Pharmacology Quiz

Autonomic Nervous System (ANS)

• The ANS is responsible for controlling involuntary actions, such as heart rate, blood pressure, and digestion
• It is divided into two branches: sympathetic (adrenergic) and parasympathetic (cholinergic)

Cholinergic Transmission

• Cholinergic transmission involves the release of acetylcholine (ACh) from the terminal end of a neuron, which then binds to cholinergic receptors on the postsynaptic neuron
• ACh can be broken down by acetylcholinesterase (AChE) into choline and acetate

Cholinergic Receptors

• There are two main types of cholinergic receptors: muscarinic (M) and nicotinic (N)
• Muscarinic receptors are further divided into M1, M2, and M3 subtypes, which are responsible for different physiological responses

Modifying Cholinergic Neurotransmission

• There are several ways to modify cholinergic neurotransmission, including:
  • Precursor transport blockade: hemicholinium
  • Choline acetyltransferase inhibition: no clinical example
  • Promote transmitter release: choline, black widow spider venom (latrotoxin)
  • Prevent transmitter release: botulinum toxin
  • Storage: vesamicol, prevents ACh storage
  • Cholinesterase inhibition: physostigmine, neostigmine

Adrenergic Transmission

• Adrenergic transmission involves the release of norepinephrine (NE) from the terminal end of a neuron, which then binds to adrenergic receptors on the postsynaptic neuron
• NE can be broken down by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)

Adrenergic Receptors

• There are two main types of adrenergic receptors: alpha (α) and beta (β)
• Alpha receptors are further divided into α1 and α2 subtypes, which are responsible for different physiological responses
• Beta receptors are further divided into β1, β2, and β3 subtypes, which are responsible for different physiological responses

Pharmacological Alteration of Adrenergic Function

• There are several ways to modify adrenergic function, including:
  • Precursor transport blockade: no clinical example
  • Tyrosine hydroxylase inhibition: metyrosine, used to treat pheochromocytoma
  • Dopa decarboxylase inhibition: carbidopa
  • Dopamine-β-hydroxylase inhibition: disulfiram
  • Monoamine oxidase inhibition: pargyline, tranylcypromine, selegiline
  • Storage: reserpine, prevents NE storage
  • Release: guanethidine, guanadrel cause initial release of NE leading to depletion of catecholamine; bretylium blocks NE release

Cholinergic Receptor Activation

• Cholinergic receptor activation can lead to various physiological responses, including:
  • Miosis (contraction of the pupil)
  • Accommodation for near vision (contraction of the ciliary muscle)
  • Decreased heart rate (negative chronotropy)
  • Decreased conduction velocity (negative dromotropy)
  • Bronchospasm (contraction of the bronchial smooth muscle)
  • Increased secretion (e.g. salivation, lacrimation)
  • Urinary incontinence (relaxation of the urinary sphincter)

Adrenergic Receptor Activation

• Adrenergic receptor activation can lead to various physiological responses, including:
  • Mydriasis (dilation of the pupil)
  • Vasoconstriction (contraction of the vascular smooth muscle)
  • Increased heart rate (positive chronotropy)
  • Increased conduction velocity (positive dromotropy)
  • Bronchodilation (relaxation of the bronchial smooth muscle)
  • Increased glycogenolysis (breakdown of glycogen to glucose)

Direct-Acting Cholinomimetics

• Direct-acting cholinomimetics bind to and activate muscarinic or nicotinic receptors
• Examples include:
  • Acetylcholine
  • Methacholine
  • Carbachol
  • Bethanechol

Indirect-Acting Cholinomimetics

• Indirect-acting cholinomimetics produce their primary effects by inhibiting acetylcholinesterase (AChE)
• Examples include:
  • Neostigmine
  • Physostigmine
  • Edrophonium

Clinical Applications

• Direct-acting cholinomimetics are used to treat:
  • Glaucoma
  • Reflux esophagitis
  • Peptic ulcer
  • Myasthenia gravis
• Indirect-acting cholinomimetics are used to treat:
  • Myasthenia gravis
  • Paralytic ileus
  • Atony of the urinary bladder
  • Alzheimer's disease

Toxicity

• Cholinesterase inhibitors can cause acute toxic effects, including:
  • Muscarinic excess (e.g. salivation, bronchial constriction, vomiting, diarrhea)
  • Nicotinic excess (e.g. muscle weakness, paralysis)
  • CNS effects (e.g. confusion, agitation, seizures)
• Treatment of acute toxicity involves:
  • Maintenance of vital signs
  • Decontamination
  • Atropine administration
  • Pralidoxime administration
  • Benzodiazepine administration for seizures### Antimuscarinic Agents
• Cause sedation and dry mouth
• Used to cause mydriasis and cycloplegia, preventing accommodation in the eye
• Examples: atropine, homatropine, cyclopentolate, and tropicamide
• Well absorbed from the conjunctival sac into the eye

Ophthalmology

• Antimuscarinic drugs used to dilate pupils and relax ciliary muscle
• Tropicamide: short-acting mydriatic with a duration of 0.5-4 hours

Respiratory Disorders

• Atropine and ipratropium used to reduce airway secretions during general anesthesia
• Ipratropium: quaternary antimuscarinic agent used by inhalation to promote bronchodilation in asthma and COPD
• Tiotropium: analog with a longer duration of action, used to treat COPD

Cardiovascular Disorders

• Atropine or similar antimuscarinic drug used to treat bradycardia due to depressed SA/AV node function
• Increases heart rate and cardiac output

Gastrointestinal Disorders

• Atropine, methscopolamine, and propantheline used in the past to reduce acid secretion in acid-peptic disease (now obsolete)
• Pirenzepine: selective M1 receptor antagonist, used to treat peptic ulcer
• Muscarinic blockers used to reduce cramping and hypermotility in transient diarrhea

Urinary Disorders

• Oxybutynin, tolterodine, or similar agents used to reduce urgency in mild cystitis and bladder spasms after urologic surgery
• Tolterodine, darifenacin, solifenacin, fesoterodine, and propiverine: slightly selective for M3 receptors, used to treat stress incontinence

Cholinergic Poisoning

• Atropine given parenterally in large doses to reduce muscarinic signs of poisoning with AChE inhibitors
• Pralidoxime used to regenerate active AChE

Toxicity

• Atropine toxicity causes "dry as a bone, blind as a bat, hot as a pistol, red as a beet, mad as a hatter" symptoms
• Treatment is usually symptomatic, with physostigmine used to manage severe tachycardia

Nicotinic Antagonists

• Ganglion-blocking drugs, such as hexamethonium, mecamylamine, and trimethaphan, used to treat hypertension
• Not used clinically due to multiple side effects
• Recent interest focused on nicotinic receptors in the CNS and their relation to nicotine addiction and Tourette's syndrome

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Adrenoceptors

• Classified as alpha, beta, or dopamine receptors
• Epinephrine is a single prototype agonist with effects at all alpha- and beta-receptor types
• Mechanism of action: direct activation of alpha, beta, or dopamine receptors, or indirect activation through release of stored catecholamines or inhibition of reuptake

Direct-Acting Sympathomimetics

• Phenylephrine: alpha1 agonist, used as a decongestant and to raise blood pressure
• Midodrine: alpha1 agonist, used to treat orthostatic hypotension
• Alpha2-selective agonists: decrease blood pressure through actions in the CNS, used to treat hypertension
• Oxymetazoline: direct-acting alpha agonist, used as a topical decongestant

Mixed-Acting Sympathomimetics

• Ephedrine: indirect-acting and direct-acting sympathomimetic, used to treat asthma and narcolepsy
• Pseudoephedrine: indirect-acting sympathomimetic, used as a decongestant

Indirect-Acting Sympathomimetics

• Amphetamines: displace stored catecholamine transmitter and inhibit reuptake of released transmitter
• Examples: amphetamine, methamphetamine, methylphenidate, and modafinil

Dopamine Agonists

• Used to treat Parkinson's disease, prolactinemia, and cardiogenic shock
• Examples: levodopa, fenoldopam, and dopamine

Clinical Uses

• Anaphylaxis: epinephrine is the drug of choice
• CNS: amphetamines and methylphenidate used to treat narcolepsy and ADHD
• Eyes: alpha agonists used to reduce conjunctival itching and congestion
• Bronchi: beta2-selective agonists used to treat asthma and COPD
• CVS: alpha agonists used to treat shock, beta agonists used to treat heart failure
• Genitourinary Tract: beta2 agonists used to suppress premature labor, alpha agonists used to treat enuresis

Alpha Adrenergic Blockers

• Phentolamine: non-selective alpha blocker, used to treat pheochromocytoma and hypertension
• Phenoxybenzamine: irreversible alpha blocker, used to treat pheochromocytoma
• Prazosin: selective alpha1 blocker, used to treat hypertension and BPH
• Terazosin: selective alpha1 blocker, used to treat hypertension and BPH
• Doxazosin: selective alpha1 blocker, used to treat hypertension and BPH
• Tamsulosin: selective alpha1A blocker, used to treat BPH

Other Alpha-Adrenergic Blockers

• Alfuzosin: selective alpha1 blocker, used to treat BPH

• Silodosin: selective alpha1A blocker, used to treat BPH

• Indoramin: selective alpha1 blocker, used to treat hypertension### Alpha-Adrenergic Blockers

• Urapidil is an α1 antagonist with weak α2-agonist and 5-HT1A-agonist actions, used in Europe as an antihypertensive agent and for BPH.

• Labetalol and carvedilol have both α1-selective and β-antagonistic effects.

• Chlorpromazine and Haloperidol are potent dopamine receptor antagonists, also antagonizing α receptors.

• Trazodone is an antidepressant that blocks α1 receptors.

• Ergot derivatives (e.g., ergotamine and dihydroergotamine) cause reversible α-receptor blockade, likely via a partial agonist action.

• Yohimbine is an α2-selective antagonist, used in treating orthostatic hypotension by promoting NE release through blockade of α2 receptors in the CNS and periphery.

Clinical Uses of Alpha-Adrenergic Blockers

• Pheochromocytoma: a tumor of the adrenal medulla or sympathetic ganglion cells, secreting catecholamines, especially norepinephrine and epinephrine.
• Hypertensive Emergencies: labetalol is commonly used.
• Chronic Hypertension: prazosin family of α1-selective antagonists are efficacious in treating mild to moderate systemic hypertension.
• Peripheral Vascular Disease: alpha-receptor blockers are not effective; calcium channel blockers are preferred.
• Urinary Obstruction: benign prostatic hyperplasia (BPH) is common in elderly men; surgical treatments are effective in relieving urinary symptoms, and drug therapy (prazosin, doxazosin, and terazosin) is efficacious in many patients.
• Erectile Dysfunction: yohimbine was previously used but abandoned; sildenafil and other cGMP phosphodiesterase inhibitors are the drugs of choice.

Beta Adrenoreceptor Blockers

Effects on the Cardiovascular System

• Beta-blocking drugs given chronically lower blood pressure in patients with hypertension.
• Inhibition of β2-mediated vasodilation and renin release via β1 blockade.

Effects on the Respiratory System

• Increase in airway resistance via blockade of β2 receptors.

Effects on the Eye

• Reduce intraocular pressure and decrease aqueous humor production.

Metabolic and Endocrine Effects

• Inhibit sympathetic nervous system stimulation of lipolysis and glycogenolysis.

Effects Not Related to Beta-Blockade

• Prevent precipitation of asthma and excessive bradycardia; have membrane-stabilizing effects.

Clinical Pharmacology

• Hypertension: beta blockers are not as effective as other drug classes in preventing stroke or cardiovascular events in hypertension; used in combination with other drugs if the patient has coronary artery disease or a history of MI.
• Ischemic Heart Disease: reduce the frequency of anginal episodes, improve exercise tolerance, and prolong survival in patients with myocardial infarction.
• Cardiac Arrhythmias: beta antagonists are often effective in treating both supraventricular and ventricular arrhythmias.
• Heart Failure: metoprolol, bisoprolol, and carvedilol are effective in reducing mortality in selected patients with chronic heart failure.
• Other Cardiovascular Disorders: increase stroke volume in some patients with obstructive cardiomyopathy.
• Glaucoma: timolol and related β antagonists are suitable for local use in the eye because they lack local anesthetic properties.
• Hyperthyroidism: beta blockers block adrenoceptors, inhibiting peripheral conversion of thyroxine to triiodothyronine; propranolol has been used extensively in patients with thyroid storm.
• Neurologic Diseases: propranolol reduces the frequency and intensity of migraine headache; other beta-receptor antagonists with preventive efficacy include metoprolol, atenolol, timolol, and nadolol.
• Neurologic Diseases: propranolol reduces tremors via sympathetic blockade; also used in the symptomatic treatment of anxiety and alcohol withdrawal.

Clinical Toxicity

• Bradycardia is the most common adverse cardiac effect of β-blocking drugs.
• CNS effects include mild sedation, vivid dreams, and rarely, depression.
• Major adverse effects relate to the predictable consequences of β blockade, including bradycardia, atrioventricular blockade, and heart failure.
• Patients with airway disease may suffer severe asthma attacks; beta blockers reduce insulin secretion and cause sexual dysfunction.