Topiramate is a new drug that has shown promise in the treatment of epilepsy. Since preliminary evaluation has been encouraging, double-blind, placebo-controlled trials were established in an effort to better define the effectiveness, safety and appropriate dose range of topiramate for refractory partial epilepsy. The objective of this study was to evaluate a medium-to-high dose range consisting of daily dosages of 600, 800, and 1,000 mg of topiramate.

A total of 190 patients with epilepsy, aged from 18 to 68, were enrolled in the study. Over 90% of the patients had a history of complex partial seizures, and over 60% also had secondary generalized seizures. Patients were randomly assigned to one of four groups: placebo (47 patients), 600 (48 patients), 800 (48 patients), or 1,000 (47 patients) mg topiramate (Topamax) per day.

During the 18-week treatment period, the rate of reduction in average monthly seizure rates was 1% for placebo, 41% for 600 mg/day and 800 mg/day topiramate, and 38% for 1,000 mg/day topiramate. Patients who experienced a 50% or greater reduction in the frequency of seizures included 9% of those in the placebo group, 44% in the 600 mg/day topiramate group, 40% in the 800 mg/day topiramate group, and 38% in the 1,000 mg/day topiramate group. While none of the patients in the placebo group experienced improvement of 75% to 100% in the frequency of seizures, 20% of the patients given topiramate were improved to this extent. Topiramate therapy was discontinued in 16% of patients because of side effects, the most common of which were dizziness, headache, fatigue and confusion.

The results of this study indicate that topiramate is highly effective and generally well tolerated in the treatment of refractory partial epilepsy. Dosages of topiramate greater than 600 mg/day do not appear to result in significantly greater effectiveness and may result in more side effects. However, individuals who are able to tolerate higher dosages may receive additional benefit. The investigators suggest that future studies should be aimed at better characterization of the adverse effects of topiramate. Evaluations of the safety and effectiveness of smaller doses and smaller dosage increments are also indicated.

1. Would topiramate be effective in the treatment of other forms of epilepsy, or only refractory partial epilepsy?

The primary studies that have been completed and were submitted to the U.S. FDA for approval were conducted in patients with refractory partial epilepsy. Open-label studies of this medication included patients who had other types of epilepsy and anecdotal experience suggests the drug may be effective in other seizure types. There are currently ongoing studies looking at other seizure types such as generalized epilepsies and the Lennox-Gastaut Syndrome. The Lennox-Gastaut syndrome is a severe form of epilepsy typically seen in childhood and is considered one of the most difficult epileptic syndromes to treat. Results of these studies may be presented at national meetings in the next year or two.

2. Is topiramate synthetic or derived from a natural substance? How was it discovered?

Topiramate is a synthetic compound developed by the Johnson & Johnson Pharmaceutical Research Institute. Its effectiveness in epilepsy was discovered through the collaborative program of the National Institutes for Health Epilepsy Branch. The Epilepsy Branch program allows corporations to submit compounds that might be effective in epilepsy to be evaluated in a series of animal tests and compared to standard antiepileptic drugs. This program has screened thousands of compounds over the last two decades. Topiramate was one of the compounds found to be highly effective in animal models and so was moved on to testing in humans with epilepsy.

3. Are there any trials planned to compare the efficacy and safety of topiramate with other similar drugs?

Most experts in the field feel that such trials are definitely necessary in order to compare the efficacy and tolerability of these medications. Unfortunately, these comparative trials require large numbers of patients, a tremendous effort to organize, and are extremely costly. It is my understanding that several companies have preliminary plans for such comparative trials. At the present time I am not involved in any of these trials and do not believe that any comparative trials are ongoing in the United States.

4. What is known about the long-term effects of topiramate (Topamax)?

In the database submitted to the FDA consisting of approximately 3,000 patients, there did not seem to be any consistent abnormalities of the function of the liver or bone marrow as seen with some other medications. Some patients at the University of Cincinnati Epilepsy Treatment Center have been on the medication for over eight years without significant problems.

5. Has its safety in children been evaluated?

Trials evaluating topiramate’s safety and effectiveness in children are currently underway. Preliminary data are encouraging; however, we must wait for the final results of these efficacy and safety trials in order to fully determine its role in the treatment of children.

Answer. My experience with valproate [Depakote] has been in adults, in which population it is very well-tolerated and rarely the cause of any significant cognitive problems; it can sometimes cause drowsiness, but this is usually mild and dose-related. You may be interested in a Swiss study by Despland [ref: Schweiz Rundsch Med Prax Oct 1994] that reviewed the literature on valproate use in epilepsy from 1976 to 1994 (the drug has been used in Switzerland since 1967). This author found valproate “to be a remarkably safe and effective antiepileptic drug…in children and adults.”

It is associated with fewer neurologic side effects than other major antiepileptic drugs, and “…had minimal impact on cognitive function and was associated with fewer cognitive and behavioral problems than phenytoin [Dilantin] and phenobarbital.”

Side effects of valproate can include weight gain, mild GI effects, tremor, and hair loss, but these may respond to dosage adjustment or other measures. Keep in mind, also, that seizures themselves often leave childen feeling helpless, scared, and “different” from other kids, so that the valproate may, indeed, be an important ally in your daughter’s quality of life. I would suggest, in any case, that you discuss the question of long-term effects on learning and creativity with your daughter’s physician.

Bottom line

• The problem of musculoskeletal pain is enormous and growing rapidly. Nonpharmacologic approaches are valuable but the pharmacologic armamentarium is extremely limited. After acetaminophen has been tried, the remaining medications are either narcotics or nonsteroidal anti-inflammatory drugs, each of which has its own potential problems.

• Topical capsaicin is effective for some patients and might be worth trying. Newer cyclooxygenase-2 inhibitor nonsteroidal agents have recently become available, but their effectiveness and long-term adverse effect profile remain unclear. Their cost is substantially higher than the cost of many older agents.

• Many patients continue to suffer with musculoskeletal pain despite use of currently available treatments. For them, we might be justified in trying topical NSAIDs after a thorough discussion of the potential advantages and adverse effects.

• Topical nonsteroidal anti-inflammatory drugs could play a much larger role in treatment of acute and chronic musculoskeletal disorders if long-term safety data were available and if they received Canadian approval for these indications.

What is the most likely diagnosis?

What is the most appropriate medication for this condition?

In addition to its therapeutic actions, what other effects might this medication produce?

Answers to case: Opioid overdose

Summary: An 18-year-old unresponsive man presents with pinpoint pupils, shallow respirations, and multiple intravenous track marks on his arms bilaterally.

Most likely diagnosis: Opioid overdose, likely heroin.

Most appropriate medication for this condition: Naloxone.

Additional effects this medication might produce: Symptoms of precipitated withdrawal that may include lacrimation, rhinorrhea, sweating, dilated pupils, diarrhea, abdominal cramping, and tremor.

Clinical correlation

Opioids are drugs with morphine-like activity that reduce pain and induce tolerance and physical dependence. Certain individuals seek the euphoria obtained from the intravenous injection of opioids such as heroin. There are three different cell receptors specific for opioids: mu, kappa, and delta (µ, k, δ), all of which exist as multiple subtypes. This patient has the classic signs of opioid overdose: somnolence, respiratory depression, and miosis. Stimulation of the mu receptor results in analgesia (supraspinal and spinal), respiratory depression, euphoria, and physical dependence. Continuous, heavy use of opioids can result in tolerance, where more drug is required to obtain the same euphoric “high,” and also to physical dependence. Naloxone, a competitive antagonist of opioids, is used to treat opioid overdose. Its intravenous administration leads to an almost immediate reversal of all effects of the opioids.

In individuals who are physically dependent, administration of naloxone will immediately precipitate opioid withdrawal, which consists of a constellation of signs and symptoms that include nausea and vomiting, muscle aches, lacrimation or rhinorrhea, diarrhea, fever, and dilated pupils. Likewise, when someone physically dependent on opioids ceases its administration there is a more slowly developing (hours or days) constellation of symptoms of opioid withdrawal that includes sensitivity to touch and light, goose flesh, auto-nomic hyperactivity, GI distress, joint and muscle aches, yawning, salivation, lacrimation, urination, defecation, and a depressed or anxious mood. In general, physical dependence induced by opioids with a short half-life tend to result in a rapid severe withdrawal, while physical dependence induced by opioids with a long half-life tends to be associated with a less severe and more gradual course of withdrawal. Although very uncomfortable, opioid withdrawal is generally not life-threatening.

The opioid methadone may be administered in a daily dose to individuals physically dependent on opioids, most notably heroin, as a “maintenance therapy” or to ameliorate the symptoms of opioid withdrawal.

Approach to pharmacology of the opioids

Objectives

1. Describe the mechanism of action of opioids as analgesics.

2. Explain how opioids reduce pain.

3. List the major opioid agonists and antagonists, their therapeutic uses, and their important pharmacokinetic properties.

4. Describe the adverse effects of opioids.

Definitions

Endogenous opioid peptides: Class of natural endogenous peptides that bind to human mu, delta, and kappa opioid receptors. Four classes of such peptides have been described: (1) the pentapeptide enkephalins (met and leu), (2) the endorphins (β-endorphin), (3) the dynorphins (A, B, C), all of which are proteolytically released from larger precursor molecules, and (4) the endomorphins. Together, they may modulate a number of important functions of the body (e.g., pain, reactions to stress and anxiety).

Fasciculation: Muscular twitching of contiguous groups of muscle fibers

Lacrimation: Secretion of tears from the eyes

Rhinorrhea: Mucous-like material that comes out of the nose

Continuation:

Opioid overdose: Class

Opioid overdose: Questions – Answers

[1] A 62-year-old woman is noted to have open-angle glaucoma. She inadvertently applies excessive pilocarpine to her eyes. This may result in which of the following?

A. Bronchial smooth muscle dilation

B. Decreased gastrointestinal motility

C. Dilation of blood vessels

D. Mydriasis

[2] Muscarinic cholinergic agonists

A. Activate inhibitory G-proteins (G_i)

B. Decrease production of IP₃

C. Decrease release of intracellular calcium

D. Inhibit the activity of phospholipase C

[3] Choline esters like carbachol are most likely to cause which of the following adverse effects?

A. Anhydrosis (dry skin)

B. Delirium

C. Salivation

D. Tachycardia (rapid heart rate)

Answers

[1] C. Excessive pilocarpine may initially result in dilation of blood vessels with a drop in blood pressure and a compensatory reflex stimulation of heart rate. Higher levels will directly inhibit the heart rate. In addition, pilocarpine stimulation of muscarinic cholinoreceptors can result in miosis, bronchial smooth muscle dilation, and increased GI motility.

[2] A. In addition to activating inhibitory G-proteins (G_i), muscarinic cholinergic agonists stimulate the activity of phospholipase C, increase production of IP₃, and increase release of intracellular calcium.

[3] C. Diarrhea, salivation, and lacrimation may be seen. The heart rate is usually slowed. Choline esters do not cross the blood-brain barrier, and therefore delirium is not an adverse effect.

Pharmacology pearls

Cholinoreceptors are classified as either nicotinic or muscarinic.

Muscarinic cholinoreceptors are localized at organs such as the heart, causing a negative chronotropic effect.

Stimulation of muscarinic receptors in the smooth muscle, exocrine glands, and vascular endothelium cause bronchoconstriction, increased acid secretion, and vasodilation.

Methacholine and bethanechol are highly selective for muscarinic cholinoreceptors.

Cholinomimetic agents, including anticholinesterase inhibitors, are precluded for treatment of gastrointestinal or urinary tract disease because of mechanical obstruction, where therapy can result in increased pressure and possible perforation. They are also not indicated for patients with asthma.

The ACh released from nerve endings of the parasympathetic nervous system interacts at specialized cell membrane components called cholinoreceptors that are classified as either nicotinic or muscarinic after the alkaloids initially used to distinguish them.

Nicotinic cholinoreceptors are localized at all postganglionic neurons (the autonomic ganglia), including the adrenal medulla, and skeletal muscle endplates innervated by somatic nerves. Muscarinic cholinoreceptors are localized at organs innervated by parasympathetic postganglionic nerve endings, for example, on cardiac atrial muscle, sinoatrial node cells, and atrioventricular node cells, where activation can cause a negative chronotropic effect and delayed atrioventricular conduction. Cholinergic stimulation of muscarinic receptors in the smooth muscle, exocrine glands, and vascular endothelium can cause, respectively, bronchoconstriction, increased acid secretion, and vasodilation (Table:Effects of cholinoreceptor activation).

Table: Effects of cholinoreceptor activation

* There is no parasympathetic innervation of blood vessels. However, they have cholinoreceptors that when activated result in their dilation.

There are two subtypes of the nicotinic cholinoreceptors: N_N, localized to postganglionic neurons, and N_M, localized to the skeletal muscle endplates. There are three pharmacologically important subtypes of the muscarinic cholinoreceptors, M₁, M₂, and M₃ (two additional subtypes have been identified by cloning), that alone or in combination are localized to sympathetic postganglionic neurons (and the CNS), to the atrial muscle, sinoatrial (SA) cells, and atrioventricular (AV) node of the heart, to smooth muscle, to exocrine glands, and to the vascular endothelium that does not receive parasympathetic innervation.

Directly and indirectly acting parasympathetic cholinomimetic agents, primarily pilocarpine and bethanechol, and neostigmine, are used most often therapeutically to treat certain diseases of the eye (acute angle-closure glaucoma), the urinary tract (urinary tract retention), the gastrointestinal tract (postoperative ileus), salivary glands (xerostomia), and the neuromuscular junction (myasthenia gravis). The ACh is generally not used clinically because of its numerous actions and very rapid hydrolysis by AChE and pseudocholinesterase.

The adverse effects of direct- and indirect-acting cholinomimetics result from cholinergic excess and may include diarrhea, salivation, sweating, bronchial constriction, vasodilation, and bradycardia. Nausea and vomiting are also common. Adverse effects of cholinesterase inhibitors (most often as a result of toxicity from pesticide exposure, e.g., organophosphates) also may include muscle weakness, convulsions, and respiratory failure.

Structure

ACh is a choline ester that is not very lipid soluble because of its charged quaternary ammonium group. It interacts with both muscarinic and nicotinic cholinoreceptors. Choline esters similar in structure to ACh that are used therapeutically include methacholine, carbachol, and bethanechol. Unlike ACh and carbachol, methacholine and bethanechol are highly selective for muscarinic cholinoreceptors. Pilocarpine is a tertiary amine alkaloid.

Mechanism of Action

Muscarinic cholinoreceptors activate inhibitory G-proteins (G_i) to stimulate the activity of phospholipase C, which, through increased phospholipid metabolism, results in production of inositol triphosphate (IP₃) and DAG that lead to the mobilization, respectively, of intracellular calcium from the endoplasmic and sarcoplasmic reticulum and, through activation of protein kinase C (PK-C), the opening of smooth muscle calcium channels with an influx of extracellular calcium. Activation of muscarinic cholinoreceptors also results in altered potassium flux that results in cell hyperpolarization, and in inhibition of adenylyl cyclase activity and cAMP accumulation induced by other hormones, including the catecholamines.

The nicotinic receptor functions as a cell membrane ligand-gated ion channel pore. On interaction with ACh, the receptor undergoes a conformational change that results in influx of sodium with membrane depolarization of the nerve cell or the skeletal muscle neuromuscular endplate.

Indirectly acting parasympathetic cholinomimetic agents inhibit AChE and thereby increase ACh levels at both muscarinic and nicotinic cholinoreceptors.

Administration

Directly acting muscarinic cholinomimetic agents may be administered topically as ophthalmic preparations (pilocarpine, carbachol), orally (bethanechol, pilocarpine), or parenterally (bethanechol). Depending on the agent, an indirectly acting cholinesterase inhibitor may be administered topically, orally, or parenterally.

Pharmacokinetics

ACh is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme choline acetyltransferase and then transported into nerve ending vesicles. Like ACh, methacholine, carbachol, and bethanechol are poorly absorbed by the oral route and have limited penetration into the CNS. Pilocarpine is more lipid soluble and can be absorbed and can penetrate the CNS.

After release from nerve endings, ACh is rapidly metabolized into choline and acetate, and its effects are terminated by the action of the enzymes AChE and pseudocholinesterase. Methacholine and particularly carbachol and bethanechol are resistant to the action of cholinesterases.

Continuation: Case: Muscarinic cholinomimetic agents. Questions – Answers

What is the action of pilocarpine on the muscles of the iris and cilia?

What receptor mediates this action?

Is pilocarpine the appropriate first-line drug for treatment of primary open-angle glaucoma?

Answers to case: Muscarinic cholinomimetic agents

Summary: A 61-year-old man with open-angle glaucoma is prescribed pilo-carpine ophthalmic drops.

Action of pilocarpine on muscles of the iris and cilia: Constriction of the muscles

Receptor that mediates this action: Muscarinic cholinoreceptor

First-line drugs to treat primary open-angle glaucoma: Prostaglandin analogs

Clinical correlation

Open-angle glaucoma is a disease caused by obstruction of the outflow of aqueous humor into the canal of Schlemm, causing an increase in intraocular pressure. The use of a direct-acting muscarinic agonist, such as pilocarpine, causes contraction of the muscles of the cilia and iris. Because these are circular muscles, the pupil is constricted, which helps to relieve the outflow obstruction and lower the intraocular pressure. Although not common with the use of topical ophthalmic drops, bronchospasm and pulmonary edema has been noted with the use of pilocarpine drops. More commonly, blurred vision and myopia (nearsightedness) occur as a result of the impairment of accommodation caused by the contraction of the iris and ciliary muscles.

The use of a direct-acting muscarinic agonist such as pilocarpine to treat open-angle glaucoma is now not common due to its numerous side effects, the need to administer it up to four times per day, and the availability of other agents. Prostaglandin analogs such as latanoprost are now considered first-line therapy for this condition followed by β-adrenoceptor agonists.

Approach to muscarinic cholinomimetic agents

Objectives

1. Be able to list the receptors of the parasympathetic nervous system.

2. Contrast the actions and effects of direct and indirect stimulation of muscarinic cholinoreceptors.

3. List the therapeutic uses of parasympathomimetic agents.

4. List the adverse effects of parasympathomimetic agents.

Definitions

Parasympathetic nervous system: An anatomic division of the autonomic nervous system (the other is the sympathetic nervous system) that originates in nuclei of the CNS. Preganglionic fibers exit through cranial and sacral spinal nerves to synapse via short postganglionic nerve fibers on ganglia, many of which are in the organs they innervate.

Cholinomimetic agents: Agents that mimic the action of ACh. These act directly or indirectly to activate cholinoreceptors. Some directly acting agents (pilocarpine, bethanechol, carbachol) are designed to act selectively on either muscarinic or nicotinic cholinoreceptors, whereas indirectly acting agents (such as neostigmine, physostigmine, edrophonium, demecarium), which inhibit the enzyme acetylcholinesterase (AChE) that is responsible for the inactivation of ACh, can activate both. Pilocarpine is a directly acting cholinomimetic agent that acts chiefly at muscarinic cholinoreceptors. Additional selectivity of pilocarpine and other cholinomimetics in the treatment of glaucoma is achieved by the use of an ophthalmic (topical) preparation.

Continuation: Case: Muscarinic cholinomimetic agents. Class

To what class of antiarrhythmic does lidocaine belong?

What is lidocaine’s mechanism of action?

Answers to case: Antiarrhythmic drugs

Summary: A 62-year-old man develops symptomatic ventricular tachycardia after an MI. He is begun on IV lidocaine.

Class of antiarrhythmic to which lidocaine belongs: Ib.

Mechanism of action: Specific Na⁺ channel blocker, reduces the rate of phase 0 depolarization, primarily in damaged tissue.

Clinical correlation

Lidocaine is a common treatment for ventricular tachycardia in a patient who is symptomatic and remains conscious. It works by blocking Na⁺ channels and is highly selective for damaged tissue. This makes it useful for the treatment of ventricular ectopy associated with an MI. It is administered as an IV bolus followed by a continuous drip infusion. It is metabolized in the liver and undergoes a large first-pass effect. It has many neurological side effects, including agitation, confusion, and tremors, and can precipitate seizures.

Approach to pharmacology of the antiarrhythmics

Objectives

1. Know the classes of antiarrhythmic agents and their mechanisms of action.

2. Know the indications for the use of antiarrhythmic agents.

3. Know the adverse effects and toxicities of the antiarrhythmic agents.

Definitions

Paroxysmal atrial tachycardias (PAT): Arrhythmia caused by reentry through the AV node.

Heart block: Failure of normal conduction from atria to ventricles.

WPW: Wolff-Parkinson-White syndrome.

Antiarrhythmic drugs: Class

Arrhythmias arise as a result of improper impulse generation or improper impulse conduction. The abnormal action potentials cause disturbances in the rate of contraction or in the coordination of myocardial contraction. The molecular targets of antiarrhythmics are ion channels in the myocardium or conduction pathways; these may be direct or indirect effects.

There are four ion channels of pharmacologic importance in the heart:

Voltage-activated Na⁺ channel — SCN5A

Voltage-activated Ca²⁺ channel — L-type

Voltage-activated K⁺ channel — IKr

Voltage-activated K⁺ channel — IKs

Most antiarrhythmic drugs either bind directly to sites within the pore of a channel or indirectly alter channel activity. There are approximately 20 antiar-rhythmics approved for use today. They are classified according to which of the ion channels they affect and their mechanism of action (Table Selected antiarrhythmic agents). The major arrhythmias of clinical concern are ventricular arrhythmias, atrial arrhythmias, bradycardias, and heart blocks. There is also the pharmacologic need to convert an abnormal rhythm to normal sinus rhythm (cardioconver-sion). The class of antiarrhythmics used for any particular arrhythmia depends on the clinical circumstances. The treatment of acute, life-threatening disease, in contrast with the long-term management of chronic disease, requires a different selection of antiarrhythmics.

Table: Selected antiarrhythmic agents

* Indirect effect mediated by decreasing cAMP.

** Moricizine blocks Na⁺ channels and is usually considered a class 1 antiarrhythmic, but it has properties of Ia, Ib, and Ic drugs.

*** Solotol has α- and β-adrenergic antagonist properties and also inhibits K⁺ channels.

Class I Antiarrhythmics

Class I antiarrhythmics bind to Na⁺ channels and prevent their activation. This increases their effective refractory period and decreases conduction velocity. Class I antiarrhythmics have a greater effect on damaged tissue compared to normal tissue. This may be because of several factors:

Depolarization. Damaged tissues tend to be depolarized because of K⁺ leakage — many class I antiarrhythmics preferentially bind to depolarized tissues.

pH. Ischemic tissues are more acidic, and many class I antiarrhythmics preferentially bind to membranes at low pH.

Inactivation frequency. During arrhythmias, Na⁺ channels undergo more rapid cycles of activation/inactivation. At any given time there will be an increase in the number of inactive channels compared to normal tissues in a normal rhythm. Class I antiarrhythmics generally bind preferentially to Na⁺ channels in the inactive state.

The subclasses a, b, and c of class I antiarrhythmics are distinguished based on their ability to inhibit K⁺ channels.

Class Ia. Procainamide is a prototype class la antiarrhythmic that suppresses the activity of Na⁺ and also suppresses K⁺-channel activity. Administered IV, it is used for the acute suppression of supraventricu-lar and ventricular arrhythmias and for suppressing episodes of atrial flutter and atrial fibrillation. It may be administered orally for the long-term suppression of both supraventricular and ventricular arrhythmia, but toxicity limits this application. Procainamide can suppress sinoatrial (SA) and AV nodal activity, especially in patients with nodal disease, and cause heart block. Prolonged use of procainamide is associated with increased risk of ventricular tachycardias. Procainamide has some ganglionic blocking activity and can cause hypotension and decreased myocardial contractility. A limiting adverse effect of procainamide is the development of lupus-like syndrome characterized by skin rash, arthritis, and serositis. All patients on procainamide will develop antinuclear antibodies within 2 years. Procainamide is metabolized to IV-acetyl procainamide (NAPA), which has K⁺-channel-blocking effects. NAPA is excreted by the kidney, and plasma levels of procainamide and NAPA should both be monitored especially in patients with renal disease.

Class Ib. Lidocaine is very specific for the Na⁺ channel and it blocks both activated and inactivated states of the channel. It must be administered parenterally. Lidocaine has been used extensively to suppress ventricular arrhythmias associated with acute MI or cardiac damage (surgery). It has been used prophylactically to prevent arrhythmias in patients with MI, but there is controversy as to the overall benefit in decreasing mortality. Lidocaine is metabolized in the liver and has relatively short half-life (60 minutes). This limits its adverse effects which generally are mild and rapidly reversible. Overdose can produce sedation, hallucinations, and convulsions.

Class Ic. Flecainide inhibits both Na⁺ and K⁺ channels but shows no preference for inactivated Na⁺ channels. It delays conduction and increases refractoriness. It is effective for the control of atrial arrhythmias and it is very effective in suppressing supraventricular arrhythmias. A recent large clinical trial with patients with ischemic heart disease demonstrated that flecainide is associated with increased mortality. Currently its use is restricted to patients with atrial arrhythmias without underlying ischemic heart disease.

Class II Agents

Endogenous catecholamines increase myocardial excitability and can trigger ventricular arrhythmias. β-Adrenergic receptor blockade indirectly suppresses L-type Ca²⁺-channel activity. This slows phase 3 repolarization and lengthens the refractory period. Reduction in sympathetic tone depresses automaticity, decreases AV conduction, and decreases heart rate and contractility. Beta blockers are useful for the long-term suppression of ventricular arrhythmias particularly in patients at risk for sudden cardiac arrest. Beta blockers are most effective in patients with increased adrenergic activity:

• Surgical or anesthetic stress.

• Anginal pain and MI.

• Congestive heart failure and ischemic heart disease.

• Hyperthyroidism.

• Beta blockers have been shown to reduce mortality and second cardiovascular events by 25-40% in patients with post-MI.

There are a large number of beta blockers approved for use as antiarrhythmics. Two of particular interest are

1. d,l-sotalol, which is particularly effective as an antiarrhythmic agent because it combines inhibition of K⁺ channels with beta-blocker activity

2. Metoprolol, a specific β₁ antagonist, which reduces the risk of pulmonary complications

d,l-sotalol is a racemic mixture; 1-sotalol is an effective, nonselective β-adrenergic antagonist; and d-sotalol is a class III antiarrhythmic that inhibits K⁺ channels. It is an oral agent with a long half-life (20 hours) that can maintain therapeutic blood levels with once a day dosing. d,l-sotalol is useful for the long-term suppression of ventricular arrhythmias, especially in patients at risk of sudden death. It is also used to suppress atrial flutter and fibrillation and paroxysmal atrial tachycardia. It is a valuable adjunct in the use of implantable cardiac defibrillators, decreasing the number of events that require defibrillation. At low doses, the P-adrenergic-blocking activity, and associated adverse effects, predominates. At higher doses, the K⁺-channel inhibitory effects predominate with the risk of developing ventricular tachycardia.

Class III Antiarrhythmics

Drugs in this class include bretylium, dofetilide, and amiodarone. These agents act predominantly to inhibit cardiac K⁺ channels (IKr). This lengthens the time to repolarize and prolongs the refractory period. Amiodarone is also a potent inhibitor of Na⁺ channels and has α- and β-adrenergic antagonist activity.

Amiodarone has an unusual structure related to thyroxine. It can be administered IV or orally, but its actions differ depending on route of administration. IV-administered amiodarone has acute effects to inhibit K⁺-channel activity, slowing repolarization, and increasing the refractory period of all myocardial cell types. Administered orally in a more chronic setting, it leads to long-term alterations in membrane properties with a reduction in both Na⁺-and K⁺-channel activity and decrease in adrenergic receptor activity. Amiodarone is used extensively for ventricular and atrial arrhythmias and has little myocardial depressant activity, allowing it to be used in patients with diminished cardiac function. Administered IV, amiodarone is effective in treating ventricular tachycardia and to prevent recurrent ventricular tachycardia, and to suppress atrial fibrillation. Oral amiodarone is useful for arrhythmias that have not responded to other drugs (such as adenosine) and for long-term suppression of arrhythmias in patients at risk of sudden cardiac death.

Amiodarone has little myocardial toxicity, does not impair contractility, and rarely induces arrhythmias. Most of the adverse effects of amiodarone result from its long half-life (13-103 days) and poor solubility. Amiodarone deposits in the lung and can cause irreversible pulmonary damage. Similarly, amiodarone can be deposited in the cornea causing visual disturbances or in the skin where it can cause a bluish tinge.

Class IV Antiarrhythmics

The class IV antiarrhythmics act by directly blocking the activity of L-type Ca²⁺ channels. Verapamil and diltiazem are the major members of this class, and they have a similar pharmacology. Verapamil blocks both active and inactive Ca²⁺ channels and has effects that are equipotent in cardiac and peripheral tissues. The dihydropyridines such as nifedipine have little effect on Ca²⁺ channels in the myocardium, but are effective in blocking Ca²⁺ channels in the vasculature. Verapamil has marked effects on both SA and AV nodes because these tissues are highly dependent on Ca²⁺ currents. AV node conduction and refractory period are prolonged and the SA node is slowed. Verapamil and diltiazem are useful for reentrant supraventricu-lar tachycardias and can also be used to reduce the ventricular rate in atrial flutter or fibrillation. The major adverse effect of verapamil is related to its inhibition of myocardial contractility. It can cause heart block at high doses.

Other Antiarrhythmics

Adenosine is a very short-acting drug (approximately 10 seconds) used specifically to block PAT. Adenosine binds to purinergic A1 receptors.

Activation of these receptors leads to increased potassium conductance and decreased in calcium influx. This results in hyperpolarization and a decrease in Ca²⁺-dependent action potentials. The effect in the AV node is marked with a decrease in conduction and an increase in nodal refractory period. Effects on the SA node are smaller. Adenosine is nearly 100 percent effective in converting PAT to sinus rhythm. Adenosine must be given IV, and because of its short half-life, it has few adverse effects. Flushing and chest pain are frequent but typically resolve quickly.

Digoxin blocks Na⁺-K⁺-ATPase and indirectly increases intracellular Ca²⁺. In the myocardium this causes an increase in contractility; in nerve tissue the predominant effect is to increase neurotransmitter release; and the parasympathetic system (vagus) is affected more than the sympathetic system. The increased vagal tone results in increased stimulation of mus-carinic acetylcholine receptors that slow conduction in the AV node. Digoxin is very effective controlling the ventricular response rate in patients with atrial fibrillation or flutter. Digoxin can be administered IV to acutely treat atrial arrhythmias or orally for long-term suppression of abnormal atrial rhythms. Digitalis is less effective than adenosine in PAT and should not be used in Wolff-Parkinson-White syndrome.

Atropine is a muscarinic antagonist that can be used in some brady-cardias and heart blocks. It can be administered to reverse heart block caused by increased vagal tone such as an MI or digitalis toxicity. Atropine is administered IV, and it exerts its effect within minutes.

Questions

[1] Which of the following is the most effective agent for converting paroxysmal atrial tachycardia to normal sinus rhythm?

A. Adenosine

B. Atropine

C. Digoxin

D. Lidocaine

[2] Which of the following best describes a pharmacologic property of amiodarone?

A. a-Adrenergic agonist

B. P-Adrenergic agonist

C. Activation of Ca²⁺ channels

D. Inhibition of K⁺ channels

[3] A 45-year-old man is noted to have dilated cardiomyopathy with atrial fibrillation and a rapid ventricular rate. An agent is used to control the ventricular rate, but the cardiac contractility is also affected, placing him in pulmonary edema. Which of the following agents was most likely used?

A. Amiodarone

B. Digoxin

C. Nifedipine

D. Verapamil

Answers

[1] A. Adenosine is nearly 100 percent effective in converting PAT. Digoxin could be used but is less effective.

[2] D. Amiodarone blocks both Na⁺ and K⁺ channels and has α- and β-adrenoreceptor antagonist activities. The latter would indirectly decrease Ca²⁺-channel activity.

[3] D. Verapamil is a calcium-channel-blocking agent that slows conduction in the AV node, but it also has a negative inotropic effect on the heart.

Pharmacology pearls

Amiodarone is typically the first choice in acute ventricular arrhythmias.

Adenosine is the best choice to convert PAT to sinus rhythm.

Long-term benefit of using class I antiarrhythmics is uncertain, but mortality is not decreased.

Beta blockers have been shown to reduce mortality and second cardiovascular events by 25-40% in patients post-MI.

Table: Drugs of abuse

Questions

[1] Alcohol is oxidized by which of the following enzymes?

A. Acetate oxidase

B. ADH

C. Aldehyde dehydrogenase

D. Monoamine oxidase

[2] Which of the following is the most common adverse effect resulting from chronic ethanol abuse?

A. Cirrhosis

B. Cutaneous vasodilation

C. Disinhibited j udgment

D. Respiratory depression

[3] Which of the following is a drug of abuse that blocks the dopamine uptake transporter?

A. Alcohol

B. Cocaine

C. Marijuana

D. Nicotine

Answers

[1] B. Alcohol is oxidized in the liver, stomach, and other organs to acetaldehyde by the cytosolic enzyme ADH and the hepatic microso-mal enzymes. Acetaldehyde is oxidized to acetate by mitochondrial hepatic aldehyde dehydrogenase.

[2] A. Liver cirrhosis is an effect of chronic alcohol use. Disinhibited judgment, respiratory depression, and cutaneous vasodilation are acute effects of alcohol.

[3] B. Cocaine is a drug of abuse that binds the dopamine reuptake transporter. Ethanol may nonspecifically disrupt cell membrane protein functions. Marijuana interacts with G-protein-coupled cannabinoid receptors. Nicotine mimics the action of acetylcholine.

Pharmacology pearls

Alcohol is the most widely used drug of abuse.

Delirium Tremens, a syndrome associated with the abrupt discontinuation of alcohol in a chronic abuser, carries a high mortality rate if not promptly identified and treated.

Withdrawal from other drugs of abuse may cause unpleasant symptoms for the patient, but is rarely life threatening.

In all hypotheses of addiction, increased concentrations of dopamine in the mesolimbic system is considered the neurochemical correlate of dependence and addiction.

What are the acute pharmacologic effects of ethanol?

What are the chronic pharmacologic effects of ethanol?

How is alcohol metabolized?

What is the pharmacologic basis for using benzodiazepines to manage alcohol withdrawal?

Answers to case: Drugs of abuse

Summary: A 50-year-old man is displaying symptoms and signs of acute alcohol withdrawal.

Symptoms of acute ethanol toxicity: Disinhibited behavior and judgment, slurred speech, impaired motor function, depressed and impaired mental function, respiratory depression, cutaneous vasodilation, diuresis, gastrointestinal side effects, and impaired myocardial contractility.

Symptoms of chronic ethanol toxicity: Alcoholic fatty liver, alcoholic hepatitis, cirrhosis, liver failure, peripheral neuropathy, alcohol amnesic syndrome, pancreatitis, gastritis, fetal alcohol syndrome, nutritional deficiencies, cardiomyopathy, cerebellar degeneration.

Metabolism of alcohol: Oxidized primarily in the liver but also in the stomach and other organs to acetaldehyde by the cytosolic enzyme alcohol dehydrogenase (ADH) and by hepatic microsomal enzymes; acetaldehyde is oxidized to acetate by hepatic mitochondrial aldehyde dehydrogenase.

Benzodiazepines in alcohol withdrawal: Both alcohol and the benzodiazepines enhance the effect of y-aminobutyric acid (GABA) on GABA_A neuroreceptors, resulting in decreased overall brain excitability. This cross-reactivity explains why relatively long-acting benzodiazepines (e.g., lorazepam, chlordiazepoxide) can be substituted for alcohol in a detoxification program.

Clinical correlation

Ethanol is the most widely used CNS depressant. It is rapidly absorbed from the stomach and small intestine and distributed in total body water. Its exact mechanism of action is not known, but may be related to its generally disruptive effects on cell membrane protein functions throughout the body, including effects on signaling pathways in the CNS. At low doses it is oxidized by cytoplasmic ADH. At higher doses it is also oxidized by liver microsomal enzymes, which may be induced by chronic use. These enzymes are rapidly saturated by the concentrations of alcohol achieved by even one or two alcoholic drinks so that its rate of metabolism becomes independent of plasma concentration. Tolerance to the intoxicating effects of alcohol can develop with chronic use. Cross-tolerance with barbiturates and benzodiazepines may also develop. Because of this cross-tolerance effect, benzodiazepines are the most commonly used agents for the treatment of alcohol withdrawal, a potentially life-threatening syndrome commonly seen 2-3 days after the abrupt cessation of alcohol use by a chronic abuser. A long-acting benzodiazepine can be taken, and gradually tapered, to mitigate this effect. Disulfiram is also used on occasion to manage alcoholism. It is a drug that inhibits aldehyde dehydrogenase that in the presence of alcohol causes an accumulation of acetaldehyde, which results in a highly aversive reaction consisting of flushing, severe headache, nausea and vomiting, and confusion. Naltrexone, an opioid antagonist, is yet another drug used to manage alcoholism.

Approach to pharmacology of ethanol

Objectives

1. Define drug abuse, drug tolerance, drug dependence, and drug addiction.

2. List the common drugs of abuse and their properties.

3. List the adverse effects of the common drugs of abuse.

Definitions

Drug abuse: Nonmedical use of a drug taken to alter consciousness or to change body image that is often regarded as unacceptable by society. Not to be confused with drug misuse.

Drug tolerance: Decreased response to a drug with its continued administration that can be overcome by increasing the dose. A cellular tolerance develops to certain drugs of abuse that act on the CNS because of a poorly understood biochemical or homeostatic adaptation of neurons to the continued presence of the drug. Also, in addition to a cellular tolerance, a metabolic tolerance can develop to the effects of some drugs because they increase the synthesis of enzymes responsible for their own metabolism (alcohol, barbiturates).

Drug dependence: Continued need of the user to take a drug. Psychologic dependence is the compulsive behavior of a user to continue to use a drug no matter the personal or medical consequences. Inability to obtain the drug activates a “craving” that is very discomforting. Physical or physiologic dependence is a consequence of drug abstinence after chronic drug use that results in a constellation of signs and symptoms that are often opposite to the initial effects of the drug and to those sought by the user. Psychologic dependence generally precedes physical dependence but, depending on the drug, does not necessarily lead to it. The development of physical dependence, the degree of which varies considerably for different drugs of abuse, is always associated with the development of tolerance, although the exact relationship is unclear.

Drug addiction: A poorly defined, imprecise term with little clinical significance that indicates the presence of psychologic and physical dependence.

Continuation: Drugs of abuse. Class