which of the following is an action of amphetamine-like agents?

Increase the release of catecholamines Signup and view all the answers

What is the primary clinical application of α-methyl dopa?

Treatment of hypertension Signup and view all the answers

How do NET inhibitors function within the adrenergic system?

Inhibit norepinephrine transport back into neurons Signup and view all the answers

Which compound is primarily released instead of norepinephrine due to false transmitter formation?

Alpha-methyl norepinephrine Signup and view all the answers

Study Notes

Adrenergic Agents: Agonists and Antagonists

Adrenergic agents are drugs that mimic or block the effects of the sympathetic nervous system. They work by affecting receptors in the body.

Synthesis of Norepinephrine

The rate-limiting step in norepinephrine synthesis is the hydroxylation of tyrosine.

Norepinephrine Uptake

Norepinephrine is actively transported into storage vesicles where it is protected from degradation.
Reserpine inhibits this transport.

Norepinephrine Release

Calcium influx triggers the release of norepinephrine from vesicles into the synaptic cleft.
Guanethidine and bretylium block this release.

Norepinephrine Metabolism

Norepinephrine is metabolized by enzymes like COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase).

Removal of Norepinephrine

Norepinephrine is rapidly taken back up into the presynaptic neuron.
Inhibitors like cocaine and imipramine block this reuptake.

Binding to Receptors

Norepinephrine binds to postsynaptic receptors, activating them.

Adrenergic Neuron Blockers

Form false transmitters (e.g., α-methyl dopa).
Deplete storage sites (e.g., reserpine).
Inhibit release and enhance uptake (e.g., guanethidine).
Stimulate presynaptic α2 receptors (e.g., clonidine, α-methyl dopa).

α2 Selective Agonists

Clonidine, methyldopa, guanabenz, and guanfacine are used for hypertension, opioid withdrawal, ADHD, and hot flashes.
Major side effects are drowsiness and sedation.
The indication/use is primarily hypertension.

Effects in Humans: Epinephrine, Norepinephrine, & Isoprenaline

IV infusions of epinephrine, norepinephrine, and isoprenaline show different effects on blood pressure, peripheral resistance, and heart rate.

Indirect Sympathomimetics -1

Amphetamine-like agents enter neurons.
Interact with VMAT2.
Promote neurotransmitter release increasing cytoplasmic neurotransmitter.
Used for ADHD (e.g. amphetamine, methamphetamine, methylphenidate, modafinil).

Indirect Sympathomimetics -2

Cocaine, Duloxetine, Atomexetine, Reboxetine inhibit neurotransmitter reuptake, increasing neurotransmitter concentrations.
Duloxetine and Atomexetine are antidepressants. Reboxetine is a norepinephrine reuptake inhibitor.

Clinical Use of Amphetamine-Like Drugs

ADHD (Methylphenidate, Dexamfetamine)
Narcolepsy (Amphetamine-like drugs to stimulate CNS, Dexamfetamine and Modafinil)
Suppress appetite (not currently used)

Amphetamine

Non-selective adrenergic agonist.
Acts mainly indirectly by enhancing norepinephrine (NE) and dopamine (DA) release
Lipid-soluble, absorbed from intestines, stimulating the CNS (e.g., restlessness, insomnia)
Half-life (t1/2) is 45-60 minutes.
Metabolized in the liver.

Amphetamines - Side Effects

Chronic use causes tolerance, tachyphylaxis, dependence, addiction, paranoia, psychosis, and hypertension.

Beta Receptors on Body Organs

Eyes: Beta receptors in the ciliary epithelium produce aqueous humor. Blocking receptors decreases humor production.
CVS: Beta 1 receptors in the heart increase heart rate with stimulation.
Pulmonary: Beta 2 receptors cause bronchodilation in bronchial smooth muscles.
Kidney: Promotes renin release, contributes to blood pressure regulation.

β1 and β2 – Adrenoceptor Agonists

Stimulation leads to increased cAMP levels, cellular effects, increased calcium release in the heart, and relaxation in smooth muscles.
Effects include increasing heart contractility and rate, relaxing smooth muscles.

Adrenoceptors (beta)

Beta 1 receptors, the site & stimulation effects are on heart
Beta 2 receptors, bronchodilation effects are in the bronchial smooth muscle
Beta 3 receptors are in adipose tissue & regulates metabolism

Clinical Effects of β-receptor Stimulation

β1 stimulation increases heart rate, myocardial contractility, lipolysis, and renin release.
β2 stimulation relaxes bronchi, smooth muscle of arterioles, skeletal muscles, and uterus.
β3 stimulation increases lipolysis and heat production.

β1 Selective Agonists & Antagonists

Dobutamine is a β1 selective agonist.
Atenolol, esmolol, metoprolol, and others are β1 selective antagonists used for hypertension, angina, and arrhythmias.

Beta 1 Adrenoreceptor Agonist: Dobutamine

Synthetic, direct-acting β1-selective agonist.
Short half-life (10-15 min)
Metabolized in the liver
Increases cardiac output (CO) with minimal effect on heart rate (HR).
Less arrhythmogenic than dopamine.
Used in heart failure and septic/cardiogenic shock.

Sympathomimetic Catecholamines

Endogenous catecholamines (norepinephrine, epinephrine, dopamine).
Synthetic catecholamines (isoprenaline). -a1 sympathomimetic agents (midodrine, phenylephrine).
Oxymetazoline.

Adrenoreceptor Agonists: Side Effects

Cardiovascular side effects of sympathomimetic drugs include hypertension, cardiac arrhythmias, myocardial infarction, and angina exacerbation.
Eyes: Increased Intraocular Pressure (IOP) leading to glaucoma.

Adrenoreceptor Antagonists

α-blockers (non-selective and selective)
β-blockers (non-selective, selective, and with intrinsic sympathomimetic activity (ISA)).

Alpha Blockers (non-selective)

Phenoxybenzamine (non-competitive, irreversible) and phentolamine (competitive, reversible) block α-adrenergic receptors, primarily affecting α1 receptors.
Uses include malignant hypertension, pheochromocytoma, and clonidine withdrawal.
Decreases heart workload, reducing risk of myocardial infarction.

Alpha 1 Selective Blockers

Alpha 1 blockers (prazosin, terazosin, doxazosin, tamsulosin) block alpha-1 receptors.
Uses include hypertension, benign prostatic hyperplasia (BPH), and Raynaud's phenomenon
Side effects include nasal congestion and hypotension.

Beta Blockers (β1 selective)

Atenolol, betaxolol, esmolol, metoprolol, bisoprolol, and nebivolol block β1-receptors.

Beta Blockers (non-selective)

Propranolol, timolol, nadolol, and pindolol block both beta 1 and 2 receptors.
Contraindicated in asthma patients due to potential bronchospasm.

Beta Blockers - Uses

Hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction, glaucoma, migraine, thyrotoxicosis, and essential tremors.

Beta Blockers with ISA

Acebutolol, PIndolol
Lower blood pressure while maintaining heart rate.

Alpha and Beta Antagonists

Labetalol and carvedilol block both alpha and beta receptors and are used to treat hypertension, particularly during pregnancy and in severe hypertension.

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Description

This quiz focuses on adrenergic agents, specifically their agonists and antagonists, and the synthesis, release, metabolism, and removal of norepinephrine. Test your knowledge on key concepts such as receptor binding and transport mechanisms involved in the sympathetic nervous system.