Adrenergic Agents and Norepinephrine Overview

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.

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.