SUMMARY Drugs Used For Cholinomimetic Effects

122 SECTION II Autonomic Drugs
SUMMARY Drugs Used for Cholinomimetic Effects

Clinical Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Applications Interactions
DIRECT-ACTING CHOLINE ESTERS

Muscarinic agonist Activates M1, M2, and M3 Postoperative and
receptors in all peripheral neurogenic ileus and Toxicity:
nicotinic receptors urinary retention Excessive parasympathomimetic effects,
secretion, smooth muscle especially bronchospasm in asthmatics
contraction (except vascular Interactions: Additive with other
smooth muscle relaxes), parasympathomimetics
and changes in heart rate
Carbachol: Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol; used topically almost exclusively for glaucoma
DIRECT-ACTING MUSCARINIC ALKALOIDS OR SYNTHETICS

Like bethanechol, partial Like bethanechol Glaucoma; Sjögren’s Toxicity & interactions:
agonist syndrome Like bethanechol
Cevimeline: Synthetic M3-selective; similar to pilocarpine
DIRECT-ACTING NICOTINIC AGONISTS

Agonist at both NN and Activates autonomic Medical use in smoking Toxicity:
NM receptors postganglionic neurons Acutely increased gastrointestinal (GI) activity,
(both sympathetic and use in smoking and in
parasympathetic) and insecticides
skeletal muscle Interactions:
neuromuscular end plates Additive with CNS stimulants
NN receptors
Varenicline: Selective partial agonist at α4β2 nicotinic receptors; used exclusively for smoking cessation
SHORT-ACTING CHOLINESTERASE INHIBITOR (ALCOHOL)

Alcohol, binds briefly Amplifies all actions of ACh Diagnosis and acute
to active site of treatment of myasthenia Toxicity:
acetylcholinesterase activity and somatic gravis Interactions: Additive with
(AChE) and prevents neuromuscular parasympathomimetics
access of acetylcholine transmission
(ACh)
INTERMEDIATE-ACTING CHOLINESTERASE INHIBITORS (CARBAMATES)

Forms covalent bond with Like edrophonium, but Myasthenia gravis Oral and parenteral; quaternary amine, does not
AChE, but hydrolyzed and longer-acting Toxicity &
released neurogenic ileus and interactions: Like edrophonium
urinary retention
Pyridostigmine: Like neostigmine, but longer-acting (4–6 h); used in myasthenia

Physostigmine: Like neostigmine, but natural alkaloid tertiary amine; enters CNS
LONG-ACTING CHOLINESTERASE INHIBITORS (ORGANOPHOSPHATES)

Like neostigmine, but Like neostigmine, but Toxicity: Brow ache, uveitis, blurred
released more slowly longer-acting glaucoma vision
Malathion: Insecticide, relatively safe for mammals and birds because metabolized by other enzymes to inactive products; some medical use as ectoparasiticide
Parathion, others: Insecticide, dangerous for all animals; toxicity important because of agricultural use and exposure of farm workers (see text)
Sarin, others: “Nerve gas,” used exclusively in warfare and terrorism
CHAPTER 8 Cholinoceptor-Blocking Drugs 135
SUMMARY Drugs with Anticholinergic Actions

Mechanism Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Clinical Applications Interactions
MOTION SICKNESS DRUGS

Unknown mechanism in Reduces vertigo, Prevention of motion Transdermal patch used for motion sickness
CNS postoperative nausea sickness and postoperative Toxicity:
nausea and vomiting Tachycardia, blurred vision, xerostomia,
Interactions: With other
antimuscarinics
GASTROINTESTINAL DISORDERS
Competitive antagonism Reduces smooth muscle Irritable bowel syndrome, t½
at M3 receptors and secretory activity of minor diarrhea Toxicity:
gut Tachycardia, confusion, urinary retention,
Interactions:
With other antimuscarinics
Hyoscyamine: Longer duration of action
OPHTHALMOLOGY
Competitive antagonism Causes mydriasis and Retinal examination; Toxicity:
at all M receptors cycloplegia prevention of synechiae Increased intraocular pressure in closed-angle
after surgery Interactions: With other
antimuscarinics
Homatropine: Shorter duration of action (12–24 h) than atropine

Cyclopentolate: Shorter duration of action (3–6 h)
Tropicamide: Shortest duration of action (15–60 min)
RESPIRATORY (ASTHMA, COPD)

Competitive, nonselective Reduces or prevents Prevention and relief of Toxicity:
antagonist at M receptors bronchospasm acute episodes of Interactions: With other
bronchospasm antimuscarinics
Tiotropium, aclidinium, and umeclidinium: Longer duration of action; used once daily
URINARY
Slightly M3-selective Reduces detrusor smooth Urge incontinence; Toxicity:
muscarinic antagonist muscle tone, spasms postoperative spasms Tachycardia, constipation, increased intraocular
Interactions: With other antimuscarinics
Darifenacin, solifenacin, and tolterodine: Tertiary amines with somewhat greater selectivity for M3 receptors
Trospium: Quaternary amine with less CNS effect
CHOLINERGIC POISONING
Nonselective competitive Blocks muscarinic excess Mandatory antidote for Intravenous infusion until antimuscarinic
antagonist at all at exocrine glands, heart, severe cholinesterase
muscarinic receptors in smooth muscle inhibitor poisoning Toxicity: Insignificant as long as AChE
CNS and periphery inhibition continues
Very high affinity for Regenerates active AChE; Usual antidote for early- Toxicity: Can cause
phosphorus atom but can relieve skeletal stage (48 h) cholinesterase muscle weakness in overdose
does not enter CNS muscle end plate block inhibitor poisoning

AChE, acetylcholinesterase; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; IM, intramuscular.
170 SECTION II Autonomic Drugs
β antagonists in insulin-dependent diabetic patients who are sub- compared with that in diabetics receiving nonselective β-adrenoceptor
ject to frequent hypoglycemic reactions if alternative therapies are antagonists. There is considerable potential benefit from these drugs
available. Beta1-selective antagonists offer some advantage in these in diabetics after a myocardial infarction, so the balance of risk versus
patients, since the rate of recovery from hypoglycemia may be faster benefit must be evaluated in individual patients.
SUMMARY Sympathetic Antagonists

Pharmacokinetics,
Subclass, Drug Mechanism of Action Effects Clinical Applications Toxicities, Interactions
ALPHA-ADRENOCEPTOR ANTAGONISTS
Irreversibly blocks α1 and α2 Lowers blood pressure (BP)
catecholamine states Toxicity: Orthostatic
to baroreflex activation
Reversibly blocks α1 and α2 Blocks α-mediated Pheochromocytoma Half-life ~45 min after IV
vasoconstriction, lowers BP, injection
increases HR (baroreflex)
Block α1, but not α2 Lower BP Larger depressor effect with

hyperplasia first dose may cause
orthostatic hypotension
Slightly selective for α1A α1A blockade may relax Benign prostatic hyperplasia Orthostatic hypotension may
prostatic smooth muscle be less common with this
more than vascular smooth subtype
muscle
Blocks α2 Raises BP and HR Male erectile dysfunction May cause anxiety

central sympathetic activity
norepinephrine transporter is
release blocked
β > α1 block Lowers BP with limited HR Hypertension Toxicity:

carvedilol section increase Less tachycardia than other
below) α1 agents
BETA-ADRENOCEPTOR ANTAGONISTS
Block β1 and β2 Toxicity:
renin
(topical timolol)
Block β1 > β2 Toxicity:
asthma betaxolol)
1
Blocks β2 > β1 Increases peripheral No clinical indication Toxicity: Asthma provocation
resistance
β1, β2, with intrinsic Toxicity:

sympathomimetic (partial HR
agonist) effect of bradycardia
1
1
1
β > α1 block Heart failure Toxicity:

1
Fatigue
1
(see
labetalol above)
(continued)
CHAPTER 10 Adrenoceptor Antagonist Drugs 171
Pharmacokinetics,
β1 > β2 Very brief cardiac Rapid control of BP and
β blockade arrhythmias, thyrotoxicosis, Toxicity: Bradycardia
and myocardial ischemia
intraoperatively
TYROSINE HYDROXYLASE INHIBITOR

Blocks tyrosine hydroxylase Pheochromocytoma Toxicity: Extrapyramidal
extrapyramidal effects (due
dopamine, norepinephrine, to low dopamine in CNS)
and epinephrine
1
Not available in the USA.
P R E P A R A T I O N S A V A I L A B L E*
GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

ALPHA BLOCKERS Carvedilol Coreg
Alfuzosin Uroxatral Esmolol Brevibloc
Doxazosin Generic, Cardura Labetalol Generic, Normodyne, Trandate
Phenoxybenzamine Dibenzyline Levobunolol Betagan Liquifilm, others
Phentolamine Generic Metipranolol OptiPranolol
Prazosin Generic, Minipress Metoprolol Generic, Lopressor, Toprol
Silodosin Rapaflo Nadolol Generic, Corgard
Tamsulosin Flomax Nebivolol Bystolic
Terazosin Generic, Hytrin Penbutolol Levatol
Tolazoline Priscoline Pindolol Generic, Visken
BETA BLOCKERS Propranolol Generic, Inderal
Acebutolol Generic, Sectral Sotalol Generic, Betapace
Atenolol Generic, Tenormin Timolol
Betaxolol Oral Generic, Blocadren
Oral Kerlone Ophthalmic Generic, Timoptic
Ophthalmic Generic, Betoptic TYROSINE HYDROXYLASE INHIBITOR
Bisoprolol Generic, Zebeta Metyrosine Demser
Carteolol
Oral Cartrol
Ophthalmic Generic, Ocupress
∗
In the USA.
REFERENCES Blakely RD, DeFelice LJ: All aglow about presynaptic receptor regulation of
neurotransmitter transporters. Mol Pharmacol 2007;71:1206.
Ambrosio G et al: β-Blockade with nebivolol for prevention of acute ischaemic
Blaufarb I, Pfeifer TM, Frishman WH: Beta-blockers: Drug interactions of clinical
events in elderly patients with heart failure. Heart 2011;97:209.
significance. Drug Saf 1995;13:359.
Arnold AC et al: Combination ergotamine and caffeine improves seated blood
Boyer TD: Primary prophylaxis for variceal bleeding: Are we there yet? Gastroen-
pressure and presyncopal symptoms in autonomic failure. Front Physiol
terology 2005;128:1120.
2014;5:270.
Brantigan CO, Brantigan TA, Joseph N: Effect of beta blockade and beta stimula-
Ayers K et al: Differential effects of nebivolol and metoprolol on insulin sensitivity
tion on stage fright. Am J Med 1982;72:88.
and plasminogen activator inhibitor in the metabolic syndrome. Hyperten-
sion 2012;59:893. Bristow M: Antiadrenergic therapy of chronic heart failure: Surprises and new
opportunities. Circulation 2003;107:1100.
Bell CM et al: Association between tamsulosin and serious ophthalmic adverse
events in older men following cataract surgery. JAMA 2009;301:1991. Cleland JG: Beta-blockers for heart failure: Why, which, when, and where. Med
Clin North Am 2003;87:339.
Berruezo A, Brugada J: Beta blockers: Is the reduction of sudden death related to
pure electrophysiologic effects? Cardiovasc Drug Ther 2008;22:163. Eisenhofer G et al: Current progress and future challenges in the biochemical
diagnosis and treatment of pheochromocytomas and paragangliomas. Horm
Bird ST et al: Tamsulosin treatment for benign prostatic hyperplasia and risk
Metab Res 2008;40:329.
of severe hypotension in men aged 40-85 years in the United States: Risk
window analyses using between and within patient methodology. BMJ Ellison KE, Gandhi G: Optimising the use of beta-adrenoceptor antagonists in
2013;347:f6320. coronary artery disease. Drugs 2005;65:787.
CHAPTER 11 Antihypertensive Agents 191
and brain injury. Rather, blood pressure should be lowered by nitroprusside, nitroglycerin, labetalol, calcium channel blockers,
about 25%, maintaining diastolic blood pressure at no less than fenoldopam, and hydralazine. Esmolol is often used to manage
100–110 mm Hg. Subsequently, blood pressure can be reduced to intraoperative and postoperative hypertension. Diuretics such as
normal levels using oral medications over several weeks. The paren- furosemide are administered to prevent the volume expansion that
teral drugs used to treat hypertensive emergencies include sodium typically occurs during administration of powerful vasodilators.
SUMMARY Drugs Used in Hypertension

Pharmacokinetics,
DIURETICS
Block Na/Cl transporter in Reduce blood volume and Hypertension, mild heart
Hydrochlorothiazide, renal distal convoluted tubule poorly understood vascular failure
chlorthalidone effects
Block Na/K/2Cl transporter in Severe hypertension, heart See Chapter 15
Furosemide renal loop of Henle failure
Block aldosterone receptor in Increase Na and decrease K Aldosteronism, heart
eplerenone renal collecting tubule failure, hypertension
reduction in heart failure
mortality
SYMPATHOPLEGICS, CENTRALLY ACTING

Activate α2 adrenoceptors Reduce central sympathetic
methyldopa also used in withdrawal Toxicity:
release from noradrenergic from abused drugs hemolytic anemia
nerve endings
SYMPATHETIC NERVE TERMINAL BLOCKERS

Blocks vesicular amine Reduces all sympathetic effects, Hypertension but rarely
transporter in noradrenergic especially cardiovascular, and used Toxicity: psychiatric depression,
nerves and depletes reduce blood pressure gastrointestinal disturbances
transmitter stores
Interferes with amine release Same as reserpine Same as reserpine Severe orthostatic
guanadrel and replaces norepinephrine
in vesicles
limited
` BLOCKERS
Selectively block α1 Prevent sympathetic Toxicity: Orthostatic
adrenoceptors prostatic hyperplasia hypotension
prostatic smooth muscle tone
a BLOCKERS
Block β1 receptors; carvedilol Prevent sympathetic cardiac See Chapter 10
also blocks α receptors;
nebivolol also releases nitric secretion
oxide
Propranolol: Nonselective prototype β blocker
Metoprolol and atenolol: Very widely used β1-selective blockers
VASODILATORS
Nonselective block of L-type Reduce cardiac rate and output Hypertension, angina, See Chapter 12
calcium channels arrhythmias
Block vascular calcium Reduce vascular resistance Hypertension, angina See Chapter 12
amlodipine, other channels > cardiac calcium
dihydropyridines channels
Causes nitric oxide release Toxicity: Angina,
Metabolite opens K channels also used to treat hair loss
in vascular smooth muscle
tachycardia Minoxidil: Hypertrichosis
(continued)
192 SECTION III Cardiovascular-Renal Drugs
Pharmacokinetics,
PARENTERAL AGENTS
Releases nitric oxide Powerful vasodilation Hypertensive emergencies
Activates D1 receptors Toxicity: Excessive
Opens K channels in hypoglycemia hypotension, shock
α, β blocker
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

Inhibit angiotensin-converting Reduce angiotensin II levels Toxicity: Cough,
others enzyme diabetes
bradykinin
ANGIOTENSIN RECEPTOR BLOCKERS (ARBS)

Block AT1 angiotensin Same as ACE inhibitors but no Toxicity: Same as ACE
others receptors increase in bradykinin inhibitors but less cough
RENIN INHIBITOR
Inhibits enzyme activity Reduces angiotensin I and II and Hypertension Toxicity: Hyperkalemia,
of renin aldosterone
teratogen
REFERENCES Mente A et al: Associations of urinary sodium excretion with cardiovascular events
in individuals with and without hypertension: A pooled analysis of data from
Appel LJ et al: Intensive blood-pressure control in hypertensive chronic kidney four studies. Lancet 2016;388:465.
disease. N Engl J Med 2010;363:918.
Nwankwo T et al: Hypertension among adults in the United States: National
Arguedas JA, Leiva V, Wright JM: Blood pressure targets for hyperten- Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief
sion in people with diabetes mellitus. Cochrane Database Syst Rev 2013;133:1.
2013;10:CD008277.
Olde Engberink RH et al: Effects of thiazide-type and thiazide-like diuretics on
Aronow WS et al: ACCF/AHA 2011 expert consensus document on hypertension cardiovascular events and mortality: Systematic review and meta-analysis.
in the elderly: A report of the American College of Cardiology Founda- Hypertension 2015;65:1033.
tion Task Force on Clinical Expert Consensus Documents. Circulation
Rossignol P et al: The double challenge of resistant hypertension and chronic
2011;123:2434.
kidney disease. Lancet 2015;386:1588.
Calhoun DA et al: Resistant hypertension: diagnosis, evaluation, and treatment:
Roush GC, Sica DA: Diuretics for hypertension: A review and update. Am J
A scientific statement from the American Heart Association Professional
Hypertens 2016;29:1130.
Education Committee of the Council for High Blood Pressure Research.
Circulation 2008;117:e510. Sacks FM, Campos H: Dietary therapy in hypertension. N Engl J Med 2010;362:2102.
Diao D et al: Pharmacotherapy for mild hypertension. Cochrane Database Syst Sharma P et al: Angiotensin-converting enzyme inhibitors and angiotensin recep-
Rev 2012;8:CD006742. tor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney
disease. Cochrane Database Syst Rev 2011;10:CD007751.
Ettehad D et al: Blood pressure lowering for prevention of cardiovascular
disease and death: A systematic review and meta-analysis. Lancet SPRINT Research Group: A randomized trial of intensive versus standard blood-
2016;387:957. pressure control. N Engl J Med 2015;373:2103.
James PA et al: 2014 evidence-based guideline for the management of high blood Thompson AM et al: Antihypertensive treatment and secondary prevention of
pressure in adults: Report from the panel members appointed to the Eighth cardiovascular disease events among persons without hypertension: A meta-
Joint National Committee (JNC 8). JAMA 2014;311:507. analysis. JAMA 2011;305:913.
Krause T et al: Management of hypertension: Summary of NICE guidance. BMJ Weber MA et al: Clinical practice guidelines for the management of hypertension
2011;343:d4891. in the community a statement by the American Society of Hypertension and
the International Society of Hypertension. J Hypertens 2014;32:3.
Lv J et al: Antihypertensive agents for preventing diabetic kidney disease. Cochrane
Database Syst Rev 2012;12:CD004136. Whelton PK et al: Sodium, blood pressure, and cardiovascular disease: Further
evidence supporting the American Heart Association sodium reduction
Mancia GF et al: 2013 practice guidelines for the management of arterial hyper-
recommendations. Circulation 2012;126:2880.
tension of the European Society of Hypertension (ESH) and the European
Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Williamson JD et al: Intensive vs standard blood pressure control and cardiovascu-
Arterial Hypertension. J Hypertens 2013;31:1925. lar disease outcomes in adults aged >/=75 years: A randomized clinical trial.
JAMA 2016;315:2673.
Margolis KL et al: Effect of home blood pressure telemonitoring and pharmacist
management on blood pressure control: A cluster randomized clinical trial. Wiysonge CS, Opie LH: Beta-blockers as initial therapy for hypertension. JAMA
JAMA 2013;310:46. 2013;310:1851.
Marik PE, Varon J: Hypertensive crises: Challenges and management. Chest Xie X et al: Effects of intensive blood pressure lowering on cardiovascular and renal
2007;131:1949. outcomes: Updated systematic review and meta-analysis. Lancet 2016;387:435.
pulmonary capillary wedge pressure are particularly useful in patients Vasodilators in use in patients with acute decompensation include
with acute myocardial infarction and acute heart failure. Patients nitroprusside, nitroglycerine, and nesiritide. Reduction in after-
with acute myocardial infarction are often treated with emergency load often improves ejection fraction, but improved survival has
revascularization using either coronary angioplasty and a stent, or a not been documented. A small subset of patients in acute heart
thrombolytic agent. Even with revascularization, acute failure may failure will have dilutional hyponatremia, presumably due to
develop in such patients. increased vasopressin activity. A V1a and V2 receptor antagonist,
Intravenous treatment is the rule in drug therapy of acute conivaptan, is approved for parenteral treatment of euvolemic
heart failure. Among diuretics, furosemide is the most commonly hyponatremia. Some clinical trials have indicated that this drug
used. Dopamine or dobutamine are positive inotropic drugs with and related V2 antagonists (tolvaptan) may have a beneficial
prompt onset and short durations of action; they are most useful effect in some patients with acute heart failure and hyponatremia.
in patients with failure complicated by severe hypotension. Levo- However, vasopressin antagonists do not seem to reduce mortality.
simendan has been approved for use in acute failure in Europe, Clinical trials are under way with the myosin activator, omecamtiv
and noninferiority has been demonstrated against dobutamine. mecarbil.
SUMMARY Drugs Used in Heart Failure

Pharmacokinetics,
DIURETICS
Loop diuretic: Decreases NaCl Increased excretion of salt Acute and chronic heart
and KCl reabsorption in thick Toxicity: Hypovolemia,
ascending limb of the loop of preload and afterload hypokalemia, orthostatic
Henle in the nephron (see hypotension, ototoxicity,
Chapter 15) peripheral edema sulfonamide allergy
Decreases NaCl reabsorption in Same as furosemide, but

the distal convoluted tubule much less efficacious Toxicity: Hyponatremia,
hypokalemia, hyperglycemia,
shown to reduce mortality hyperuricemia, hyperlipidemia,
sulfonamide allergy
Three other loop diuretics: Bumetanide and torsemide similar to furosemide; ethacrynic acid not a sulfonamide
Many other thiazides: All basically similar to hydrochlorothiazide, differing only in pharmacokinetics
ALDOSTERONE ANTAGONISTS
Blocks cytoplasmic aldosterone Increased salt and water Chronic heart failure
receptors in collecting tubules Toxicity:
remodeling adrenal tumor) Hyperkalemia, antiandrogen
membrane effect actions
shown to reduce mortality
Eplerenone: Similar to spironolactone; more selective antimineralocorticoid effect; no significant antiandrogen action; has been shown to reduce mortality
ANGIOTENSIN ANTAGONISTS
Angiotensin-converting Arteriolar and venous Chronic heart failure
enzyme (ACE) inhibitors: formation by inhibiting in large doses so duration
conversion of AI to AII aldosterone secretion Toxicity: Cough,
shown to reduce mortality hyperkalemia, angioneurotic
Interactions: Additive
with other angiotensin
antagonists
Angiotensin receptor Antagonize AII effects at AT1 Like ACE inhibitors Toxicity:
blockers (ARBs): receptors patients intolerant to ACE Hyperkalemia; angioneurotic
Interactions: Additive
to reduce mortality with other angiotensin
antagonists
Enalapril, many other ACE inhibitors: Like captopril

Candesartan, valsartan, many other ARBs: Like losartan
(continued)
CHAPTER 13 Drugs Used in Heart Failure 225
Pharmacokinetics,
BETA BLOCKERS
Competitively blocks β1 Chronic heart failure: To slow Toxicity:
Bronchospasm, bradycardia,
understood other effects in moderate and severe heart atrioventricular block, acute
and interactions
Metoprolol, bisoprolol, nebivolol: Select group of b blockers that have been shown to reduce heart failure mortality
CARDIAC GLYCOSIDE
Na+/K+-ATPase inhibition results Increases cardiac contractility Chronic symptomatic heart
glycosides are used in reduced Ca2+ expulsion and Toxicity: Nausea,
outside the USA) increased Ca2+ stored in effect (slowed sinus heart rate,
sarcoplasmic reticulum slowed atrioventricular been shown to reduce arrhythmias
conduction) mortality but does reduce
rehospitalization
VASODILATORS
Venodilators: Releases nitric oxide (NO) Acute and chronic heart Toxicity:
preload and ventricular Postural hypotension,
(see Chapter 12) stretch
Interactions: Additive with other
vasodilators and synergistic
with phosphodiesterase type 5
inhibitors
Arteriolar dilators: Probably increases NO Reduces blood pressure Hydralazine plus nitrates may Toxicity:
synthesis in endothelium reduce mortality in African- Tachycardia, fluid retention,
(see Chapter 11) increased cardiac output Americans lupus-like syndrome
Combined arteriolar Releases NO spontaneously Marked vasodilation Acute cardiac

and venodilator: decompensation Toxicity: Excessive hypotension,
afterload thiocyanate and cyanide
(malignant hypertension) Interactions: Additive
with other vasodilators
BETA-ADRENOCEPTOR AGONISTS
Beta1-selective agonist Increases cardiac Acute decompensated
contractility, output heart failure Toxicity: Arrhythmias
Interactions: Additive with
other sympathomimetics
Dopamine receptor agonist Increases renal blood flow Acute decompensated heart
β and Toxicity: Arrhythmias
α adrenoceptors cardiac force and blood Interactions: Additive with
pressure sympathomimetics
BIPYRIDINES
Phosphodiesterase type 3 Vasodilator; lower peripheral Acute decompensated heart
increases mortality in Toxicity: Arrhythmias
breakdown increases cardiac chronic failure Interactions: Additive with
contractility other arrhythmogenic agents
NATRIURETIC PEPTIDE
Activates BNP receptors, Acute decompensated failure
increases cGMP Toxicity: Renal damage,
reduce mortality hypotension, may increase
mortality
NEPRILYSIN INHIBITOR
Inhibits neprilysin, thus Vasodilator
in combination with reducing breakdown of ANP reduces mortality and in combination with ARB
valsartan [ARNI]) and BNP; valsartan inhibits rehospitalizations Toxicity: Hypotension,
action of angiotensin on its angioedema
receptors
Relevant structural heart disease No or minimal heart disease including

ESC: Heart failure, CAD, valvular heart disease, LVH hypertension without LVH
ACCF/AHA/HRS: heart failure, CAD, valvular heart disease, LVH ESC: Includes LVH with preserved LV function
CCS only considers heart failure or LVEF < 35% CCS: Including CAD, LVH, and HFpEF
Heart failure Coronary artery Hypertension Paroxysmal Persistent

disease with LVH AF AF
Dronedarone Dronedarone ESC: Ablation possible Dronedarone

Sotalol Amiodarone as first-line therapy Flecainide
US: Only Amiodarone Propafenone
Sotalol
Catheter
ablation for AF
Amiodarone Catheter Amiodarone

Dofetilide ablation for AF
CCS: Sotalol when LVEF > 35%
FIGURE 14–11 Selection of rhythm control therapies depends on presence and nature of any underlying heart disease. Patients
may be divided into two broad categories: those with and those without underlying heart disease. Patient with heart failure, left ventricular
ejection fraction (LVEF) less than 35%, coronary artery disease (CAD), valvular heart disease, and left ventricular hypertrophy (LVH) fall into the
first category. The second category includes patients with mild LVH and with heart failure but a preserved ejection fraction (HFpEF). The
recommendations are based on the guidelines of the American College of Cardiology Foundation (ACCF), the American Heart Association
(AHA), the Heart Rhythm Society (HRS), and the Canadian Cardiology Society (CCS). AF, atrial fibrillation; ESC, European Society of Cardiology;
LV, left ventricle.
SUMMARY Antiarrhythmic Drugs

CLASS 1A
INa (primary) and IKr Slows conduction velocity and Most atrial and ventricular
(secondary) blockade metabolism to N-acetylprocainamide
potential duration and dissociates choice for most sustained (NAPA; see text) and renal elimination
from INa channel with intermediate ventricular arrhythmias
associated with acute Toxicity:
on sinoatrial (SA) and atrioventricular myocardial infarction
(AV) nodes produces reversible lupus-related
symptoms
Quinidine: Similar to procainamide but more toxic (cinchonism, torsades); rarely used in arrhythmias; see Chapter 52 for malaria
Disopyramide: Similar to procainamide but significant antimuscarinic effects; may precipitate heart failure; not commonly used
CLASS 1B
Sodium channel (INa) Blocks activated and inactivated Terminates ventricular
blockade tachycardias and prevents
not prolong and may shorten action ventricular fibrillation after Toxicity:
potential cardioversion Neurologic symptoms
Mexiletine: Orally active congener of lidocaine; used in ventricular arrhythmias, chronic pain syndromes
(continued)
CHAPTER 14 Agents Used in Cardiac Arrhythmias 251

CLASS 1C
Sodium channel (INa) Dissociates from channel with slow Supraventricular arrhythmias
blockade in patients with normal heart ∼ Toxicity: Proarrhythmic
potential duration
conditions (post-myocardial
infarction)
Propafenone: Orally active, weak β-blocking activity; supraventricular arrhythmias; hepatic metabolism
Moricizine: Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic. Withdrawn in USA.
CLASS 2
β-Adrenoceptor Direct membrane effects (sodium Atrial arrhythmias and
blockade channel block) and prolongation of prevention of recurrent Toxicity: Asthma, AV blockade, acute
infarction and sudden death Interactions: With other
node automaticity and AV nodal cardiac depressants and hypotensive
conduction velocity drugs
Esmolol: Short-acting, IV only; used for intraoperative and other acute arrhythmias
CLASS 3
Blocks IKr, INa, ICa-L Prolongs action potential duration Serious ventricular
channels, β arrhythmias and
adrenoceptors supraventricular Toxicity:
incidence of torsades de pointes arrhythmias Bradycardia and heart block in diseased
heart, peripheral vasodilation,
Interactions: Many,
based on CYP metabolism
IKr block Prolongs action potential, effective Maintenance or restoration Toxicity: Torsades
refractory period of sinus rhythm in atrial de pointes (initiate in hospital with
fibrillation Interactions: Additive with
other QT-prolonging drugs
Sotalol: β-Adrenergic and IKr blocker, direct action potential prolongation properties, use for ventricular arrhythmias, atrial fibrillation
Ibutilide: Potassium channel blocker, may activate inward current; IV use for conversion in atrial flutter and fibrillation
Dronedarone: Amiodarone derivative; multichannel actions, reduces mortality in patients with atrial fibrillation
Vernakalant: Investigational in the USA, multichannel actions in atria, prolongs atrial refractoriness, effective in atrial fibrillation
CLASS 4
Calcium channel Slows SA node automaticity and AV Supraventricular tachycardias,
(ICa-L type) blockade hypertension, angina Toxicity
& Interactions: See Chapter 12
pressure
Diltiazem: Equivalent to verapamil
MISCELLANEOUS
Activates inward Very brief, usually complete AV Paroxysmal supraventricular Toxicity:
rectifier IK Ca blockade tachycardias Flushing, chest tightness, dizziness
Interactions: Minimal
Normalizes or increases
interacts with Na+/K+- plasma Mg2+ induced arrhythmias Toxicity: Muscle weakness in overdose
ATPase, K+, and Ca2+
channels
Increases K+ Digitalis-induced arrhythmias Toxicity: Reentrant arrhythmias,

permeability, K+ conduction velocity in heart fibrillation or arrest in overdose
currents hypokalemia
296 SECTION IV Drugs with Important Actions on Smooth Muscle
cavity, and the endocardial tissue of the heart. These changes was sometimes used as a substitute for LSD by members of the
occurred insidiously over months and presented as hydronephro- so-called drug culture.
sis (from obstruction of the ureters) or a cardiac murmur (from Contraindications to the use of ergot derivatives consist of the
distortion of the valves of the heart). In some cases, valve damage obstructive vascular diseases, especially symptomatic coronary
required surgical replacement. As a result, this drug was with- artery disease, and collagen diseases.
drawn from the US market. Similar fibrotic change has resulted There is no evidence that ordinary use of ergotamine for
from the chronic use of non-ergot 5-HT agonists promoted in the migraine is hazardous in pregnancy. However, most clinicians
past for weight loss (fenfluramine, dexfenfluramine). counsel restraint in the use of the ergot derivatives by preg-
Other toxic effects of the ergot alkaloids include drowsi- nant patients. Use to deliberately cause abortion is contrain-
ness and, in the case of methysergide, occasional instances of dicated because the high doses required often cause dangerous
central stimulation and hallucinations. In fact, methysergide vasoconstriction.
SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot

Alkaloids
Mechanism Clinical Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Applications Interactions
H1 ANTIHISTAMINES
First generation:
Competitive Reduces or prevents histamine IgE immediate Toxicity:
antagonism/inverse effects on smooth muscle, allergies; especially Sedation when used in hay fever, muscarinic
agonism at H1 hay fever, urticaria blockade symptoms, orthostatic hypotension
receptors muscarinic and α adrenoceptors Interactions: Additive sedation with other
sedative, antiemetic,
and anti-motion CYP2D6, may prolong action of some β blockers
sickness drug
Second generation:
Competitive Reduces or prevents histamine IgE immediate Toxicity: Sedation and
antagonism/inverse effects on smooth muscle, allergies; especially Interactions: Minimal
agonism at H1 immune cells hay fever, urticaria
receptors
Other first-generation H1 blockers: Chlorpheniramine is a less sedating H1 blocker with fewer autonomic effects. Doxylamine, a strongly sedating H1 blocker, is available
over-the-counter in many sleep-aid formulations and in Diclegis (in combination with pyridoxine) for use in nausea and vomiting of pregnancy
Other second-generation H1 blockers: Loratadine, desloratadine, and fexofenadine are very similar to cetirizine
H2 ANTIHISTAMINES
SEROTONIN AGONISTS
5-HT1B/1D:
Partial agonist at Effects not fully understood Migraine and cluster Toxicity:
5-HT1B/1D receptors headache Paresthesias, dizziness, coronary
calcitonin gene-related peptide Interactions: Additive with
and perivascular edema in other vasoconstrictors
cerebral circulation
Other triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan): Similar to sumatriptan except for pharmacokinetics (2–6 h duration of action);
much more expensive than generic sumatriptan
5-HT2C:
Agonist at 5-HT2C Appears to reduce appetite Obesity Toxicity: Dizziness,
receptors headache, constipation
5-HT4:
(continued)
CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 297
Mechanism Clinical Pharmacokinetics, Toxicities,

Subclass, Drug of Action Effects Applications Interactions
SEROTONIN BLOCKERS
5-HT2:
Competitive Prevents vasoconstriction and Hypertension Toxicity: Hypotension
available in USA) blockade at 5-HT2 bronchospasm of carcinoid
receptors syndrome associated with
carcinoid tumor
5-HT3:
ERGOT ALKALOIDS
Vasoselective:
Mixed partial agonist Causes marked smooth muscle Migraine and cluster Toxicity:
effects at 5-HT2 and contraction but blocks headache Prolonged vasospasm causing angina,
α adrenoceptors α-agonist vasoconstriction gangrene; uterine spasm
Uteroselective:
Mixed partial agonist Postpartum bleeding
effects at 5-HT2 and selectivity for uterine smooth Toxicity: Same as ergotamine
α adrenoceptors muscle
CNS selective:
Central nervous Hallucinations Toxicity:
diethylamide system 5-HT2 and abused Prolonged psychotic state, flashbacks
dopamine agonist
2 antagonist in
periphery
Bromocriptine, pergolide: Ergot derivatives used in Parkinson’s disease (see Chapter 28) and prolactinoma (see Chapter 37). Pergolide used in equine
Cushing’s disease
P R E P A R A T I O N S A V A I L A B L E

ANTIHISTAMINES (H 1 BLOCKERS) * Fexofenadine Generic, Allegra
Azelastine Generic, Astelin (nasal), Optivar
Hydroxyzine Generic, Vistaril
(ophthalmic)
Ketotifen Generic, Zaditor
Brompheniramine Brovex, Dimetapp, others
Levocabastine Livostin
Buclizine Bucladin-S Softabs
Levocetirizine Generic, Xyzal
Carbinoxamine Generic, Histex
Loratadine Generic, Claritin
Cetirizine Generic, Zyrtec
Chlorpheniramine Generic, Chlor-Trimeton Meclizine Generic, Antivert, Bonine
Clemastine Generic, Tavist Olopatadine Patanol, Pataday
Cyclizine Generic, Marezine Phenindamine Nolahist
Cyproheptadine Generic, Periactin Promethazine Generic, Phenergan
Desloratadine Generic, Clarinex Triprolidine Generic, Zymine, Tripohist
Dimenhydrinate †
Generic, Dramamine H 2 BLOCKERS
Diphenhydramine Generic, Benadryl See Chapter 62.
Doxylamine Diclegis (combination with 5-HT AGONISTS

pyridoxine), Unisom Sleep Tabs Almotriptan Axert
Epinastine Generic, Elestat Eletriptan Relpax
(continued)
CHAPTER 22 Sedative-Hypnotic Drugs 393
of sedative-hypnotics. However, it should not be assumed that elimination. Cross-dependence, defined as the ability of one drug
the degree of tolerance achieved is identical for all pharmacologic to suppress abstinence symptoms from discontinuance of another
effects. There is evidence that the lethal dose range is not altered drug, is quite marked among sedative-hypnotics. This provides
significantly by the long-term use of sedative-hypnotics. Cross- the rationale for therapeutic regimens in the management of
tolerance between the different sedative-hypnotics, including withdrawal states: Longer-acting drugs such as chlordiazepoxide,
ethanol, can lead to an unsatisfactory therapeutic response when diazepam, and phenobarbital can be used to alleviate withdrawal
standard doses of a drug are used in a patient with a recent history symptoms of shorter-acting drugs, including ethanol.
of excessive use of these agents. However, there have been very few
reports of tolerance development when eszopiclone, zolpidem, or
zaleplon was used for less than 4 weeks. Drug Interactions
With the long-term use of sedative-hypnotics, especially if The most common drug interactions involving sedative-hypnotics
doses are increased, a state of physiologic dependence can occur. are interactions with other CNS depressant drugs, leading to addi-
This may develop to a degree unparalleled by any other drug tive effects. These interactions have some therapeutic usefulness
group, including the opioids. Withdrawal from a sedative-hypnotic when these drugs are used as adjuvants in anesthesia practice. How-
can have severe and life-threatening manifestations. Withdrawal ever, if not anticipated, such interactions can lead to serious conse-
symptoms range from restlessness, anxiety, weakness, and ortho- quences, including enhanced depression with concomitant use of
static hypotension to hyperactive reflexes and generalized seizures. many other drugs. Additive effects can be predicted with concomi-
Symptoms of withdrawal are usually more severe following discon- tant use of alcoholic beverages, opioid analgesics, anticonvulsants,
tinuance of sedative-hypnotics with shorter half-lives. However, and phenothiazines. Less obvious but just as important is enhanced
eszopiclone, zolpidem, and zaleplon appear to be exceptions to CNS depression with a variety of antihistamines, antihypertensive
this, because withdrawal symptoms are minimal following abrupt agents, and antidepressant drugs of the tricyclic class.
discontinuance of these newer short-acting agents. Symptoms Interactions involving changes in the activity of hepatic
are less pronounced with longer-acting drugs, which may partly drug-metabolizing enzyme systems have been discussed (see also
accomplish their own “tapered” withdrawal by virtue of their slow Chapters 4 and 66).
SUMMARY SEDATIVE-HYPNOTICS
Mechanism of Pharmacokinetics,
Subclass, Drug Action Effects Clinical Applications Toxicities, Interactions
BENZODIAZEPINES
Bind to specific GABAA Dose-dependent depressant Half-lives from 2–40 h (clorazepate longer)
receptor subunits at effects on the CNS including
central nervous sedation and relief of anxiety Toxicity: Extensions of
system (CNS) neuronal
synapses facilitating Interactions: Additive CNS
GABA-mediated respiratory depression depression with ethanol and many other
chloride ion channel disorders drugs
opening frequency
hyperpolarization
BENZODIAZEPINE ANTAGONIST
Antagonist at Blocks actions of Management of Toxicity: Agitation,
benzodiazepine- benzodiazepines and benzodiazepine overdose
binding sites on the zolpidem but not other in benzodiazepine dependence
GABAA receptor sedative-hypnotic drugs
BARBITURATES
Bind to specific GABAA Dose-dependent depressant Anesthesia (thiopental) Half-lives from 4–60 h (phenobarbital
receptor subunits at effects on the CNS including
CNS neuronal sedation and relief of anxiety phenobarbital 20% renal elimination
synapses facilitating (phenobarbital) Toxicity: Extensions of CNS depressant
GABA-mediated
chloride ion channel respiratory depression Interactions: Additive CNS
opening duration depression with ethanol and many other
relationship than
hyperpolarization benzodiazepines metabolizing enzymes
(continued)
394 SECTION V Drugs That Act in the Central Nervous System
NEWER HYPNOTICS
Bind selectively to a Rapid onset of hypnosis with Sleep disorders, especially
subgroup of GABAA few amnestic effects or day- those characterized by Toxicity: Extensions of CNS depressant
receptors, acting like after psychomotor difficulty in falling asleep
benzodiazepines to depression or somnolence Interactions: Additive CNS depression with
enhance membrane ethanol and many other drugs
hyperpolarization
MELATONIN RECEPTOR AGONISTS

Activates MT1 and MT2 Rapid onset of sleep with Sleep disorders, especially
receptors in minimal rebound insomnia or those characterized by Toxicity:
suprachiasmatic nuclei withdrawal symptoms difficulty in falling asleep Interactions:
in the CNS Fluvoxamine inhibits metabolism
1 and MT2 agonist, recently approved for non-24-hour sleep disorder
OREXIN ANTAGONIST
Blocks binding of Promotes sleep onset and Sleep disorders, especially CYP450 metabolism is inhibited by
orexins, duration those characterized by fluconazole, verapamil, and grapefruit juice
neuropeptides that difficulty in falling asleep
promote wakefulness impairment
5-HT-RECEPTOR AGONIST
Mechanism uncertain: Slow onset (1–2 weeks) of Generalized anxiety states
Partial agonist at 5-HT Toxicity:
receptors but affinity Interactions:
for D2 receptors also no additive CNS depression CYP3A4 inducers and inhibitors
possible with sedative-hypnotic drugs

BENZODIAZEPINES Pentobarbital Generic, Nembutal Sodium
Alprazolam Generic, Xanax Phenobarbital Generic, Luminal Sodium
Chlordiazepoxide Generic, Librium Secobarbital Generic, Seconal
Clonazepam Generic, Tranxene MISCELLANEOUS
Clorazepate Generic, Klonopin DRUGS
Diazepam Generic, Valium Buspirone Generic, BuSpar
Estazolam Generic, ProSom Chloral hydrate Generic, Aquachloral
Supprettes
Flurazepam Generic, Dalmane
Eszopiclone Lunesta
Lorazepam Generic, Ativan
Hydroxyzine Generic, Atarax,
Midazolam Generic, Versed
Vistaril
Oxazepam Generic, Serax
Meprobamate Generic, Equanil,
Quazepam Generic, Doral Miltown
Temazepam Generic, Restoril Paraldehyde Generic
Triazolam Generic, Halcion Ramelteon Rozerem
BENZODIAZEPINE ANTAGONIST Suvorexant Belsomra
Flumazenil Generic, Romazicon Tasimelteon Hetlioz
BARBITURATES Zaleplon Sonata
Amobarbital Amytal Zolpidem Generic, Ambien,
Mephobarbital Mebaral (withdrawn) Ambien-CR
Three stages of ethylene glycol overdose occur. Within the first with fomepizole is initiated immediately, as described above for
few hours after ingestion, there is transient excitation followed by methanol poisoning, and continued until the patient’s serum
CNS depression. After a delay of 4–12 hours, severe metabolic ethylene glycol concentration drops below a toxic threshold
acidosis develops from accumulation of acid metabolites and lac- (20–30 mg/dL). Intravenous ethanol is an alternative to fomepi-
tate. Finally, deposition of oxalate crystals in renal tubules occurs, zole in ethylene glycol poisoning. Hemodialysis effectively
followed by delayed renal insufficiency. The key to the diagnosis removes ethylene glycol and its toxic metabolites and is recom-
of ethylene glycol poisoning is recognition of anion gap acidosis, mended for patients with a serum ethylene glycol concentration
osmolar gap, and oxalate crystals in the urine in a patient without above 50 mg/dL, significant metabolic acidosis, and significant
visual symptoms. renal impairment. Fomepizole has reduced the need for hemo-
As with methanol poisoning, early fomepizole is the standard dialysis, especially in patients with less severe acidosis and intact
treatment for ethylene glycol poisoning. Intravenous treatment renal function.
SUMMARY THE ALCOHOLS AND ASSOCIATED DRUGS

Mechanism of
Subclass, Drug Action, Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions
ALCOHOLS
Multiple effects on Antidote in methanol and ethylene Toxicity:
neurotransmitter glycol poisoning; topical antiseptic Acutely, central nervous system depression and respiratory
receptors, ion channels,
and signaling pathways pancreas, gastrointestinal tract, and central and peripheral
Interactions:
conversion of acetaminophen to toxic metabolite
Methanol: Poisonings result in toxic levels of formate, which causes characteristic visual disturbance plus coma, seizures, acidosis, and death due to respiratory failure
Ethylene glycol: Poisoning creates toxic aldehydes and oxalate, which causes kidney damage and severe acidosis
DRUGS USED IN ACUTE ETHANOL WITHDRAWAL

BDZ receptor agonists Prevention and treatment of acute See Chapter 22
(eg, chlordiazepoxide, that facilitate GABA- ethanol withdrawal syndrome
diazepam, mediated activation of
lorazepam) GABAA receptors
1) Essential vitamin required Administered to patients suspected of Toxicity: Interactions: None

for synthesis of the having alcoholism (those exhibiting
coenzyme thiamine acute alcohol intoxication or alcohol
pyrophosphate withdrawal syndrome) to prevent
Wernicke-Korsakoff syndrome
DRUGS USED IN CHRONIC ALCOHOLISM

Nonselective competitive Reduced risk of relapse in individuals Available as an oral or long-acting parenteral formulation
antagonist of opioid with alcoholism Toxicity: GI effects and liver toxicity; will precipitate a
receptors withdrawal reaction in individuals physically dependent on
opioids and will prevent the analgesic effect of opioids
Poorly understood NMDA Reduced risk of relapse in individuals Toxicity: GI effects and rash
receptor antagonist and with alcoholism
GABAA agonist effects
Inhibits aldehyde Deterrent to drinking in individuals Toxicity: Little effect alone but severe and potentially
dehydrogenase, resulting with alcohol dependence; rarely used dangerous flushing, headache, nausea, vomiting, and
in aldehyde accumulation hypotension when combined with ethanol
during ethanol ingestion
DRUGS USED IN ACUTE METHANOL OR ETHYLENE GLYCOL TOXICITY

Inhibits alcohol Methanol and ethylene glycol Toxicity: Headache, nausea, dizziness, rare
dehydrogenase, prevents poisoning allergic reactions
conversion of methanol
and ethylene glycol to
toxic metabolites
Ethanol: Higher affinity than methanol or ethylene glycol for alcohol dehydrogenase; used to reduce metabolism of methanol and ethylene glycol to toxic products
CHAPTER 24 Antiseizure Drugs 435
had been difficult to achieve. There is little information on

antiseizure drug withdrawal in seizure-free adults. Withdrawal
ANTISEIZURE DRUGS IN
is believed to be more likely to be successful in patients with DEVELOPMENT
generalized epilepsies who exhibit a single seizure type, whereas Several potential new antiseizure drugs are in late clinical develop-
longer duration of epilepsy, an abnormal neurologic exami- ment; these are Staccato (thermal aerosol inhaled) alprazolam, for
nation, an abnormal EEG, and certain epilepsy syndromes, acute repetitive seizures; intranasal midazolam, for acute repetitive
including juvenile myoclonic epilepsy, are associated with seizures; allopregnanolone, for status epilepticus; ganaxolone,
increased risk of recurrence. Drugs are generally withdrawn for status epilepticus and rare epilepsy syndromes; cannabidiol,
slowly over a 1- to 3-month period or longer. Abrupt cessa- for epileptic encephalopathies and focal seizures; cannabidiva-
tion may be associated with return of seizures and even a risk rin, for focal seizures; cenobamate (YKP3089), for focal seizures;
of status epilepticus. Some drugs are more easily withdrawn fenfluramine, for Dravet’s syndrome; and stiripentol, for Dravet’s
than others. Physical dependence occurs with barbiturates and syndrome. Other drugs are in earlier stages of development;
benzodiazepines, and there is a well-recognized risk of rebound current information can be found on the Epilepsy Foundation
seizures with abrupt withdrawal. website at http://www.epilepsy.com/etp/pipeline_new_therapies.
SUMMARY ANTISEIZURE DRUGS

Mechanism
Type, Drug of Action Pharmacokinetics Clinical Applications Toxicities, Interactions
SODIUM CHANNEL BLOCKERS

Sodium channel Rapidly absorbed orally, with Focal and focal-to-bilateral Toxicity: Nausea, diplopia, ataxia,
blocker tonic-clonic seizures; Interactions:
trigeminal neuralgia Phenytoin, valproate, fluoxetine, verapamil,
macrolide antibiotics, isoniazid,
part to active carbamazepine-10, propoxyphene, danazol, phenobarbital,
t1/2 of parent in adults primidone, many others
initially 25–65 h, decreasing to
12–17 h with autoinduction
Oxcarbazepine: Similar to carbamazepine; 100% bioavailability; 1-2 h t1/2 but active metabolites with t1/2 of 8-12 h; fewer interactions reported
Sodium channel Nearly complete (~90%) absorption Focal seizures, generalized Toxicity: Dizziness, headache, diplopia, rash
blocker tonic-clonic seizures, absence Interactions: Valproate, carbamazepine,
seizures, other generalized oxcarbazepine, phenytoin, phenobarbital,
t1/2 8–35 h seizures; bipolar depression primidone, succinimides, sertraline,
topiramate
Sodium channel Focal seizures Toxicity:

blocker, slow Interactions:
blocking kinetics t1/2 12–14 h Minimal
Sodium channel Absorption is formulation dependent Focal seizures, tonic-clonic Toxicity: Diplopia, ataxia, gingival
fosphenytoin blocker seizures hyperplasia, hirsutism, neuropathy
Interactions: Phenobarbital, carbamazepine,
elimination, t1/2 12–36 h isoniazid, felbamate, oxcarbazepine,
topiramate, fluoxetine, fluconazole, digoxin,
quinidine, cyclosporine, steroids, oral
contraceptives, others
(continued)
Mechanism
BROAD SPECTRUM
Unknown Nearly complete (>90%) absorption Generalized tonic-clonic Toxicity: Nausea, tremor, weight gain, hair
seizures, partial seizures, Interactions:
absence seizures, myoclonic Phenobarbital, phenytoin, carbamazepine,
seizures, other generalized lamotrigine, felbamate, rifampin,
t1/2 5–16 h seizure; migraine prophylaxis ethosuximide, primidone
SV2A ligand Nearly complete (~95%) absorption Focal seizures, generalized Toxicity: Nervousness, dizziness, depression,
tonic-clonic seizures, Interactions: Rare
myoclonic seizures
in blood to inactive metabolite; ~66%
excreted unchanged in urine
t1/2 6–11 h
Brivaracetam: Similar to levetiracetam but interaction with carbamazepine
Multiple actions Focal seizures, primary Toxicity: Somnolence, cognitive slowing,

generalized seizures, Lennox- Interactions:
Gastaut syndrome; migraine Phenytoin, carbamazepine, oral
active metabolites; 20–70% excreted prophylaxis contraceptives, lamotrigine, lithium?
t1/2 20–30 h,
but decreases with concomitant drugs
Unknown Nearly complete (>90%) absorption Focal seizures, generalized Toxicity: Drowsiness, cognitive impairment,
tonic-clonic seizures, Interactions:
(40–60%) plasma protein binding myoclonic seizures Minimal
30% excreted unchanged in urine

t1/2 50–70 h
Sodium channel Lennox-Gastaut syndrome; Toxicity: Somnolence, vomiting, pyrexia,

blocker and other focal seizures Interactions: Not metabolized via
mechanisms t1/2 6–10 h P450 enzymes, but antiseizure drug
interactions may be present
excreted in urine
GABAPENTINOIDS
α2δ ligand (Ca2+ Bioavailability 50%, decreasing with Focal seizures; neuropathic Toxicity: Somnolence, dizziness, ataxia
channel and pain; postherpetic neuralgia; Interactions: Minimal
possibly other anxiety
sites)
excreted unchanged in urine
t1/2 5–9 h
α2δ ligand (Ca2+ Nearly complete (~90%) absorption Focal seizures; neuropathic Toxicity: Somnolence, dizziness, ataxia
channel and pain; postherpetic neuralgia; Interactions: Minimal
possibly other fibromyalgia; anxiety
sites) metabolized; 98% excreted unchanged
t1/2 4.5–7 h
BARBITURATES
Positive allosteric Nearly complete (>90%) absorption Focal seizures, generalized Toxicity: Sedation, cognitive issues, ataxia,
modulator of tonic-clonic seizures, Interactions: Valproate,
GABAA receptors myoclonic seizures, neonatal carbamazepine, felbamate, phenytoin,
seizures; sedation cyclosporine, felodipine, lamotrigine,
excitatory synaptic active metabolites; 20–25% excreted nifedipine, nimodipine, steroids,
responses t1/2 75–140 h theophylline, verapamil, others
Sodium channel Nearly complete (>90%) absorption Generalized tonic-clonic Toxicity: Sedation, cognitive issues, ataxia,
blocker-like but seizures, partial seizures Interactions: Similar to
converted to phenobarbital
phenobarbital
2 active metabolites (phenobarbital and
phenylethylmalonamide); 65% excreted
t1/2 10–25 h
(continued)
CHAPTER 24 Antiseizure Drugs 437
Mechanism
ABSENCE SEIZURE-SPECIFIC
Inhibit low- Nearly complete (>90%) absorption Absence seizures Toxicity: Nausea, headache, dizziness,
threshold Interactions: Valproate,
calcium channels phenobarbital, phenytoin, carbamazepine,
(T-type) metabolized in liver; no active rifampicin
metabolites; 20% excreted unchanged
t1/2 20–60 h
BENZODIAZEPINES
Positive allosteric Nearly complete (>90%) oral or rectal Status epilepticus, seizure Toxicity: Interactions: Additive
modulator of clusters; sedation, anxiety, with sedative-hypnotics
GABAA receptors muscle relaxation (muscle
spasms, spasticity), acute
alcohol withdrawal
t1/2 of
active metabolite N-desmethyldiazepam
up to 100 h
Positive allosteric Absence seizures, myoclonic Toxicity: Interactions:

modulator of seizures, infantile spasms Additive with sedative-hypnotics
GABAA receptors
metabolized in liver; no active
t1/2 12–56 h
GABA MECHANISMS OTHER THAN BARBITURATES AND BENZODIAZEPINE

GAT-1 GABA Nearly complete (~90%) absorption Focal seizures Toxicity: Nervousness, dizziness, depression,
transporter Interactions: Phenobarbital,
inhibitor (96%) bound to plasma proteins phenytoin, carbamazepine, primidone
t1/2 2–9 h
Irreversible Focal seizures, infantile Toxicity: Drowsiness, dizziness, psychosis,

inhibitor of GABA spasms Interactions: Minimal
transaminase
eliminated unchanged in urine
t1/2 5–8 h (not relevant because of
irreversible action)
POTASSIUM CHANNEL OPENER

Opens KCNQ Focal seizures Toxicity: Dizziness, somnolence, confusion,
(ezogabine) potassium Interactions: minimal
channels (~80%) bound to plasma proteins
36% excreted unchanged in urine

t1/2 7–11 h
AMPA RECEPTOR BLOCKER

Noncompetitive Focal and focal-to-bilateral Toxicity: Dizziness, somnolence, headache;
block of AMPA tonic-clonic seizures, Interactions:
receptors (95%) bound to plasma proteins generalized tonic-clonic Substantial, with increased clearance
seizures caused by CYP3A
t1/2 25–129 h
SUMMARY Drugs Used for Local Anesthesia

Subclass, Mechanism
Drug of Action Effects Clinical Applications Pharmacokinetics, Toxicities
AMIDES
Blockade of sodium Slows, then blocks, Short-duration procedures Parenteral (eg, peripheral block, but varies significantly
channels action potential
propagation infiltration, spinal, epidural, minor Toxicity: Central nervous system (CNS)
and major peripheral blocks excitation (high-volume blocks) and local neurotoxicity
Same as lidocaine Same as lidocaine Longer-duration procedures Toxicity: CNS excitation

(but not used topically or
intravenously)
ESTERS
Like lidocaine Like lidocaine Very short procedures (not
generally used topically or Toxicity: Like lidocaine
intravenously)
Same as above Same as above Procedures requiring high

surface activity and Toxicity: CNS excitation, convulsions, cardiac
sympathomimetic vasoconstriction arrhythmias, hypertension, stroke
effects
P R E P A R A T I O N S REFERENCES
A V A I L A B L E Albright GA: Cardiac arrest following regional anesthesia with etidocaine or bupi-
vacaine. Anesthesiology 1979;51:285.
American Society of Regional Anesthesia and Pain Medicine: Checklist for treat-
GENERIC NAME AVAILABLE AS ment of local anesthetic systemic toxicity. 2012. http://www.asra.com/
Articaine Septocaine checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf.
Benzocaine (topical) Generic Andavan GS, Lemmens-Gruber R: Voltage-gated sodium channels: Mutations,
Bupivacaine Generic, Marcaine, channelopathies and targets. Curr Med Chem 2011;18:377.
Sensorcaine Auroy Y et al: Serious complications related to regional anesthesia: Results of a
prospective survey in France. Anesthesiology 1997;87:479.
Chloroprocaine Generic, Nesacaine
Butterworth JF 4th, Strichartz GR: Molecular mechanisms of local anesthesia: A
Cocaine (topical) Generic review. Anesthesiology 1990;72:711.
Dibucaine (topical) Generic, Nupercainal Catterall WA, Goldin AL, Waxman SG: International Union of Pharmacology.
Dyclonine (topical lozenge) Sepacol, Sucrets, Dyclone XLVII. Nomenclature and structure-function relationships of voltage-gated
sodium channels. Pharmacol Rev 2005;57:397.
Intravenous lipid emulsion for overdose Intralipid
Cave G, Harvey M: Intravenous lipid emulsion as antidote beyond local anesthetic
Levobupivacaine Chirocaine, others toxicity: A systematic review. Acad Emerg Med 2009;16:815.
Lidocaine Generic, Xylocaine de Jong RH, Ronfeld RA, DeRosa RA: Cardiovascular effects of convulsant and
Lidocaine and hydrocortisone (patch) Generic supraconvulsant doses of amide local anesthetics. Anesth Analg 1982;61:3.
Lidocaine and bupivacaine mixture Duocaine Di Gregorio G et al: Clinical presentation of local anesthetic systemic toxicity: A
review of published cases, 1979 to 2009. Reg Anesth Pain Med 2010;35:181.
Lidocaine and prilocaine eutectic mixture EMLA cream
(topical) Drasner K: Local anesthetic systemic toxicity: a historical perspective. Reg Anesth
Pain Med 2010;35:162.
Mepivacaine Generic, Carbocaine
Drasner K: Chloroprocaine spinal anesthesia: Back to the future? Anesth Analg
Pramoxine (topical) Generic, Tronothane 2005;100:549.
Prilocaine Citanest Drasner K: Local anesthetic neurotoxicity: Clinical injury and strategies that may
Procaine Generic, Novocain minimize risk. Reg Anesth Pain Med 2002;27:576.
Proparacaine (ophthalmic) Generic, Alcaine, others Drasner K: Lidocaine spinal anesthesia: A vanishing therapeutic index? Anesthe-
siology 1997;87:469.
Ropivacaine Generic, Naropin
Drasner K et al: Cauda equina syndrome following intended epidural anesthesia.
Tetracaine Generic, Pontocaine Anesthesiology 1992;77:582.
from its stores in the sarcoplasmic reticulum (see Figures 13–1 have a hereditary alteration in Ca2+-induced Ca2+ release via the
and 27–10). This activator calcium brings about the tension- RyR1 channel or impairment in the ability of the sarcoplasmic
generating interaction of actin with myosin. Calcium is released reticulum to sequester calcium via the Ca2+ transporter (Figure
from the sarcoplasmic reticulum via a calcium channel, called the 27–10). Several mutations associated with this risk have been
ryanodine receptor (RyR) channel because the plant alkaloid identified. After administration of one of the triggering agents,
ryanodine combines with a receptor on the channel protein. In there is a sudden and prolonged release of calcium, with massive
the case of the skeletal muscle RyR1 channel, ryanodine facilitates muscle contraction, lactic acid production, and increased body
the open configuration. temperature. Prompt treatment is essential to control acidosis
and body temperature and to reduce calcium release. The latter
O
is accomplished by administering intravenous dantrolene, starting
HN N N CH NO2
with a dose of 1 mg/kg IV, and repeating as necessary to a maxi-
O mum dose of 10 mg/kg.
O
Dantrolene
ANTISPASMODICS: DRUGS USED TO
Dantrolene interferes with the release of activator calcium TREAT ACUTE LOCAL MUSCLE SPASM
through this sarcoplasmic reticulum calcium channel by binding
to the RyR1 and blocking the opening of the channel. Motor units A large number of less well-studied, centrally active drugs
that contract rapidly are more sensitive to the drug’s effects than (eg, carisoprodol, chlorphenesin, chlorzoxazone, cycloben-
are slower-responding units. Cardiac muscle and smooth muscle zaprine, metaxalone, methocarbamol, and orphenadrine) are
are minimally depressed because the release of calcium from their promoted for the relief of acute muscle spasm caused by local
sarcoplasmic reticulum involves a different RyR channel (RyR2). tissue trauma or muscle strains. It has been suggested that these
Treatment with dantrolene is usually initiated with 25 mg drugs act primarily at the level of the brainstem. Cyclobenzap-
daily as a single dose, increasing to a maximum of 100 mg four rine may be regarded as the prototype of the group. Cycloben-
times daily as tolerated. Only about one third of an oral dose of zaprine is structurally related to the tricyclic antidepressants and
dantrolene is absorbed, and the elimination half-life of the drug produces antimuscarinic side effects. It is ineffective in treating
is approximately 8 hours. Major adverse effects are generalized muscle spasm due to cerebral palsy or spinal cord injury. As a
muscle weakness, sedation, and occasionally hepatitis. result of its strong antimuscarinic actions, cyclobenzaprine may
A special application of dantrolene is in the treatment of cause significant sedation, as well as confusion and transient
malignant hyperthermia, a rare heritable disorder that can be visual hallucinations. The dosage of cyclobenzaprine for acute
triggered by a variety of stimuli, including general anesthetics (eg, injury-related muscle spasm is 20–40 mg/d orally in divided
volatile anesthetics) and neuromuscular blocking drugs (eg, succi- doses. This drug class carries risks of significant adverse events
nylcholine; see also Chapter 16). Patients at risk for this condition and abuse potential.
SUMMARY Skeletal Muscle Relaxants

Subclass, Mechanism Pharmacokinetics,
Drug of Action Effects Clinical Applications Toxicities, Interactions
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT

Agonist at nicotinic Initial depolarization causes Placement of endotracheal tube Rapid metabolism by plasma
acetylcholine (ACh) transient contractions, followed at start of anesthetic procedure
receptors, especially at by prolonged flaccid paralysis Toxicities: Arrhythmias
neuromuscular junctions contractions in status epilepticus
by repolarization that is also intra-abdominal, intraocular
stimulate ganglionic accompanied by paralysis
nicotinic ACh and cardiac pain
muscarinic ACh receptors
(continued)
CHAPTER 27 Skeletal Muscle Relaxants 489
Subclass, Mechanism Pharmacokinetics,

Drug of Action Effects Clinical Applications Toxicities, Interactions
NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS

d-Tubocurarine Competitive antagonist at Prevents depolarization by ACh, Prolonged relaxation for
nACh receptors, especially causes flaccid paralysis Toxicities: Histamine
at neuromuscular by newer nondepolarizing agents
junctions with hypotension apnea
muscarinic ACh receptors
Similar to tubocurarine Like tubocurarine but lacks Prolonged relaxation for surgical Not dependent on renal or
histamine release and
antimuscarinic effects respiratory muscles to facilitate Toxicities: Prolonged
mechanical ventilation in apnea but less toxic than atracurium
intensive care unit
Similar to cisatracurium Like cisatracurium but slight

antimuscarinic effect patients with renal impairment Toxicities: Like
cisatracurium
Vecuronium: Intermediate duration; metabolized in liver
CENTRALLY ACTING SPASMOLYTIC DRUGS

GABAB agonist, facilitates Pre- and postsynaptic inhibition Severe spasticity due to cerebral Toxicities:
spinal inhibition of motor of motor output palsy, multiple sclerosis, stroke Sedation, weakness; rebound
neurons spasticity upon abrupt withdrawal
Facilitates GABAergic Increases interneuron inhibition Chronic spasm due to cerebral Hepatic metabolism
transmission in central of primary motor afferents in palsy, stroke, spinal cord injury Toxicities:
nervous system (see See Chapter 22
Chapter 22) injury
α2-Adrenoceptor agonist Presynaptic and postsynaptic Spasm due to multiple sclerosis,

in the spinal cord inhibition of reflex motor output stroke, amyotrophic lateral Toxicities:
sclerosis Weakness, sedation, hypotension,
hepatotoxicity (rare), rebound
hypertension upon abrupt
withdrawal
CENTRALLY ACTING ANTISPASMODIC DRUGS

Poorly understood Reduction in hyperactive muscle Acute spasm due to muscle injury
inhibition of muscle Toxicities: Strong
stretch reflex in spinal antimuscarinic effects antimuscarinic effects
cord
Chlorphenesin, methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of antimuscarinic effect. Class side effect: strong central nervous system
depression; note carisoprodol is a schedule IV drug.
DIRECT-ACTING MUSCLE RELAXANTS

Blocks RyR1 Ca2+-release Reduces actin-myosin interaction IV: Malignant hyperthermia Toxicities:
channels in the
sarcoplasmic reticulum of contraction palsy, spinal cord injury, multiple warning: hepatotoxicity
skeletal muscle sclerosis
Inhibits synaptic Flaccid paralysis Upper and lower limb spasm due Direct injection into muscle
exocytosis through to cerebral palsy, multiple
clipping of vesicle fusion sclerosis; cervical dystonia, Toxicities: muscle weakness, falls
proteins in presynaptic overactive bladder, migraine,
nerve terminal hyperhidrosis
SUMMARY Drugs Used for Movement Disorders

Subclass, Mechanism Clinical Pharmacokinetics,
Drug of Action Effects Applications Toxicities, Interactions
LEVODOPA AND COMBINATIONS

Transported into the central Ameliorates all motor Parkinson’s disease: Toxicity: Gastrointestinal
nervous system (CNS) and symptoms of Parkinson’s Most efficacious therapy upset, arrhythmias, dyskinesias, on-off and
converted to dopamine (which disease and causes but not always used as wearing-off phenomena, behavioral
does not enter the CNS); also significant peripheral the first drug due to Interactions: Use with
converted to dopamine in the dopaminergic effects development of carbidopa greatly diminishes required
periphery (see text) disabling response
fluctuations over time COMT or MAO-B inhibitors prolongs duration
of effect
Levodopa + carbidopa (Sinemet, others): Carbidopa inhibits peripheral metabolism of levodopa to dopamine and reduces required dosage and toxicity; carbidopa does not
enter CNS
Levodopa + carbidopa + entacapone (Stalevo): Entacapone is a catechol-O-methyltransferase (COMT) inhibitor (see below)
DOPAMINE AGONISTS
Direct agonist at D3 receptors, Reduces symptoms of Parkinson’s disease: Toxicity: Nausea and
nonergot Can be used as initial vomiting, postural hypotension, dyskinesias,
fluctuations in levodopa confusion, impulse control disorders,
response in on-off phenomenon sleepiness
Ropinirole: Similar to pramipexole; nonergot; relatively pure D2 agonist

Bromocriptine: Ergot derivative; potent agonist at D2 receptors; more toxic than pramipexole or ropinirole; now rarely used for antiparkinsonian effect
Apomorphine: Nonergot; subcutaneous route useful for rescue treatment in levodopa-induced dyskinesia; high incidence of nausea and vomiting
MONOAMINE OXIDASE (MAO) INHIBITORS

Inhibits MAO-B selectively; Increases dopamine stores Parkinson’s disease: Toxicity & interactions: May cause
higher doses also inhibit in neurons; may have Adjunctive to levodopa serotonin syndrome with meperidine, and
MAO-A neuroprotective effects theoretically also with selective serotonin
response reuptake inhibitors, tricyclic antidepressants
Selegiline: Like rasagiline, adjunctive use with levodopa; may be less potent than rasagiline
Safinamide: Also used as adjunct to levodopa in patients with response fluctuations
COMT INHIBITORS
Inhibits COMT in periphery Reduces metabolism of Parkinson’s disease Toxicity: Increased levodopa toxicity
levodopa and prolongs its
action
Tolcapone: Like entacapone but enters CNS; some evidence of hepatotoxicity, elevation of liver enzymes
ANTIMUSCARINIC AGENTS
Antagonist at M receptors in Reduces tremor and rigidity Parkinson’s disease Toxicity: Typical antimuscarinic
basal ganglia effects—sedation, mydriasis, urinary
retention, constipation, confusion, dry mouth
Biperiden, orphenadrine, procyclidine, trihexyphenidyl: Similar antimuscarinic agents with CNS effects
DRUGS USED IN HUNTINGTON’S DISEASE

Deplete amine transmitters, Reduce chorea severity Huntington’s disease Toxicity: Hypotension, sedation,
reserpine especially dopamine, from
nerve endings Chapter 11 somewhat less toxic than reserpine
Haloperidol, fluphenazine, other neuroleptics, olanzapine: Dopamine receptor blockers, sometimes helpful
DRUGS USED IN TOURETTE SYNDROME

Block central D2 receptors Reduce vocal and motor tic Tourette syndrome Toxicity: Parkinsonism, other
haloperidol frequency, severity
see Chapter 29
disturbances
Clonidine, guanfacine: Effective in ~50% of patients; see Chapter 11 for basic pharmacology
Phenothiazines, atypical antipsychotics, clonazepam, carbamazepine: Sometimes of value
in proportion to the degree of toxicity; any value over 2 mEq/L tendency to induce the metabolism of CYP3A4 substrates make
must be considered as indicating likely toxicity. Because lithium it a more difficult drug to use with other standard treatments for
is a small ion, it is dialyzed readily. Both peritoneal dialysis and bipolar disorder. The mode of action of carbamazepine is unclear,
hemodialysis are effective, although the latter is preferred. and oxcarbazepine is not effective. Carbamazepine may be used to
treat acute mania and also for prophylactic therapy. Adverse effects
(discussed in Chapter 24) are generally no greater and sometimes
VALPROIC ACID less than those associated with lithium. Carbamazepine may be
used alone or, in refractory patients, in combination with lithium
Valproic acid (valproate), discussed in detail in Chapter 24 as an or, rarely, valproate.
antiepileptic, has been demonstrated to have antimanic effects and The use of carbamazepine as a mood stabilizer is similar to its
is now being widely used for this indication in the USA. (Gaba- use as an anticonvulsant (see Chapter 24). Dosage usually begins
pentin is not effective, leaving the mechanism of antimanic action with 200 mg twice daily, with increases as needed. Maintenance
of valproate unclear.) Overall, valproic acid shows efficacy equiva- dosage is similar to that used for treating epilepsy, ie, 800–1200
lent to that of lithium during the early weeks of treatment. It is mg/d. Plasma concentrations between 3 and 14 mg/L are con-
significant that valproic acid has been effective in some patients sidered desirable, although the optimal therapeutic range has not
who have failed to respond to lithium. For example, mixed states been established. Blood dyscrasias have figured prominently in
and rapid cycling forms of bipolar disorder may be more respon- the adverse effects of carbamazepine when it is used as an anticon-
sive to valproate than to lithium. Moreover, its side-effect profile vulsant, but they have not been a major problem with its use as
is such that one can rapidly increase the dosage over a few days a mood stabilizer. Overdoses of carbamazepine are a major emer-
to produce blood levels in the apparent therapeutic range, with gency and should generally be managed like overdoses of tricyclic
nausea being the only limiting factor in some patients. The start- antidepressants (see Chapter 58).
ing dosage is 750 mg/d, increasing rapidly to the 1500–2000 mg
range with a recommended maximum dosage of 60 mg/kg/d.
Combinations of valproic acid with other psychotropic medica-
tions likely to be used in the management of either phase of bipolar OTHER DRUGS
illness are generally well tolerated. Valproic acid is an appropriate
first-line treatment for mania, although it is not clear that it will Lamotrigine is approved as a maintenance treatment for bipolar
be as effective as lithium as a maintenance treatment in all subsets disorder. Although not effective in treating acute mania, it appears
of patients. Many clinicians advocate combining valproic acid and effective in reducing the frequency of recurrent depressive cycles
lithium in patients who do not fully respond to either agent alone. and may have some utility in the treatment of bipolar depression.
A number of novel agents are under investigation for bipolar
depression, including riluzole, a neuroprotective agent that is
CARBAMAZEPINE approved for use in amyotrophic lateral sclerosis; ketamine, a
noncompetitive NMDA antagonist previously discussed as a drug
Carbamazepine has been considered to be a reasonable alternative believed to model schizophrenia but thought to act by produc-
to lithium when the latter is less than optimally efficacious. How- ing relative enhancement of AMPA receptor activity; and AMPA
ever, the pharmacokinetic interactions of carbamazepine and its receptor potentiators.
SUMMARY Antipsychotic Drugs & Lithium

PHENOTHIAZINES
Blockade of D2 receptors α-Receptor blockade Psychiatric: schizophrenia Oral and parenteral forms, long half-lives
>> 5-HT2A receptors (fluphenazine least) (alleviate positive symptoms), with metabolism-dependent elimination
bipolar disorder (manic Toxicity: Extensions of effects on α and
THIOXANTHENE blockade (especially
chlorpromazine and antiemesis, preoperative receptors may result in akathisia,
1-receptor sedation (promethazine) dystonia, parkinsonian symptoms, tardive
blockade (chlorpromazine, dyskinesia, and hyperprolactinemia
system (CNS) depression
(thioridazine)
(continued)
CHAPTER 29 Antipsychotic Agents & Lithium 529
Mechanism of Pharmacokinetics, Toxicities,

Subclass, Drug Action Effects Clinical Applications Interactions
BUTYROPHENONE
Blockade of D2 receptors Some α blockade, but Schizophrenia (alleviates Oral and parenteral forms with
>> 5-HT2A receptors minimal M-receptor blockade positive symptoms), bipolar metabolism-dependent elimination
and much less sedation than disorder (manic phase), Toxicity: Extrapyramidal dysfunction is
the phenothiazines Huntington’s chorea, major adverse effect
Tourette syndrome
SECOND-GENERATION ANTIPSYCHOTICS
Blockade of 5-HT2A Some α blockade (clozapine, Schizophrenia—improve Toxicity: Agranulocytosis (clozapine),
receptors > blockade of risperidone, ziprasidone) and both positive and negative diabetes (clozapine, olanzapine),
D2 receptors M-receptor blockade hypercholesterolemia (clozapine,
(clozapine, olanzapine) (olanzapine or risperidone olanzapine), hyperprolactinemia
1-receptor adjunctive with lithium) (risperidone), QT prolongation
blockade (all) (ziprasidone), weight gain (clozapine,
Parkinson’s patients (low olanzapine)
(aripiprazole)
LITHIUM Mechanism of action No significant antagonistic Bipolar affective disorder— Oral absorption, renal elimination
actions on autonomic prophylactic use can prevent
inositol signaling and nervous system receptors or mood swings between mania Toxicity:
inhibits glycogen specific CNS receptors and depression Tremor, edema, hypothyroidism, renal
synthase kinase-3 (GSK-3),
a multifunctional protein Interactions: Clearance
kinase decreased by thiazides and some NSAIDs
OTHER AGENTS FOR BIPOLAR DISORDER

Mechanism of action in See Chapter 24 Valproic acid is increasingly
bipolar disorder unclear used as first choice in acute
(see Chapter 24 for
putative actions in seizure lamotrigine are also used Toxicity: Hematotoxicity and
disorders) both in acute mania and for induction of P450 drug metabolism
prophylaxis in depressive (carbamazepine), rash (lamotrigine), tremor,
phase liver dysfunction, weight gain, inhibition of
drug metabolism (valproic acid)

ANTIPSYCHOTIC AGENTS Perphenazine Generic, Trilafon
Aripiprazole Abilify Pimavanserin Nuplazid
Asenapine Saphris Pimozide Orap
Brexpiprazole Rexulti Prochlorperazine Generic, Compazine
Cariprazine Vraylar Quetiapine Generic, Seroquel
Chlorpromazine Generic, Thorazine Risperidone Generic, Risperdal
Clozapine Generic, Clozaril, others Thioridazine Generic, Mellaril
Fluphenazine Generic Thiothixene Generic, Navane
Fluphenazine decanoate Generic, Prolixin Decanoate Trifluoperazine Generic, Stelazine
Haloperidol Generic, Haldol Ziprasidone Generic, Geodon
Haloperidol ester Haldol Decanoate MOOD STABILIZERS
Iloperidone Fanapt Carbamazepine Generic, Tegretol
Loxapine Adasuve Divalproex Generic, Depakote
Lurasidone Latuda Lamotrigine Generic, Lamictal
Molindone Moban Lithium carbonate Generic, Eskalith
Olanzapine Generic, Zyprexa Topiramate Generic, Topamax
Paliperidone Invega Valproic acid Generic, Depakene
SUMMARY Opioids, Opioid Substitutes, and Opioid Antagonists

Subclass, Mechanism Clinical Pharmacokinetics,
Drug of Action Effects Applications Toxicities
OPIOID AGONISTS
Strong µ-receptor agonists
δ and anesthesia (fentanyl, morphine) except methadone, 4–6 h
κ receptors gastrointestinal transit Toxicity: Respiratory depression
rehabilitation programs
(methadone only)
Less efficacious than Like strong agonists Like strong agonists, toxicity
(codeine) dependent on genetic variation
antagonize strong of metabolism
agonists
MIXED OPIOID AGONIST-ANTAGONISTS

Partial µ agonist Like strong agonists but can Long duration of action 4–8 h
κ antagonist antagonize their effects maintenance rehabilitation
programs syndrome
κ µ antagonist Similar to buprenorphine Moderate pain Like buprenorphine
ANTITUSSIVES
Poorly understood but Reduces cough reflex Acute debilitating cough Toxicity:
strong and partial µ Minimal when taken as directed
agonists are also effective levopropoxyphene not analgesic
antitussives
OPIOID ANTAGONISTS
Antagonist at µ, δ, and Rapidly antagonizes all opioid Opioid overdose Duration 1–2 h (may have to be
κ receptors effects repeated when treating
Toxicity: Precipitates
abstinence syndrome in
dependent users
OTHER ANALGESICS USED IN MODERATE PAIN

Moderate µ agonist, Analgesia Moderate pain Toxicity:
strong NET inhibitor Headache; nausea and vomiting;
possible dependence
Mixed effects: weak µ Analgesia Toxicity: Seizures

agonist, moderate SERT opioids in chronic pain
inhibitor, weak NET syndromes
inhibitor
NET, norepinephrine reuptake transporter; SERT, serotonin reuptake transporter.

interventions, to motivate drug users to gradually reduce the dose a substantial risk of suicide—this drug is no longer used clini-
and become abstinent. cally. It was initially used in conjunction with diet and exercise
The biggest challenge is the treatment of addiction itself. Sev- for patients with a body mass index above 30 kg/m2 (27 kg/m2
eral approaches have been proposed, but all remain experimental. if associated risk factors, such as type 2 diabetes or dyslipidemia,
One approach is to pharmacologically reduce cravings. The are present). Although a recent large-scale study confirmed that
µ-opioid receptor antagonist and partial agonist naltrexone is rimonabant is effective for smoking cessation and the prevention
FDA-approved for this indication in opioid and alcohol addiction. of weight gain in smokers who quit, this indication has never been
Its effect is modest and may involve a modulation of endogenous approved. While the cellular mechanism of rimonabant remains
opioid systems. to be elucidated, data in rodents convincingly demonstrate that
Clinical trials are currently being conducted with a number this compound can reduce self-administration in naive as well as
of drugs, including the high-affinity GABAB-receptor agonist drug-experienced animals.
baclofen, and initial results have shown a significant reduction While still experimental, the emergence of a circuit model
of craving. This effect may be mediated by the inhibition of the for addiction has prompted interest in neuromodulatory inter-
dopamine neurons of the VTA, which is possible at baclofen ventions, such as deep brain stimulation (DBS) or transcranial
concentrations obtained by oral administration because of its very magnetic stimulation (TMS). Inspired by optogenetic “treat-
high affinity for the GABAB receptor. ments” in rodent models of addiction, novel protocols have
Rimonabant is an inverse agonist of the CB1 receptor that been proposed for DBS in the nucleus accumbens or TMS
behaves like an antagonist of cannabinoids. It was developed of the prefrontal cortex. Case studies seem to confirm the
for smoking cessation and to facilitate weight loss. Because of potential of such approaches, but controlled clinical studies
frequent adverse effects—most notably severe depression carrying are lacking.
SUMMARY Drugs Used to Treat Dependence and Addiction

Pharmacokinetics, Toxicities,
Subclass, Drug Mechanism of Action Effects Clinical Application Interactions
OPIOID RECEPTOR ANTAGONIST

Nonselective antagonist of Reverses the acute effects of Opioid overdose Effect much shorter than morphine
opioid receptors opioids; can precipitate (1–2 h); therefore several injections
severe abstinence syndrome required
Antagonist of opioid Blocks effects of illicit Treatment of alcoholism, Half-life 10 h (oral); 5–10 days
receptors opioids opioid addiction (depot injection)
SYNTHETIC OPIOID
Slow-acting agonist of Acute effects similar to Substitution therapy for
µ-opioid receptor morphine (see text) opioid addicts variable among individuals (range
Toxicity: Respiratory
depression, constipation, miosis,
tolerance, dependence, arrhythmia, and
withdrawal symptoms
“Enantiopure” methadone Similar to morphine and Substitution therapy Less toxic compared to racemic
containing only the left- methadone, but at half the methadone, particularly related to
enantiomer of the molecule dose of the latter cardiac adverse effects (long QT interval)
A salt containing morphine Slow-release version with a Substitution therapy

sulphate sulfate pentahydrate longer action than morphine
PARTIAL l-OPIOID RECEPTOR AGONIST

Partial agonist at µ-opioid Attenuates acute effects of Oral substitution therapy for
receptors morphine opioid addicts together with naloxone to avoid illicit IV
injections
NICOTINIC RECEPTOR PARTIAL AGONIST

Partial agonist of nicotinic Occludes “rewarding” effects Smoking cessation Toxicity: Nausea and vomiting, seizures,
acetylcholine receptor of the psychiatric changes
α4β2-type awareness of colors
Cytisine: Natural analog (extracted from laburnum flowers) of varenicline
(continued)
CHAPTER 32 Drugs of Abuse 589
Subclass, Drug Mechanism of Action Effects Clinical Application Interactions
BENZODIAZEPINES
Positive modulators of the Enhances GABAergic Delirium tremens
others GABAA receptors, increase synaptic transmission; affected by decreased liver function
frequency of channel attenuates withdrawal
opening symptoms (tremor,
hallucinations, anxiety) in
withdrawal seizures
N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST

Antagonist of NMDA May interfere with forms of Allergic reactions, arrhythmia, and low
glutamate receptors synaptic plasticity that effective only in combination or high blood pressure, headaches,
depend on NMDA receptors with counseling
hallucinations, particularly in elderly
patients
CANNABINOID RECEPTOR INVERSE AGONIST

CB1 receptor inverse agonist Decreases neurotransmitter Approved in Europe from Major depression, including increased
release at GABAergic and 2006 to 2008 to treat risk of suicide
glutamatergic synapses obesity, then withdrawn
because of major side effects
never been approved, but

remains an off-label
indication
REFERENCES Pharmacology of Drugs of Abuse

General Benowitz NL: Nicotine addiction. N Engl J Med 2010;362:2295.
Maskos U et al: Nicotine reinforcement and cognition restored by targeted expres-
Creed M, Pascoli VJ, Lüscher C: Addiction therapy. Refining deep brain stimula- sion of nicotinic receptors. Nature 2005;436:103.
tion to emulate optogenetic treatment of synaptic pathology. Science 2015;
347:659. Morton J: Ecstasy: Pharmacology and neurotoxicity. Curr Opin Pharmacol
2005;5:79.
Everitt BJ, Robbins TW: Drug addiction: Updating actions to habits to compul-
sions ten years on. Annu Rev Psychol 2016;67:23. Nichols DE: Hallucinogens. Pharmacol Ther 2004;101:131.
Goldman D, Oroszi G, Ducci F: The genetics of addictions: Uncovering the genes. Pascoli V, Terrier J, Hiver A, Lüscher C: Sufficiency of mesolimbic dopamine
Nat Rev Genet 2005;6:521. neuron stimulation for the progression to addiction. Neuron 2015;88:1054.
Lüscher C: Emergence of circuit model for addiction. Annu Rev Neurosci Snead OC, Gibson KM: Gamma-hydroxybutyric acid. N Engl J Med
2016;39:257-76. 2005;352:2721.
Redish AD, Jensen S, Johnson A: A unified framework for addiction: Vulnerabilities Sulzer D et al: Mechanisms of neurotransmitter release by amphetamines: A review.
in the decision process. Behav Brain Sci 2008;31:461. Prog Neurobiol 2005;75:406.
Walker DM, Cates HM, Heller EA, Nestler EJ: Regulation of chromatin states by Tan KR et al: Neural basis for addictive properties of benzodiazepines. Nature
drugs of abuse. Curr Opin Neurobiol 2015;30:112. 2010;463:769.
C ASE STUDY ANSWER
When found by his parents, the patient was having visual exogenous cannabis with endocannabinoids that fine-tune
hallucinations of colorful insects. Hallucinations are often synaptic transmission and plasticity. While probably not
caused by a cannabis overdose, especially when hashish is fulfilling the criteria for addiction at present, the patient is at
ingested. The slower kinetics of oral cannabis are more dif- risk as epidemiologic studies show that drug abuse typically
ficult to control compared to smoking marijuana. The poor begins in late adolescence. The fact that he is not yet using
learning performance may be due to the interference of other drugs is a positive sign.
CHAPTER 33 Agents Used in Cytopenias; Hematopoietic Growth Factors 605
are observed in 2–6 hours and the half-life is 26–35 hours. chemotherapy. Interleukin-11 is given by subcutaneous injec-
Eltrombopag is excreted primarily in the feces. tion at a dose of 50 mcg/kg daily. It is started 6–24 hours after
completion of chemotherapy and continued for 14–21 days or
until the platelet count passes the nadir and rises to more than
Pharmacodynamics 50,000 cells/µL.
Interleukin-11 acts through a specific cell surface cytokine recep- In patients with chronic immune thrombocytopenia who
tor to stimulate the growth of multiple lymphoid and myeloid failed to respond adequately to previous treatment with steroids,
cells. It acts synergistically with other growth factors to stimulate immunoglobulins, or splenectomy, romiplostim and eltrombopag
the growth of primitive megakaryocytic progenitors and, most significantly increase platelet count in most patients. Both drugs
importantly, increases the number of peripheral platelets and are used at the minimal dose required to maintain platelet counts
neutrophils. of greater than 50,000 cells/µL.
Romiplostim has high affinity for the human Mpl receptor.
Eltrombopag interacts with the transmembrane domain of the Toxicity
Mpl receptor. Both drugs induce signaling through the Mpl recep-
tor pathway and cause a dose-dependent increase in platelet count. The most common adverse effects of IL-11 are fatigue, headache,
Romiplostim is administered once weekly by subcutaneous injec- dizziness, and cardiovascular effects. The cardiovascular effects
tion. Eltrombopag is an oral drug. For both drugs, peak platelet include anemia (due to hemodilution), dyspnea (due to fluid
count responses are observed in approximately 2 weeks. accumulation in the lungs), and transient atrial arrhythmias.
Hypokalemia also has been seen in some patients. All of these
adverse effects appear to be reversible.
Clinical Pharmacology Eltrombopag is potentially hepatotoxic and liver function must
Interleukin-11 is approved for the secondary prevention of be monitored, particularly when used in patients with hepatitis C.
thrombocytopenia in patients receiving cytotoxic chemotherapy Portal vein thrombosis also has been reported with eltrombopag and
for treatment of nonmyeloid cancers. Clinical trials show that it romiplostim in the setting of chronic liver disease. In patients with
reduces the number of platelet transfusions required by patients myelodysplastic syndromes, romiplostim increases the blast count
who experience severe thrombocytopenia after a previous cycle and risk of progression to acute myeloid leukemia. Marrow fibrosis
of chemotherapy. Although IL-11 has broad stimulatory effects has been observed with thrombopoietin agonists but is generally
on hematopoietic cell lineages in vitro, it does not appear to have reversible when the drug is discontinued. Rebound thrombocytope-
significant effects on the leukopenia caused by myelosuppressive nia has been observed following discontinuation of TPO agonists.
SUMMARY Agents Used in Anemias and Hematopoietic Growth Factors

Mechanism of Clinical Pharmacokinetics, Toxicities,
Subclass, Drug Action Effects Applications Interactions
IRON
Required for Adequate supplies Iron deficiency, which manifests as Complicated endogenous system for
biosynthesis of heme required for normal absorbing, storing, and transporting iron
and heme-containing heme synthesis preparation Toxicity: Acute overdose results in
proteins, including necrotizing gastroenteritis, abdominal pain,
hemoglobin and inadequate heme bloody diarrhea, shock, lethargy, and
myoglobin production
hemochromatosis, with damage to the
heart, liver, pancreas, and other organs
Ferrous gluconate and ferrous fumarate: Oral iron preparations

Iron dextran, iron sucrose complex, sodium ferric gluconate complex, ferric carboxymaltose, and ferumoxytol: Parenteral preparations can cause pain, hypersensitivity
reactions
IRON CHELATORS
Chelates excess iron Reduces toxicity Acute iron poisoning; inherited or Preferred route of administration is IM or SC
also Chapters 57 associated with acute acquired hemochromatosis Toxicity: Rapid IV administration may cause
and 58) or chronic iron overload
susceptibility to certain infections have
occurred with long-term use
Deferasirox: Orally administered iron chelator for treatment of hemochromatosis
(continued)
606 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
Mechanism of Clinical Pharmacokinetics, Toxicities,

Subclass, Drug Action Effects Applications Interactions
VITAMIN B12
Cofactor required for Adequate supplies Vitamin B12 deficiency, which Parenteral vitamin B12 is required for
essential enzymatic required for amino acid manifests as megaloblastic anemia pernicious anemia and other malabsorption
reactions that form and fatty acid and is the basis of pernicious Toxicity: No toxicity associated
tetrahydrofolate, metabolism, and DNA anemia; hydroxocobalamin is also with excess vitamin B12
convert homocysteine synthesis used as a cyanide antidote (see
to methionine, and Chapter 58)
metabolize
L-methylmalonyl-CoA
FOLIC ACID
Precursor of an Adequate supplies Folic acid deficiency, which Oral; well-absorbed; need for parenteral
(pteroylglutamic essential donor of required for essential manifests as megaloblastic Toxicity: Folic acid is not
acid) methyl groups used biochemical reactions anemia, and prevention of toxic in overdose, but large amounts can
for synthesis of amino involving amino acid congenital neural tube defects partially compensate for vitamin B12
acids, purines, and metabolism, and purine deficiency and put people with unrecognized
deoxynucleotide and DNA synthesis B12 deficiency at risk of neurologic
consequences of vitamin B12 deficiency, which
are not compensated by folic acid
ERYTHROCYTE-STIMULATING AGENTS
Agonist of Stimulates erythroid Anemia, especially anemia IV or SC administration 1–3 times per week
erythropoietin proliferation and associated with chronic renal Toxicity: Hypertension, thrombotic
receptors expressed differentiation, and failure, HIV infection, cancer, and complications, and, very rarely, pure red cell
by red cell induces the release of
progenitors reticulocytes from the need for transfusion in patients cerebrovascular events, hemoglobin levels
bone marrow undergoing certain types of should be maintained <12 g/dL
elective surgery
Darbepoetin alfa: Long-acting glycosylated form administered weekly

Methoxy polyethylene glycol-epoetin beta: Long-acting form administered 1–2 times per month
MYELOID GROWTH FACTORS

Stimulates G-CSF Stimulates neutrophil Neutropenia associated with Toxicity: Bone pain
colony-stimulating receptors expressed progenitor proliferation congenital neutropenia, cyclic
factor (G-CSF; on mature and differentiation neutropenia, myelodysplasia, and
filgrastim) neutrophils and their
progenitors activity of mature prevention of neutropenia in
neutrophils and patients undergoing cytotoxic
extends their survival
peripheral blood cells in
hematopoietic stem preparation for autologous and
cells allogeneic stem cell transplantation
Pegfilgrastim: Long-acting form of filgrastim that is covalently linked to a type of polyethylene glycol
Tbo-filgrastim: Similar to filgrastim
GM-CSF (sargramostim): Myeloid growth factor that acts through a distinct GM-CSF receptor to stimulate proliferation and differentiation of early and late granulocytic
progenitor cells, and erythroid and megakaryocyte progenitors; clinical uses are similar to those of G-CSF, but it is more likely than G-CSF to cause fever, arthralgia,
myalgia, and capillary leak syndrome
Plerixafor: Antagonist of CXCR4 used in combination with G-CSF for mobilization of peripheral blood cells prior to autologous transplantation in patients with multiple
myeloma or non-Hodgkin’s lymphoma who responded suboptimally to G-CSF alone
MEGAKARYOCYTE GROWTH FACTORS

Recombinant form of Stimulates growth of Secondary prevention of Toxicity: Fatigue,
(interleukin-11; an endogenous multiple lymphoid and thrombocytopenia in patients headache, dizziness, anemia, fluid
IL-11) myeloid cells, including undergoing cytotoxic accumulation in the lungs, and transient
IL-11 receptors megakaryocyte chemotherapy for nonmyeloid atrial arrhythmias
cancers
the number of
circulating platelets and
neutrophils
Romiplostim: Subcutaneously administered thrombopoietin agonist approved for treatment of chronic immune thrombocytopenia with insufficient response to
corticosteroids, intravenous immunoglobulin, or splenectomy.
Eltrombopag: Orally active thrombopoietin agonist approved for treatment of chronic immune thrombocytopenia with insufficient response to corticosteroids,
intravenous immunoglobulin, or splenectomy; and for treatment of thrombocytopenia in hepatitis C to allow the use of interferon-based therapies.
CHAPTER 35 Agents Used in Dyslipidemia 639
HMG-CoA REDUCTASE INHIBITORS & REDUCTASE INHIBITORS &

BILE ACID-BINDING RESINS FENOFIBRATE
This synergistic combination is useful in the treatment of familial Fenofibrate appears to be complementary with most statins in
hypercholesterolemia but may not control levels of VLDL in some the treatment of familial combined hyperlipoproteinemia and
patients with familial combined hyperlipoproteinemia. other conditions involving elevations of both LDL and VLDL.
The combination of fenofibrate with rosuvastatin appears to
be especially well tolerated. Some other statins may interact
NIACIN & BILE ACID-BINDING RESINS unfavorably owing to effects on cytochrome P450 metabolism.
In any case, particular vigilance for liver and muscle toxicity is
This combination effectively controls VLDL levels during resin indicated.
therapy of familial combined hyperlipoproteinemia or other
disorders involving both increased VLDL and LDL levels. When
VLDL and LDL levels are both initially increased, doses of niacin COMBINATIONS OF RESINS, EZETIMIBE,
as low as 1–3 g/d may be sufficient in combination with a resin. NIACIN, & REDUCTASE INHIBITORS
The niacin-resin combination is effective for treating heterozygous
familial hypercholesterolemia. These agents act in a complementary fashion to normalize cho-
lesterol in patients with severe disorders involving elevated LDL.
The effects are sustained, and little compound toxicity has been
NIACIN & REDUCTASE INHIBITORS observed. Effective doses of the individual drugs may be lower
than when each is used alone; for example, as little as 1–2 g of
If the maximum tolerated statin dose fails to achieve the LDL niacin may substantially increase the effects of the other agents.
cholesterol goal in a patient with hypercholesterolemia, niacin
may be helpful. This combination may be useful in the treatment
of familial combined hyperlipoproteinemia. COMBINATIONS OF PCSK9 ANTIBODY
WITH STATIN AND EZETIMIBE
REDUCTASE INHIBITORS & EZETIMIBE These agents can be used together to achieve maximal reduction of
LDL. Because of the need for parenteral administration of PCSK9
This combination is synergistic in treating primary hypercho-
antibody and its expense, this therapy is reserved for patients with
lesterolemia and may be of use in the treatment of patients
familial hypercholesterolemia or atherosclerotic vascular disease
with homozygous familial hypercholesterolemia who have some
who do not respond adequately to other regimens.
receptor function.
SUMMARY Drugs Used in Dyslipidemia

Subclass, Pharmacokinetics, Toxicities,
Drug Mechanism of Action Effects Clinical Applications Interactions
STATINS
Inhibit HMG-CoA reductase Reduce cholesterol synthesis and Atherosclerotic vascular Toxicity: Myopathy,
simvastatin, upregulate low-density disease (primary and Interactions:
rosuvastatin, lipoprotein (LDL) receptors on secondary prevention)
pitavastatin interacts with CYP inhibitors/competitors
in triglycerides syndromes
Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious
FIBRATES
Peroxisome proliferator- Decrease secretion of Hypertriglyceridemia, Toxicity: Myopathy,
gemfibrozil activated receptor-alpha very-low-density lipoproteins low HDL hepatic dysfunction
(PPAR-α) agonists
high-density lipoproteins (HDL)
(continued)
640 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout
Subclass, Pharmacokinetics, Toxicities,

Drug Mechanism of Action Effects Clinical Applications Interactions
BILE ACID SEQUESTRANTS

Binds bile acids in gut Decreases LDL Elevated LDL, digitalis
toxicity, pruritus Toxicity:
with absorption of some drugs and vitamins
receptors
Cholestyramine, colesevelam: Similar to colestipol
STEROL ABSORPTION INHIBITOR

Blocks sterol transporter Inhibits reabsorption of Elevated LDL, Toxicity: Low incidence
NPC1L1 in intestine brush cholesterol excreted in bile phytosterolemia of hepatic dysfunction, myositis
border
NIACIN
Decreases catabolism of Toxicity: Gastric irritation,
lipoprotein(a) [Lp(a)], LDL Lp(a); elevated LDL in flushing, low incidence of hepatic toxicity
secretion from liver statin-unresponsive or
intolerant patients
Extended-release niacin: Similar to regular niacin

Sustained-release niacin (not the same as extended-release product): Should be avoided
PCSK9 HUMANIZED MONOCLONAL ANTIBODIES

Evolocumab Complexes PCSK9 Inhibits catabolism of LDL Familial Toxicity:
receptor hypercholesterolemia not injection site reactions, nasopharyngitis,
responsive to oral therapy flu-like symptoms, rarely myalgia,
neurocognitive and ophthalmologic events
Alirocumab Similar to evolucumab
A V A I L A B L E Afshar M, Thanassoulis G: Lipoprotein(a): new insights from modern genomics.
Curr Opin Lipidol 2017;28:170.
Ballantyne CM et al: Efficacy and safety of a novel dual modulator of adenosine
GENERIC NAME TRADE NAMES triphosphate-citrate lyase and adenosine monophosphate-activated protein
Alirocumab Praluent kinase in patients with hypercholesterolemia: Results of a multicenter, ran-
domized, double-blind, placebo-controlled, parallel-group trial. J Am Coll
Atorvastatin Generic, Lipitor
Cardiol 2013;62:1154.
Cholestyramine Generic, Questran, Prevalite Boekholdt SM et al: Levels and changes of HDL cholesterol and apolipoprotein
Colesevelam Welchol A-I in relation to risk of cardiovascular events among statin-treated patients:
Colestipol Generic, Colestid A meta-analysis. Circulation 2013;128:1504.
Evolocumab Repatha Bonow RO, Yancy CW: High-intensity statins for secondary prevention. JAMA
Cardiol 2017;2:55.
Ezetimibe Generic, Zetia
Cannon CP et al: Ezetimibe added to statin therapy after acute coronary
Fenofibrate Generic, Tricor, Antara, Lofibra syndrome. N Engl J Med 2015;372:2387.
Fluvastatin Generic, Lescol, Lescol XL Chou R et al: Statins for prevention of cardiovascular disease in adults: Evidence
Gemfibrozil Generic, Lopid report and systematic review for the US Preventive Services Task Force.
JAMA 2016;316:2008.
Lomitapide Juxtapid
Dron JS, Hegele RA: Complexity of mechanisms among human proprotein
Mipomersen Kynamro convertase subtilisin-kexin type 9 variants. Curr Opin Lipidol 2017;28:161.
Lovastatin Generic, Mevacor, Altoprev Elam M, Lovato E, Ginsberg H: The role of fibrates in cardiovascular disease
Niacin, nicotinic acid, vitamin B3 Generic only prevention, The ACCORD–lipid perspective. Curr Opin Lipidol 2011;22:55.
Lovaza Gaudet D et al: Antisense inhibition of apolipoprotein C-III in patients with
hypertriglyceridemia. N Engl J Med 2015;373:438.
Pitavastatin Livalo
Gouni-Berthold I et al: Systematic review of published phase 3 data on anti-
Pravastatin Generic, Pravachol PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J
Rosuvastatin Generic, Crestor Clin Pharmacol 2016;82:1412.
Simvastatin Generic, Zocor International Atherosclerosis Society: IAS Position Paper: Global Recommenda-
tions for the Management of Dyslipidemia. Available at: www.athero.org/
COMBINATION TABLETS
IASPositionPaper.asp.
Ezetimibe/simvastatin Vytorin Jacobson TA et al: On behalf of the NLA Expert Panel. National Lipid Association
Niacin/lovastatin extended-release Advicor recommendations for patient-centered management of dyslipidemia: Part 2.
Niacin/simvastatin extended-release Simcor J Clin Lipidol 2015;9:S1.
682 SECTION VII Endocrine Drugs
15 minutes, with renal and hepatic metabolism via reduction of bleeding. High-dose vasopressin as a 40-unit intravenous bolus
the disulfide bond and peptide cleavage. injection may be given to replace epinephrine in the Advanced
Desmopressin can be administered intravenously, subcutane- Cardiovascular Life Support (ACLS) resuscitation protocol for
ously, intranasally, or orally. The half-life of circulating desmo- pulseless arrest.
pressin is 1.5–2.5 hours. Nasal desmopressin is available as a unit Desmopressin is also used for the treatment of coagulopathy in
dose spray that delivers 10 mcg per spray; it is also available with hemophilia A and von Willebrand disease (see Chapter 34).
a calibrated nasal tube that can be used to deliver a more precise
dose. Nasal bioavailability of desmopressin is 3–4%, whereas oral Toxicity & Contraindications
bioavailability is less than 1%.
Headache, nausea, abdominal cramps, agitation, and allergic reac-
tions occur rarely. Overdosage can result in hyponatremia and
Pharmacodynamics seizures.
Vasopressin activates two subtypes of G protein–coupled recep- Vasopressin (but not desmopressin) can cause vasoconstriction
tors (see Chapter 17). V1 receptors are found on vascular smooth and should be used cautiously in patients with coronary artery
muscle cells and mediate vasoconstriction via the coupling protein disease. Nasal insufflation of desmopressin may be less effective
Gq and phospholipase C. V2 receptors are found on renal tubule when nasal congestion is present.
cells and reduce diuresis through increased water permeability
and water resorption in the collecting tubules via Gs and adenylyl
cyclase. Extrarenal V2-like receptors regulate the release of coagu- VASOPRESSIN ANTAGONISTS
lation factor VIII and von Willebrand factor, which increases
platelet aggregation. A group of nonpeptide antagonists of vasopressin receptors has
been investigated for use in patients with hyponatremia or acute
heart failure, which is often associated with elevated concentrations
Clinical Pharmacology of vasopressin. Conivaptan has high affinity for both V1a and V2
Vasopressin and desmopressin are treatments of choice for receptors. Tolvaptan has a 30-fold higher affinity for V2 than for
pituitary diabetes insipidus. The dosage of desmopressin is V1 receptors. In several clinical trials, both agents promoted the
10–40 mcg (0.1–0.4 mL) in two to three divided doses as a excretion of free water, relieved symptoms, and reduced objective
nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times signs of hyponatremia and heart failure. Conivaptan, administered
daily. The dosage by injection is 1–4 mcg (0.25–1 mL) every intravenously, and tolvaptan, given orally, are approved by the
12–24 hours as needed for polyuria, polydipsia, or hypernatre- FDA for treatment of hyponatremia. Tolvaptan treatment dura-
mia. Bedtime desmopressin therapy, by intranasal or oral admin- tion is limited to 30 days due to risk of hepatotoxicity, including
istration, ameliorates nocturnal enuresis by decreasing nocturnal life-threatening liver failure. Several other nonselective nonpeptide
urine production. Vasopressin infusion is effective in some vasopressin receptor antagonists are being investigated for these
cases of esophageal variceal bleeding and colonic diverticular conditions (see Chapter 15).
SUMMARY Hypothalamic & Pituitary Hormones1

GROWTH HORMONE (GH)

Recombinant form of Restores normal growth and Replacement in GH deficiency Toxicity: Pseudotumor
metabolic GH effects in cerebri, slipped capital femoral
through GH receptors GH-deficient individuals children with certain conditions epiphysis, edema, hyperglycemia,
to increase production associated with short stature (see progression of scoliosis, risk of
of IGF-I in some children with short Table 37–4 asphyxia in severely obese patients
stature not due to GH with Prader-Willi syndrome and upper
deficiency airway obstruction or sleep apnea
IGF-I AGONIST
Recombinant form of Improves growth and Replacement in IGF-I deficiency that Toxicity: Hypoglycemia,
IGF-I that stimulates metabolic IGF-I effects in is not responsive to exogenous GH intracranial hypertension, increased
IGF-I receptors individuals with IGF-I liver enzymes
deficiency due to severe GH
resistance
(continued)
CHAPTER 37 Hypothalamic & Pituitary Hormones 683
SOMATOSTATIN ANALOGS
Toxicity:
Lanreotide: Similar to octreotide; available as a long-acting formulation for acromegaly
GH RECEPTOR ANTAGONIST
Toxicity:
GONADOTROPINS: FOLLICLE-STIMULATING HORMONE (FSH) ANALOGS

Toxicity:
Follitropin beta: A recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains
Urofollitropin: Human FSH purified from the urine of postmenopausal women
Menotropins (hMG): Extract of the urine of postmenopausal women; contains both FSH and LH activity
GONADOTROPINS: LUTEINIZING HORMONE (LH) ANALOGS

Toxicity:
Choriogonadotropin alfa: Recombinant form of hCG

Lutropin: Recombinant form of human LH
Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity
GONADOTROPIN-RELEASING HORMONE (GnRH) ANALOGS
Toxicity:
Gonadorelin: Synthetic human GnRH

Other GnRH analogs: Goserelin, buserelin, histrelin, nafarelin, and triptorelin
GONADOTROPIN-RELEASING HORMONE (GnRH) RECEPTOR ANTAGONISTS

Toxicity:
Cetrorelix: Similar to ganirelix, approved for controlled ovarian stimulation

Degarelix and abarelix: Approved for advanced prostate cancer
(continued
DOPAMINE AGONISTS
Activates dopamine Suppresses pituitary Treatment of hyperprolactinemia Administered orally or, for
D2 receptors secretion of prolactin and, hyperprolactinemia, vaginally
less effectively, GH (see Chapter 28) Toxicity: Gastrointestinal
disturbances, orthostatic hypotension,
CNS motor control and headache, psychiatric disturbances,
behavior vasospasm and pulmonary infiltrates
in high doses
Cabergoline: Another ergot derivative with similar effects
OXYTOCIN Activates oxytocin Increased uterine Induction and augmentation of Toxicity:

receptors contractions Fetal distress, placental abruption,
hemorrhage after delivery uterine rupture, fluid retention,
hypotension
OXYTOCIN RECEPTOR ANTAGONIST

Blocks oxytocin Decreased uterine Tocolysis for preterm labor Toxicity: Concern about
receptors contractions (not available in the USA) increased rates of infant death; not
FDA approved
VASOPRESSIN RECEPTOR AGONISTS

Relatively selective Acts in the kidney collecting Pituitary diabetes insipidus Toxicity:
vasopressin V2 receptor duct cells to decrease the Gastrointestinal disturbances,
agonist headache, hyponatremia, allergic
extrarenal V2 receptors to Willebrand disease reactions
increase factor VIII and von
Willebrand factor
Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices
VASOPRESSIN RECEPTOR ANTAGONIST

Antagonist of Reduced renal excretion of Hyponatremia in hospitalized Toxicity: Infusion site
vasopressin V1a and water in conditions patients reactions
V2 receptors associated with increased
vasopressin
Tolvaptan: Similar but more selective for vasopressin V2 receptors; oral administration; treatment course limited to 30 days due to risk of hepatotoxicity
1
See Tables 37–2 and 37–3 for summaries of the clinical uses of the rarely used hypothalamic and pituitary hormones not described in this table.
CHAPTER 38 Thyroid & Antithyroid Drugs 701
SUMMARY Drugs Used in the Management of Thyroid Disease

Mechanism of Action Pharmacokinetics, Toxicities,
Subclass, Drug and Effects Indications Interactions
THYROID PREPARATIONS
4) Activation of nuclear receptors Hypothyroidism See Table 38–1
3) results in gene expression with RNA Toxicity: See
formation and protein synthesis Table 38–4 for symptoms of thyroid excess
ANTITHYROID AGENTS
THIOAMIDES
Inhibit thyroid peroxidase reactions Hyperthyroidism
peripheral deiodination of T4 and T3 Toxicity: Nausea, gastrointestinal

(primarily PTU) distress, rash, agranulocytosis, hepatitis
(PTU black box), hypothyroidism
IODIDES
Inhibit organification and hormone Preparation for surgical thyroidectomy Toxicity:
Rare (see text)
vascularity of the gland
BETA BLOCKERS
β blockers Inhibition of β adrenoreceptors Hyperthyroidism, especially thyroid
lacking partial agonist activity 4 to T3 conversion (only Toxicity: Asthma, AV
propranolol) hypertension, and atrial fibrillation blockade, hypotension, bradycardia
RADIOACTIVE IODINE 131I (RAI)

Radiation destruction of thyroid
parenchyma euthyroid or on β blockers before Toxicity:
Sore throat, sialitis, hypothyroidism
nursing mothers
A V A I L A B L E General
American Thyroid Association: Professional Guidelines. Available at: www.thyroid.
GENERIC NAME AVAILABLE AS org/professionals/ata-professional-guidelines/.
THYROID AGENTS American Thyroid Association Task Force on Radiation Safety et al: Radiation
safety in the treatment of patients with thyroid diseases by radioiodine 131I:
Levothyroxine (T4) Generic, Levoxyl, Levo-T, Practice recommendations of the American Thyroid Association. Thyroid
Levothroid, Levolet*, 2011;21:335.
Novothyrox, Synthroid,
Chen AY et al: American Thyroid Association Statement on Optimal Surgical
Tirosint (capsule), Unithroid Management of Goiter. Thyroid 2014;24:181.
Liothyronine (T3) Generic, Cytomel, Triostat (IV) Cooper DS, Ladenson PW: The thyroid gland. In: Gardner DG, Shoback D (editors):
Liotrix (a 4:1 ratio of T4: T3) Thyrolar Greenspan’s Basic & Clinical Endocrinology, 9th ed. McGraw-Hill, 2011.
Thyroid desiccated (USP) Generic, Armour, Nature- Haugen BR et al: 2015 American Thyroid Association Management Guidelines
Throid, Westhroid for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer:
The American Thyroid Association Guidelines Task Force on Thyroid
ANTITHYROID AGENTS Nodules and Differentiated Thyroid Cancer. Thyroid 2016;26:1.
Radioactive iodine (131I) sodium Iodotope, Sodium Iodide Rugge JB, Bougatsos C, Chou R: Screening and treatment of thyroid dysfunction:
I 131 Therapeutic An evidence review for the U.S. Preventive Services Task Force. Ann Intern
Methimazole Generic, Tapazole Med. 2015;162:35.
Potassium iodide U.S. Department of Health and Human Services: Potassium iodide as a
thyroid blocking agent in radiation emergencies. Available at: www.fda.
Oral solution (SSKI) ThyroShield
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
Oral solution (Lugol’s solution) Lugol’s solution UCM080542.pdf.
Oral potassium iodide tablets IOSAT, Thyro-Block, Thyro-Safe
Propylthiouracil [PTU] Generic Thyroid Hormone Action
DIAGNOSTIC AGENT
Chatterjee VK et al: Thyroid in 2012: Advances in thyroid development, hormone
Thyrotropin; recombinant human TSH Thyrogen action and neoplasia. Nat Rev Endocrinol 2013;9:74.
∗ Galli E, Pingitore A, Iervasi G: The role of thyroid hormone in the pathophysiology
Not available in United States.
of heart failure: Clinical evidence. Heart Fail Rev 2010;15:155.
correction of these variables must be monitored closely. Low-dose state subsequent to the onset of puberty and glycemic control. In
insulin therapy may be required. type 1 diabetes, end-stage chronic kidney disease develops in up
to 40% of patients, compared with less than 20% of patients with
type 2 diabetes. Proliferative retinopathy ultimately develops in
Chronic Complications of Diabetes both types of diabetes but has a slightly higher prevalence in type
Late clinical manifestations of diabetes mellitus include a number of 1 patients (25% after 15 years’ duration). In patients with type 1
pathologic changes that involve small and large blood vessels, cranial diabetes, complications from end-stage chronic kidney disease are
and peripheral nerves, the skin, and the lens of the eye. These lesions a major cause of death, whereas patients with type 2 diabetes are
lead to hypertension, end-stage chronic kidney disease, blindness, more likely to have macrovascular diseases leading to myocardial
autonomic and peripheral neuropathy, amputations of the lower infarction and stroke as the main causes of death. Cigarette use adds
extremities, myocardial infarction, and cerebrovascular accidents. significantly to the risk of both microvascular and macrovascular
These late manifestations correlate with the duration of the diabetic complications in diabetic patients.
SUMMARY Drugs Used for Diabetes

Mechanism of Clinical Pharmacokinetics,
Subclass, Drug Action Effects Applications Toxicities, Interactions
INSULINS
Activate insulin receptor Reduce circulating glucose Type 1 and type 2
glulisine, inhaled regular diabetes Toxicity:
Hypoglycemia, weight gain,
lipodystrophy (rare)
degludec
SULFONYLUREAS
Insulin secretagogues: Reduce circulating glucose in Type 2 diabetes
Close K+ channels in patients with functioning Toxicity: Hypoglycemia, weight
beta cells gain
1
insulin release
Tolazamide, tolbutamide, chlorpropamide, acetohexamide: Older sulfonylureas, lower potency, greater toxicity; rarely used
MEGLITINIDE ANALOGS; D-PHENYLANALINE DERIVATIVE

Insulin secretagogue: In patients with functioning Type 2 diabetes
1
Similar to sulfonylureas beta cells, reduce circulating
with some overlap in glucose Toxicity: Hypoglycemia
binding sites
BIGUANIDES
Activates AMP kinase Decreases circulating Type 2 diabetes
glucose Toxicity:
renal gluconeogenesis Gastrointestinal symptoms, lactic
impaired renal/hepatic function
hypoxic/acidotic states, alcoholism
ALPHA-GLUCOSIDASE INHIBITORS
Inhibit intestinal Reduce conversion of starch Type 2 diabetes Toxicity:
1
α-glucosidases and disaccharides to
use if impaired renal/hepatic
postprandial hyperglycemia function, intestinal disorders
THIAZOLIDINEDIONES
Regulate gene Reduce insulin resistance Type 2 diabetes Toxicity:
expression by binding Fluid retention, edema, anemia,
to PPAR-γ and PPAR-α weight gain, macular edema, bone
CHF, hepatic disease
(continued)
CHAPTER 41 Pancreatic Hormones & Antidiabetic Drugs 769
Mechanism of Clinical Pharmacokinetics,

Subclass, Drug Action Effects Applications Toxicities, Interactions
GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS

Analogs of GLP-1: Bind Reduce post-meal glucose Type 2 diabetes, Toxicity: Nausea,
albiglutide, dulaglutide to GLP-1 receptors excursions: Increase glucose- liraglutide only: headache, vomiting, anorexia, mild
mediated insulin release, obesity weight loss, pancreatitis, C-cell
lower glucagon levels, slow tumors in rodents
gastric emptying, decrease
appetite
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

Block degradation of Reduces post-meal glucose Type 2 diabetes
linagliptin, alogliptin, GLP-1, raise circulating excursions: Increases Toxicity: Rhinitis, upper
vildagliptin1 GLP-1 levels glucose-mediated insulin respiratory infections, headaches,
release, lowers glucagon pancreatitis, rare allergic reactions
levels, slows gastric
emptying, decreases
appetite
SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

Block renal glucose Increase glucosuria, lower Type 2 diabetes Toxicity:
empagliflozin resorption plasma glucose levels Genital and urinary tract infections,
polyuria, pruritus, thirst, osmotic
diuresis, constipation
ISLET AMYLOID POLYPEPETIDE ANALOG

Analog of amylin: Binds Reduces post-meal glucose Type 1 and type 2
to amylin receptors excursions: Lowers glucagon diabetes Toxicity: Nausea,
levels, slows gastric anorexia, hypoglycemia, headache
emptying, decreases
appetite
BILE ACID SEQUESTRANT

Bile acid binder: Lowers Reduces glucose levels Type 2 diabetes
glucose through Toxicity: Constipation, indigestion,
unknown mechanisms flatulence
DOPAMINE AGONIST
D2 receptor agonist: Reduces glucose levels Type 2 diabetes Toxicity: Nausea,
Lowers glucose through vomiting, dizziness, headache
unknown mechanism
1
Not available in United States.
CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 789
may be involved. The disease is fairly common, although symp- 6 months if necessary. The principal toxicity of etidronate is the
tomatic bone disease is less common. Recent studies indicate that development of osteomalacia and an increased incidence of frac-
this infection may produce a factor that increases the stimulation tures when the dosage is raised substantially above 5 mg/kg per
of bone resorption by 1,25(OH)2D. The biochemical parameters day. The newer bisphosphonates such as risedronate and alendro-
of elevated serum alkaline phosphatase and urinary hydroxypro- nate do not share this adverse effect. Some patients treated with
line are useful for diagnosis. Along with the characteristic radio- etidronate develop bone pain similar in nature to the bone pain of
logic and bone scan findings, these biochemical determinations osteomalacia. This subsides after stopping the drug. The principal
provide good markers by which to follow therapy. adverse effect of alendronate and the newer bisphosphonates is
The goal of treatment is to reduce bone pain and stabilize or gastric irritation when used at these high doses. This is reversible
prevent other problems such as progressive deformity, fractures, on cessation of the drug.
hearing loss, high-output cardiac failure, and immobilization
hypercalcemia. Calcitonin and bisphosphonates are the first-line
agents for this disease. Calcitonin is administered subcutaneously ENTERIC OXALURIA
or intramuscularly in doses of 50–100 MRC (Medical Research
Council) units every day or every other day. Nasal inhalation at Patients with short bowel syndromes and associated fat malab-
200–400 units/d is also effective. Higher or more frequent doses sorption can present with renal stones composed of calcium and
have been advocated when this initial regimen is ineffective. oxalate. Such patients characteristically have normal or low urine
Improvement in bone pain and reduction in serum alkaline phos- calcium levels but elevated urine oxalate levels. The reasons for
phatase and urine hydroxyproline levels require weeks to months. the development of oxaluria in such patients are thought to be
Often a patient who responds well initially loses the response to twofold: first, in the intestinal lumen, calcium (which is now
calcitonin. This refractoriness is not correlated with the develop- bound to fat) fails to bind oxalate and no longer prevents its
ment of antibodies. absorption; second, enteric flora, acting on the increased sup-
Sodium etidronate, alendronate, risedronate, and tiludronate ply of nutrients reaching the colon, produce larger amounts of
are the bisphosphonates currently approved for clinical use in Pag- oxalate. Although one would ordinarily avoid treating a patient
et’s disease of bone in the United States. Other bisphosphonates, with calcium oxalate stones with calcium supplementation, this
including pamidronate, are being used in other countries. The is precisely what is done in patients with enteric oxaluria. The
recommended doses of bisphosphonates are etidronate, 5 mg/kg increased intestinal calcium binds the excess oxalate and prevents
per day; alendronate, 40 mg/d; risedronate, 30 mg/d; and tiludro- its absorption. Calcium carbonate (1–2 g) can be given daily in
nate, 400 mg/d. Long-term remission (months to years) may be divided doses, with careful monitoring of urinary calcium and
expected in patients who respond to a bisphosphonate. Treatment oxalate to be certain that urinary oxalate falls without a danger-
should not exceed 6 months per course but can be repeated after ous increase in urinary calcium.
SUMMARY Major Drugs Used in Diseases of Bone Mineral Homeostasis

Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities
VITAMIN D, METABOLITES, ANALOGS

3) Regulate gene transcription Stimulate intestinal calcium Osteoporosis, Hypercalcemia, hypercalciuria
2) via the vitamin D receptor absorption, bone resorption, renal osteomalacia, renal
calcium and phosphate reabsorption failure, malabsorption, have much longer half-lives
psoriasis than the metabolites and
analogs
BISPHOSPHONATES
Suppress the activity of Inhibit bone resorption and Osteoporosis, bone Adynamic bone, possible renal
osteoclasts in part via secondarily bone formation metastases, failure, rare osteonecrosis of the
inhibition of farnesyl hypercalcemia jaw, rare subtrochanteric (femur)
pyrophosphate synthesis fractures
(continued)
Mechanism of Clinical
Subclass, Drug Action Effects Applications Toxicities
HORMONES
These hormones act via their Teriparatide stimulates bone turnover Both are used in Teriparatide may cause
cognate G protein–coupled hypercalcemia and
receptors resorption is used for hypercalcemia hypercalciuria
Recombinant full-length rhPTH1-84 increases RANKL, Hypoparathyroidism Hypercalcemia, hypercalciuria
PTH; acts on the same decreases sclerostin, enhances
receptors as teriparatide calcium reabsorption from the kidney
SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Interacts selectively with Inhibits bone resorption without Osteoporosis Does not prevent hot flashes
estrogen receptors stimulating breast or endometrial
hyperplasia thromboembolism
RANK LIGAND (RANKL) INHIBITOR

Blocks bone resorption Osteoporosis May increase risk of infections
to RANKL and prevents it
from stimulating osteoclast
differentiation and function
CALCIUM RECEPTOR AGONIST

Activates the calcium- Inhibits PTH secretion Hyperparathyroidism Nausea
sensing receptor
MINERALS
Multiple physiologic actions Strontium suppresses bone Osteoporosis Ectopic calcification
phosphate through regulation of resorption and increases bone
multiple enzymatic
pathways required for bone mineralization or phosphate

VITAMIN D, METABOLITES, AND ANALOGS PHOSPHATE AND PHOSPHATE BINDER
Calcifediol (25(OH)D3) Rayaldee Phosphate
Calcitriol Oral: solution Fleet Phospho-soda, K-Phos-
Oral Generic, Rocaltrol Neutral, Neutra-Phos, Neutra-
Phos-K
Parenteral Calcijex
Sevelamer carbonate or HCl Renagel, Renvela
Cholecalciferol (D3) Generic, Delta-D
(vitamin D3) Lanthanum carbonate Fosrenol
Doxercalciferol Generic, Hectorol BISPHOSPHONATES
Ergocalciferol (D2) (vitamin Generic, Drisdol, others Alendronate sodium Generic, Fosamax
D2, calciferol) Etidronate disodium Generic, Didronel
Paricalcitol Ibandronate sodium Generic, Boniva
CALCIUM Pamidronate disodium Generic, Aredia
Calcium acetate (25% calcium) Generic, PhosLo Risedronate sodium Actonel, Atelvia
Calcium carbonate (40% calcium) Generic, Tums, Cal-Sup, Os-Cal 500 Tiludronate disodium Skelid
Calcium chloride (27% calcium) Generic
Calcium citrate (21% calcium) Generic, Cal-C-Caps, Cal-Cee OTHER DRUGS
Calcium glubionate Neo-Calglucon, Calcionate, Calcitonin-salmon Miacalcin, Calcimar, Salmonine
(6.5% calcium) Calciquid Cinacalcet Sensipar
Calcium gluceptate Generic Denosumab Prolia, Xgeva
(8% calcium)
Gallium nitrate Ganite
Calcium gluconate Generic
(9% calcium) Sodium fluoride Generic
Calcium lactate (13% calcium) Generic Teriparatide (1-34 active segment Forteo
of PTH)
Tricalcium phosphate Posture
(39% calcium) Recombinant human PTH 1-84 Natpara
840 SECTION VIII Chemotherapeutic Drugs
data documenting their safety. Oral or intravenously adminis- many potential adverse effects are uncommon, the FDA called for
tered fluoroquinolones have also been associated with peripheral updated warnings for all fluoroquinolones in 2016, stating that
neuropathy. Neuropathy can occur at any time during treatment these agents should be reserved for patients who do not have alter-
with fluoroquinolones and may persist for months to years after native options, particularly in less severe infections such as upper
the drug is stopped. In some cases it may be permanent. Although respiratory infections or uncomplicated cystitis.
SUMMARY Sulfonamides, Trimethoprim, and Fluoroquinolones

Subclass, Drug Mechanism of Action Effects Clinical Applications Interactions
FOLATE ANTAGONISTS
Synergistic combination of Bactericidal activity
sulfamethoxazole folate antagonists blocks against susceptible
purine production and bacteria P jiroveci 5:1 ratio of sulfamethoxazole to
nucleic acid synthesis Toxicity: Rash, fever, bone
marrow suppression, hyperkalemia,
nephrotoxicity
Sulfadiazine: Oral; first-line therapy for toxoplasmosis when combined with pyrimethamine
Trimethoprim: Oral; used alone only for lower urinary tract infections; may be safely prescribed to patients with sulfonamide allergy
Pyrimethamine: Oral; first-line therapy for toxoplasmosis when combined with sulfadiazine; coadminister with leucovorin to limit bone marrow toxicity
Pyrimethamine-sulfadoxine: Oral; second-line malaria treatment
FLUOROQUINOLONES
Inhibits DNA replication by Bactericidal activity Urinary tract infections
binding to DNA gyrase and against susceptible
topoisomerase IV bacteria Toxicity:
Gastrointestinal upset, neurotoxicity,
tendonitis
Levofloxacin: Oral, IV; L-isomer of ofloxacin; once-daily dosing; renal clearance; “respiratory” fluoroquinolone with improved activity versus pneumococcus
Moxifloxacin: Oral, IV; “respiratory” fluoroquinolone; once-daily dosing; improved activity versus anaerobes and M tuberculosis; hepatic clearance results in lower urinary
levels so use in urinary tract infections is not recommended
Gemifloxacin: Oral; “respiratory” fluoroquinolone

GENERAL-PURPOSE SULFONAMIDES PYRIMETHAMINE
Sulfadiazine Generic Pyrimethamine Daraprim
SULFONAMIDES FOR SPECIAL APPLICATIONS Pyrimethamine-sulfadoxine Generic, Fansidar
Mafenide Generic, Sulfamylon QUINOLONES & FLUOROQUINOLONES
Silver sulfadiazine Generic, Silvadene Ciprofloxacin Generic, Cipro, Cipro I.V., Ciloxan
Sulfacetamide sodium Generic
Gemifloxacin Factive
TRIMETHOPRIM Levofloxacin
Generic, Proloprim, Moxifloxacin Generic, Avelox, others
Norfloxacin Noroxin
Generic, Bactrim, Septra, others Ofloxacin Generic, Floxin, Ocuflox
CHAPTER 47 Antimycobacterial Drugs 851
RIFAMPIN and a major portion of the drug is excreted in feces. Clofazimine

is stored widely in reticuloendothelial tissues and skin, and its
Rifampin (see earlier discussion) in a dosage of 600 mg daily is crystals can be seen inside phagocytic reticuloendothelial cells. It
highly effective in leprosy and is given with at least one other drug is slowly released from these deposits, so the serum half-life may
to prevent emergence of resistance. Even a dose of 600 mg per be 2 months. A common dosage of clofazimine is 100–200 mg/d
month may be beneficial in combination therapy. orally. The most prominent adverse effect is discoloration of the
skin and conjunctivae. Gastrointestinal side effects are common.
This medication is no longer commercially available, but it can
CLOFAZIMINE be obtained through established programs. For example, an inves-
tigational new drug (IND) program is established in the USA
Clofazimine is a phenazine dye used in the treatment of multi- through the National Hansen’s Disease Program. Internation-
bacillary leprosy, which is defined as having a positive smear from ally, ministries of health can make requests directly to the World
any site of infection. Its mechanism of action has not been clearly Health Organization.
established. Absorption of clofazimine from the gut is variable,
SUMMARY First-Line Antimycobacterial Drugs

ISONIAZID Inhibits synthesis of mycolic Bactericidal activity against First-line agent for
acids, an essential susceptible strains of Toxicity:
component of mycobacterial M tuberculosis Hepatotoxic, peripheral neuropathy (give
cell walls against nontuberculous pyridoxine to prevent)
mycobacteria
RIFAMYCINS
Inhibits DNA-dependent RNA Bactericidal activity against First-line agent for

polymerase, thereby blocking susceptible bacteria and
production of RNA mycobacterial infections Toxicity: Rash,
rapidly emerges when used nephritis, thrombocytopenia, cholestasis,
as a single drug in the meningococcal colonization, flu-like syndrome with intermittent
treatment of active infection staphylococcal infections dosing
Rifabutin: Oral; similar to rifampin but less cytochrome P450 induction and fewer drug interactions
Rifapentine: Oral; long-acting analog of rifampin that may be given once weekly in select cases during the continuation phase of tuberculosis treatment or for treatment
of latent tuberculosis
PYRAZINAMIDE Bacteriostatic activity against “Sterilizing” agent used

pyrazinamide is converted to susceptible strains of during first 2 months of metabolites are renally cleared so use
the active pyrazinoic acid M tuberculosis 3 doses weekly if creatinine clearance
under acidic conditions in bactericidal against actively duration of therapy to be Toxicity: Hepatotoxic,
macrophage lysosomes dividing organisms shortened to 6 months hyperuricemia
ETHAMBUTOL Inhibits mycobacterial Bacteriostatic activity against Given in four-drug initial

arabinosyl transferases, which susceptible mycobacteria combination therapy for
are involved in the tuberculosis until drug Toxicity: Retrobulbar neuritis
polymerization reaction of
arabinoglycan, an essential used for nontuberculous
component of the mycobacterial infections
mycobacterial cell wall
CHAPTER 48 Antifungal Agents 861
Topical and shampoo forms of ketoconazole are also available

and useful in the treatment of seborrheic dermatitis and pityriasis
TOPICAL ALLYLAMINES
versicolor. Several other azoles are available for topical use (see Terbinafine and naftifine are allylamines available as topical
Preparations Available). creams (see Chapter 61). Both are effective for treatment of tinea
cruris and tinea corporis. These are prescription drugs in the USA.
SUMMARY Antifungal Drugs

POLYENE MACROLIDE
Forms pores in fungal Loss of intracellular contents Localized and systemic
membranes (which contain through pores is fungicidal Cryptococcus
ergosterol) but not in
mammalian (cholesterol-
containing) membranes Toxicity:
Interactions: Additive with
other renal toxic drugs
PYRIMIDINE ANALOG
Interferes with DNA and RNA Synergistic with Cryptococcus and
synthesis selectively in fungi chromoblastomycosis Toxicity: Myelosuppression
toxicity in host due to DNA infections
and RNA effects
AZOLES
Blocks fungal P450 enzymes Broad spectrum but toxicity
and interferes with interferes with mammalian restricts use to topical Interferes with steroid hormone
ergosterol synthesis P450 function therapy synthesis and phase I drug metabolism
Same as for ketoconazole Much more selective than Broad spectrum: ,

ketoconazole Cryptococcus, blastomycosis, into central nervous system (CNS)
coccidioidomycosis, : Low toxicity
histoplasmosis
ECHINOCANDINS
Blocks β-glucan synthase Prevents synthesis of fungal Fungicidal Toxicity:
cell wall used in aspergillosis Minor gastrointestinal effects, flushing
Interactions: Increases cyclosporine
levels (avoid combination)
ALLYLAMINE
Inhibits epoxidation of Reduces ergosterol Mucocutaneous fungal Toxicity:
infections Gastrointestinal upset, headache,
levels are toxic to fungi fungal cell membrane Interactions: None
reported
902 SECTION VIII Chemotherapeutic Drugs
SUMMARY Miscellaneous Antimicrobials

NITROIMIDAZOLE
Disruption of electron Bactericidal activity t½ 8 h)
transport chain against susceptible C difficile colitis
anaerobic bacteria and Toxicity: Gastrointestinal upset
protozoa
Tinidazole: Oral; similar to metronidazole but dosed once daily; approved for trichomonas, giardiasis, and amebiasis
MACROLIDE
Inhibits bacterial RNA Bactericidal in C difficile colitis Toxicity:
polymerase Gram-positive bacteria Nonspecific gastrointestinal upset
RIFAMYCIN
Inhibits bacterial RNA Bactericidal activity in Travelers’ diarrhea, hepatic Toxicity:
polymerase Gram-positive and encephalopathy, C difficile Nausea
Gram-negative bacteria colitis, irritable bowel syndrome
URINARY ANTISEPTICS
Not fully understood Bacteriostatic or Uncomplicated urinary tract t½
bactericidal activity
and inhibits multiple against susceptible prophylaxis Toxicity: Gastrointestinal upset
bacterial enzyme systems bacteria
Methenamine hippurate and methenamine mandelate: Oral; release formaldehyde at acidic pH in the urine; used only for prophylaxis, not treatment, of urinary tract infections
P R E P A R A T I O N S
A V A I L A B L E REFERENCES
Bischoff WE et al: Handwashing compliance by health care workers: The impact
of introducing an accessible, alcohol-based hand antiseptic. Arch Intern Med
GENERIC NAME AVAILABLE AS 2000;160:1017.
MISCELLANEOUS ANTIMICROBIAL DRUGS Chambers HF, Winston LG: Mupirocin prophylaxis misses by a nose. Ann Intern
Colistimethate sodium Generic, Coly-Mycin M Med 2004;140:484.
Fidaxomicin Dificid Gordin FM et al: Reduction in nosocomial transmission of drug-resistant bacte-
ria after introduction of an alcohol-based hand-rub. Infect Control Hosp
Methenamine hippurate Generic, Hiprex Epidemiol 2005;26:650.
Methenamine mandelate Generic, Mandelamine Hoonmo LK, DuPont HL: Rifaximin: A unique gastrointestinal-selective antibi-
Metronidazole Generic, Flagyl, Metro otic for enteric diseases. Curr Opin Gastroenterol 2010;26:17.
Mupirocin Generic, Bactroban, Centany Humphreys PN: Testing standards for sporicides. J Hosp Infect 2011;77:193.
Nitrofurantoin Generic, Macrodantin, Macrobid Louie TJ et al: Fidaxomicin versus vancomycin for Clostridium difficile infection.
N Engl J Med 2011;364:422.
Polymyxin B (Polymyxin B sulfate) Generic
Medical Letter: Tinidazole (Tindamax)—a new anti-protozoal drug. Med Lett
DISINFECTANTS, ANTISEPTICS, & STERILANTS Drugs Ther 2004;46:70.
Benzalkonium Generic, Zephiran Meyer GW: Endoscope disinfection. www.uptodate.com/contents/endoscope-
Benzoyl peroxide Generic disinfection. UpToDate 2017.
Chlorhexidine gluconate topical Generic, Hibiclens, Betasept, Noorani A et al: Systematic review and meta-analysis of preoperative antisepsis
with chlorhexidine versus povidone-iodine in clean-contaminated surgery.
others
Br J Surg 2010;97:1614.
Chlorhexidine gluconate, Peridex, Periogard Rutala WA, Weber DJ: Disinfection and sterilization in health care facilities: an
oral rinse: 0.12% overview and current issues. Infect Dis Clin N Am 2016;30:609.
Glutaraldehyde Cidex Rutala WA, Weber DJ: New disinfection and sterilization methods. Emerg Infect
Iodine aqueous Generic, Lugol’s Solution Dis 2001;7:348.
Iodine tincture Generic Widmer AF, Frei R: Decontamination, disinfection, and sterilization. In: Murray
PR et al (editors): Manual of Clinical Microbiology, 7th ed. American Society
Nitrofurazone Generic, Furacin
for Microbiology, 1999.
Ortho-phthalaldehyde Cidex OPA
Povidone-iodine Generic, Betadine
Silver nitrate Generic
Thimerosal Generic, Mersol
CHAPTER 62 Drugs Used in the Treatment of Gastrointestinal Diseases 1115
SUMMARY Drugs Used Primarily for Gastrointestinal Conditions

DRUGS USED IN ACID-PEPTIC DISEASES

Irreversible blockade of H+/ Long-lasting reduction of Peptic ulcer, Half-lives much shorter than duration of
inhibitors (PPIs), eg, K+-ATPase pump in active stimulated and nocturnal gastroesophageal reflux
omeprazole, parietal cells of stomach acid secretion disease, erosive gastritis stomach acid may reduce absorption of
lansoprazole some drugs and increase that of others
H2-receptor blockers, eg, cimetidine: Effective reduction of nocturnal acid but less effective against stimulated secretion; very safe, available over the counter (OTC).
Cimetidine, but not other H2 blockers, is a weak antiandrogenic agent and a potent CYP enzyme inhibitor
Sucralfate: Polymerizes at site of tissue damage (ulcer bed) and protects against further damage; very insoluble with no systemic effects; must be given four times daily
Antacids: Popular OTC medication for symptomatic relief of heartburn; not as useful as PPI and H2 blockers in peptic diseases
DRUGS STIMULATING MOTILITY
D2 Increases gastric emptying Gastric paresis (eg, in Parkinsonian symptoms due to block of
inhibition of acetylcholine and intestinal motility central nervous system (CNS) D2
neurons in enteric nervous (see below) receptors
system
Domperidone: Like metoclopramide, but less CNS effect; not available in USA
Cholinomimetics: Neostigmine often used for colonic pseudo-obstruction in hospitalized patients
Macrolides: Erythromycin useful in diabetic gastroparesis but tolerance develops
LAXATIVES
Osmotic agents increase Usually causes evacuation Simple constipation; Magnesium may be absorbed and cause
hydroxide, other water content of stool within 4–6 h, sooner in bowel prep for toxicity in renal impairment
nonabsorbable salts large doses endoscopy (especially
and sugars polyethylene glycol
[PEG] solutions)
Bulk-forming laxatives: Methylcellulose, psyllium, etc: increase volume of colon contents, stimulate evacuation
Stimulants: senna, cascara; stimulate activity; may cause cramping
Stool surfactants: Docusate, mineral oil; lubricate stool, ease passage
Chloride channel activators: Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content; linaclotide, guanylyl cyclase-C
agonist, stimulates chloride secretion by CFTR
Opioid receptor antagonists: Alvimopan, methylnaltrexone; block intestinal μ-opioid receptors but do not enter CNS, so analgesia is maintained
ANTIDIARRHEAL DRUGS
Activates μ-opioid receptors Slows motility in gut with Nonspecific, Mild cramping but little or no CNS
in enteric nervous system negligible CNS effects noninfectious diarrhea toxicity
Diphenoxylate: Similar to loperamide, but high doses can cause CNS opioid effects and toxicity
Colloidal bismuth compounds: Subsalicylate and citrate salts available. OTC preparations popular and have some value in travelers’ diarrhea due to adsorption of toxins
Kaolin + pectin: Adsorbent compounds available OTC in some countries
DRUGS FOR IRRITABLE BOWEL SYNDROME (IBS)
5-HT3 antagonist of high Reduces smooth muscle Approved for severe

potency and duration of activity in gut diarrhea-predominant
binding IBS in women
Anticholinergics: Nonselective action on gut activity, usually associated with typical antimuscarinic toxicity
Chloride channel activator: Lubiprostone (see above); useful in constipation-predominant IBS in women; linaclotide (see above): useful in adults with constipation-
predominant IBS
(continued)
1116 SECTION X Special Topics

ANTIEMETIC DRUGS
5-HT3 blockade in gut and Extremely effective in First-line agents in Usually given IV but orally active in
5-HT3 antagonists CNS with shorter duration of preventing chemotherapy- cancer chemotherapy;
binding than alosetron induced and postoperative also useful for postop
nausea and vomiting emesis transit
NK1-receptor blocker in CNS Interferes with vomiting Effective in reducing

both early and delayed
dopamine, or steroid emesis in cancer interactions
receptors chemotherapy
Corticosteroids: Mechanism not known but useful in antiemetic IV cocktails

Antimuscarinics (scopolamine): Effective in emesis due to motion sickness; not other types
Antihistaminics: Moderate efficacy in motion sickness and chemotherapy-induced emesis
Phenothiazines: Act primarily through block of D2 and muscarinic receptors
Cannabinoids: Dronabinol is available for use in chemotherapy-induced nausea and vomiting, but is associated with CNS marijuana effects
DRUGS USED IN INFLAMMATORY BOWEL DISEASE (IBD)
Topical therapeutic action Mild to moderately Sulfasalazine causes sulfonamide

eg, mesalamine in be inhibition of eicosanoid severe Crohn’s disease toxicity and may cause GI upset,
many formulations inflammatory mediators cause toxicity and ulcerative colitis myalgias, arthralgias, myelosuppression
Generalized suppression of Moderately severe to

antimetabolites, eg, promote apoptosis of immune processes severe Crohn’s disease
6-mercaptopurine, and ulcerative colitis hepatotoxicity, but rare with
methotrexate blocks dihydrofolate methotrexate at the low doses used
reductase
Bind tumor necrosis factor Suppression of several Infliximab: Moderately

eg, infliximab, others and prevent it from binding to aspects of immune severe to severe Crohn’s
its receptors function, especially TH1 disease and ulcerative dangerous systemic fungal and bacterial
lymphocytes infections
in Crohn’s disease
Corticosteroids: Generalized anti-inflammatory effect; see Chapter 39
PANCREATIC SUPPLEMENTS
Replacement enzymes from Improves digestion of Pancreatic insufficiency

animal pancreatic extracts dietary fat, protein, and due to cystic fibrosis, incidence of gout
carbohydrate pancreatitis,
pancreatectomy
Pancreatin: Similar pancreatic extracts but much lower potency; rarely used
BILE ACID THERAPY FOR GALLSTONES AND PRIMARY BILIARY CIRRHOSIS
Reduces cholesterol secretion Dissolves gallstones Gallstones in patients May cause diarrhea
into bile and concentration of refusing or not eligible
endogenous hepatocyte bile inflammation and fibrosis
salts primary biliary cirrhosis
Binds to hepatocyte nuclear Reduces hepatic Treatment of primary Severe pruritus

farnesoid X receptor inflammation and fibrosis biliary cirrhosis in
patients with
inadequate response to
ursodiol
DRUGS USED TO TREAT VARICEAL HEMORRHAGE
Somatostatin analog May alter portal blood flow Patients with bleeding Reduced endocrine and exocrine
and variceal pressures varices or at high risk of
repeat bleeding
Beta blockers: Reduce cardiac output and splanchnic blood flow; see Chapter 10

SUMMARY Drugs Used For Cholinomimetic Effects

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122 SECTION II Autonomic Drugs

SUMMARY Drugs Used for Cholinomimetic Effects

DIRECT-ACTING CHOLINE ESTERS

DIRECT-ACTING MUSCARINIC ALKALOIDS OR SYNTHETICS

Cevimeline: Synthetic M3-selective; similar to pilocarpine

DIRECT-ACTING NICOTINIC AGONISTS

SHORT-ACTING CHOLINESTERASE INHIBITOR (ALCOHOL)

INTERMEDIATE-ACTING CHOLINESTERASE INHIBITORS (CARBAMATES)

Pyridostigmine: Like neostigmine, but longer-acting (4–6 h); used in myasthenia

LONG-ACTING CHOLINESTERASE INHIBITORS (ORGANOPHOSPHATES)

SUMMARY Drugs with Anticholinergic Actions

MOTION SICKNESS DRUGS

Hyoscyamine: Longer duration of action

Homatropine: Shorter duration of action (12–24 h) than atropine

RESPIRATORY (ASTHMA, COPD)

Interactions: With other antimuscarinics

SUMMARY Sympathetic Antagonists

Block α1, but not α2 Lower BP Larger depressor effect with

Blocks α2 Raises BP and HR Male erectile dysfunction May cause anxiety

β > α1 block Lowers BP with limited HR Hypertension Toxicity:

Block β1 > β2 Toxicity:

β1, β2, with intrinsic Toxicity:

β > α1 block Heart failure Toxicity:

TYROSINE HYDROXYLASE INHIBITOR

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

SUMMARY Drugs Used in Hypertension

SYMPATHOPLEGICS, CENTRALLY ACTING

SYMPATHETIC NERVE TERMINAL BLOCKERS

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

ANGIOTENSIN RECEPTOR BLOCKERS (ARBS)

SUMMARY Drugs Used in Heart Failure

Decreases NaCl reabsorption in Same as furosemide, but

Enalapril, many other ACE inhibitors: Like captopril

Combined arteriolar Releases NO spontaneously Marked vasodilation Acute cardiac

Relevant structural heart disease No or minimal heart disease including

Heart failure Coronary artery Hypertension Paroxysmal Persistent

Dronedarone Dronedarone ESC: Ablation possible Dronedarone

Amiodarone Catheter Amiodarone

SUMMARY Antiarrhythmic Drugs

Mechanism Pharmacokinetics, Toxicities,

Diltiazem: Equivalent to verapamil

Increases K+ Digitalis-induced arrhythmias Toxicity: Reentrant arrhythmias,

SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot

Mechanism Clinical Pharmacokinetics, Toxicities,

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Clemastine Generic, Tavist Olopatadine Patanol, Pataday

Cyclizine Generic, Marezine Phenindamine Nolahist

Cyproheptadine Generic, Periactin Promethazine Generic, Phenergan

Desloratadine Generic, Clarinex Triprolidine Generic, Zymine, Tripohist

Diphenhydramine Generic, Benadryl See Chapter 62.

Doxylamine Diclegis (combination with 5-HT AGONISTS

MELATONIN RECEPTOR AGONISTS

1 and MT2 agonist, recently approved for non-24-hour sleep disorder

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

SUMMARY THE ALCOHOLS AND ASSOCIATED DRUGS

DRUGS USED IN ACUTE ETHANOL WITHDRAWAL

1) Essential vitamin required Administered to patients suspected of Toxicity: Interactions: None

DRUGS USED IN CHRONIC ALCOHOLISM

DRUGS USED IN ACUTE METHANOL OR ETHYLENE GLYCOL TOXICITY

had been difficult to achieve. There is little information on

SUMMARY ANTISEIZURE DRUGS

SODIUM CHANNEL BLOCKERS