CHAPTER 11 Drugs Used in Hypertension 101

DRUG SUMMARY TABLE: Drugs Used in Hypertension

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Diuretics (see also Chapter 15)

Hydrochlorothiazide, Block Na/Cl transporter in Hypertension, mild Oral Hypokalemia, hypergly-
chlorthalidone distal convoluted tubule edema Duration: 8–12 h cemia, hyperuricemia,
hyperlipidemia
Furosemide Block Na/K/2Cl transporter Hypertension, heart Oral, parenteral Hypokalemia, hypovolemia,
in thick ascending limb failure, edema, Duration: 2–3 h ototoxicity
hypercalcemia

Sympathoplegics
Centrally acting
Clonidine Agonist at α2 Hypertension Oral and transdermal Sedation, danger of severe
CNS this results in decreased rebound hypertension if
SANS outflow transdermal 1 wk suddenly stopped
Methyldopa Prodrug converted to meth- Hypertension Oral Sedation, induces hemo-
ylnorepinephrine in CNS, Duration: 12–24 h lytic antibodies
with effects like clonidine
Ganglion blockers
Hexamethonium Obsolete prototype nico- None Oral, parenteral; no CNS Severe orthostatic hypoten-
tinic acetylcholine (ACh) effect sion, constipation, blurred
vision, sexual dysfunction
blocks all ANS transmission
Trimethaphan: IV, obsolete short-acting ganglion blocker for hypertensive emergencies, controlled hypotension
Mecamylamine: oral ganglion blocker, several hours’ duration, enters CNS

Postganglionic neuron blockers

Reserpine Blocks vesicular pump Obsolete in hyperten- Oral -
(VMAT) in adrenergic sion, Huntington’s Duration: 5 days ric depression (high doses)
neurons disease

Guanadrel: blocks release of norepinephrine, depletes stores; oral, long duration; severe orthostatic hypotension (guanethidine, a similar drug,
was withdrawn in the United States)

Alpha blockers
Prazosin Selective α1 Mild hypertension, Oral First dose orthostatic
reduces peripheral vascu- benign prostatic Duration: 6–8 h hypotension
hyperplasia
smooth muscle tone

Doxazosin, terazosin: similar to prazosin but longer duration of action

Beta blockers
Propranolol Prototype nonselective β Oral, parenteral Bronchospasm in asth-
other applications (see Duration: 6–8 h (extended
Chapter 10) release forms available) depression, sexual dys-
reduction in renin release function, sedation, sleep
disturbances
Atenolol, metoprolol: like propranolol but β1-selective; fewer adverse effects
Labetalol, carvedilol: combined α and β blockade; oral and parenteral
(Continued )
102 PART III Cardiovascular Drugs

DRUG SUMMARY TABLE: Drugs Used in Hypertension (Continued)

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Vasodilators, oral
Calcium channel blockers
Nifedipine, other Prototype L-type calcium Hypertension, angina Oral Constipation
dihydropyridines Duration: 6–24 h
moderate vascular effect
with weak cardiac effect
Verapamil, diltiazem oral and parenteral; also used in arrhythmias; greater cardiodepressant effects than dihydropyridines; verapamil blocks
P-glycoprotein transporter (see Chapter 5)
Older oral vasodilators
Hydralazine Probably causes release of Hypertension (also used Oral Tachycardia, salt and
nitric acid (NO) by endothe- in heart failure in com- Duration: 6–8 h water retention, lupus-like
bination with isosorbide syndrome
dilation dinitrate)
Minoxidil Prodrug, sulfate metabolite Severe hypertension Oral, topical Marked tachycardia, salt
opens K+ channels, causes Duration: 6–8 h and water retention
arteriolar smooth muscle
hyperpolarization and
vasodilation

Vasodilators, parenteral
Nitroprusside Releases NO from drug Hypertensive emer- Parenteral only Excessive hypotension
molecule
decompensation requires constant infusion cause thiocyanate and
cyanide toxicity
Diazoxide K+ channel opener in Hypertensive emergencies Parenteral for hyperten-
smooth muscle, secretory sion, oral for insulinoma excessive hypotension
cells insulin-secreting tumors
Fenoldopam D1 - Hypertensive Parenteral only, very short Excessive hypotension
lar dilation emergencies duration

Renin antagonist
Aliskiren Hypertension Oral Angioedema, renal
angiotensin I synthesis Duration: 12 h impairment

Angiotensin antagonists
ACE inhibitors
Captopril Hypertension, diabetic Oral
angiotensin II synthesis renal disease, heart Half-life: 2.2 h but large
failure doses provide duration
of 12 h
Benazepril, enalapril, lisinopril, others: like captopril but longer half-lives
Angiotensin II receptor blockers (ARBs)
Losartan Blocks AT1 receptors Hypertension Oral
Duration: 6–8 h
Candesartan, irbesartan, others: like losartan
ACE, angiotensin-converting enzyme; ANS, autonomic nervous system; CNS, central nervous system; SANS, sympathetic autonomic nervous system.
 CHAPTER 12 Drugs Used in the Treatment of Angina Pectoris 111

DRUG SUMMARY TABLE: Drugs Used in Angina

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Short-acting nitrate
Nitroglycerin, Releases nitric oxide (NO), Acute angina pectoris Rapid onset (1 min) Tachycardia, orthostatic
sublingual (SL) increases cGMP (cyclic hypotension, headache
guanosine monophos- syndrome
phate), and relaxes vascu-
lar smooth muscle
Isosorbide dinitrate (SL): like nitroglycerin SL but slightly longer acting (20–30 min)

Intermediate-acting nitrate
Nitroglycerin, oral Like nitroglycerin SL Prophylaxis of angina Same as nitroglycerin SL
2–4 h
dinitroglycerin
Isosorbide dinitrate and mononitrate, oral: like nitroglycerin oral
Pentaerythritol tetranitrate and other oral nitrates: like nitroglycerin oral

Long-acting nitrate
Transdermal Like nitroglycerin oral Prophylaxis of angina - Same as nitroglycerin SL
nitroglycerin tion of absorption: 24 h
after 10–12 h exposure to
(tachyphylaxis) drug

Ultrashort-acting nitrite
Amyl nitrite Same as nitroglycerin SL Volatile liquid, vapors are Same as nitroglycerine SL
some recreational use

Calcium channel blockers

Verapamil Blocks L-type Ca2+ chan- Angina (both atheroscle- Oral, parenteral Constipation, pretibial
nels in smooth muscle rotic and vasospastic), Duration: 6–8 h edema, flushing, dizziness

intracellular Ca2+ arrhythmias; migraine depression, hypotension

Diltiazem: like verapamil; shorter half-life
Nifedipine Dihydropyridine Ca2+ Angina, hypertension -
channel blocker; vascular Duration: 6–8 h pation, cardiac effect
> cardiac effect
Amlodipine, felodipine, nicardipine, nisoldipine: like nifedipine but longer acting

Beta blockers
Propranolol Blocks sympathetic effects Angina, hypertension, Oral, parenteral See Chapter 10
on heart and blood arrhythmias, migraine, Duration: 6 h
performance anxiety
release
Atenolol, metoprolol, other β blockers: like propranolol; most have longer duration of action

Other antianginal drugs

Ranolazine Blocks late Na+ current Angina Oral QT prolongation on ECG
in myocardium, reduces Duration: 10–12 h
cardiac work
Ivabradine Blocks pacemaker Na+ Investigational: angina, Oral, administered twice Unknown
current (If) in sinoatrial heart failure daily
node, reduces heart rate

Drugs for erectile dysfunction

Sildenafil, tadalafil, Block phosphodiesterase Erectile dysfunction in Oral Interaction with nitrates
vardenafil men Duration: hours
176 PART IV Drugs with Important Actions on Smooth Muscle

DRUG SUMMARY TABLE: Bronchodilators & Other Drugs Used in Asthma & COPD
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Short-acting a agonists
Albuterol Beta2-selective agonist Asthma acute attack relief Inhalation (aerosol) Tremor, tachycardia
drug of choice (not for Duration: 2–4 h
prophylaxis)
Metaproterenol, terbutaline: similar to albuterol; terbutaline also available as oral and parenteral formulations

Long-acting a agonists
Salmeterol, formoterol, Beta2-selective agonists; Asthma prophylaxis (not Inhalation (aerosol) Tremor, tachycardia,
indacaterol, vilanterol bronchodilation; potentiation - Duration: 12–24 h cardiovascular events
of corticosteroid action caterol and vilanterol for
COPD

Nonselective sympathomimetics

Epinephrine, Nonselective β activation Asthma (obsolete) Inhalation (aerosol, Excess sympathomimetic

isoproterenol α nebulizer) effect (Chapter 9)
agonist Duration: 1–2 h

Indirect-acting sympathomimetic
Ephedrine Releases stored catechol- Asthma (obsolete) Oral Insomnia, tremor,
Duration: 6–8 h anorexia, arrhythmias
sympathetic effects

Methylxanthines

Theophylline Phosphodiesterase inhibi- Asthma, especially pro- Oral slow-release Insomnia, tremor,
tion, adenosine receptor phylaxis against nocturnal Duration: 12 h anorexia, seizures,
attacks arrhythmias
poorly understood

Roflumilast: a nonpurine molecule with effects similar to theophylline but more selective for PDE4; approved for COPD

Caffeine: similar to theophylline with increased CNS effect, not used in asthma or COPD

Theobromine: similar to theophylline with increased cardiac effect, not used in asthma or COPD

Antimuscarinic agents
Ipratropium, tiotropium, Competitive pharmacologic Asthma and chronic Inhalation (aerosol) Dry mouth, cough
aclidinium muscarinic antagonists obstructive pulmonary Duration: several hours
disease

Unknown mechanism, possibly mast cell stabilizers

Cromolyn, nedocromil Reduce release of inflamma- Rarely used prophylaxis Inhaled aerosol for Cough
tory and bronchoconstrictor of asthma; cromolyn also
mediators from sensitized used for ophthalmic, application for other
mast cells nasopharyngeal, and gas- applications
trointestinal allergy Duration: 3–6 h
(Continued )
 CHAPTER 20 Drugs Used in Asthma & Chronic Obstructive Pulmonary Disease 177

DRUG SUMMARY TABLE: Bronchodilators & Other Drugs Used in Asthma & COPD (Continued )
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions

Leukotriene antagonists
Montelukast, Pharmacologic antagonists at Prophylaxis of asthma Oral Minimal
zafirlukast LTD4 receptors Duration: 12–24 h

Zileuton Inhibitor of lipoxygenase Prophylaxis of asthma Oral Elevation of liver enzymes

Duration: 12 h
leukotrienes

Corticosteroids
Inhaled
Beclomethasone, Inhibition of phospholipase Prophylaxis of asthma: Inhalation Pharyngeal candidiasis
others A2 drugs of choice Duration: 10–12 h -
cyclooxygenase roid toxicity (eg, adrenal
suppression)

Systemic
Prednisone, others Like inhaled corticosteroids Treatment of severe Oral See Chapter 39
refractory chronic asthma Duration: 12–24 h
Prednisolone: parenteral for status asthmaticus; similar to prednisone

Antibodies
Omalizumab Binds IgE antibodies on mast Prophylaxis of severe, Extremely expensive
cells; reduces reaction to refractory asthma not as several courses of
inhaled antigen responsive to all other injections yet well documented
drugs
 CHAPTER 24 Antiseizure Drugs 207

DRUG SUMMARY TABLE: Antiseizure Drugs

Pharmacokinetics and
Subclass Mechanism of Action Clinical Applications Interactions Toxicities

Cyclic ureides
Phenytoin Blocks voltage-gated Na+ Generalized tonic-clonic Variable absorption, Ataxia, diplopia, gingival
channels and partial seizures dose-dependent elimina- hyperplasia, hirsutism,
tion; protein binding; neuropathy
many drug interactions
Phenobarbital Enhances GABAA receptor Same as above Long half-life, inducer of Sedation, ataxia
responses
Ethosuximide Decreases Ca2+ currents Absence seizures Long half-life GI distress, dizziness,
(T-type) headache

Tricyclics
Carbamazepine Blocks voltage-gated Na+ Generalized tonic-clonic Well absorbed, active Ataxia, diplopia, headache,
channels and decreases and partial seizures nausea
glutamate release interactions

Benzodiazepines
Diazepam Enhance GABAA receptor Status epilepticus See Chapter 22 Sedation
responses
Clonazepam Absence and myoclonic See Chapter 22 Similar to above
seizures, infantile spasms

GABA derivatives
Gabapentin Blocks Ca2+ channels Generalized tonic-clonic Variable bioavailability Ataxia, dizziness,
and partial seizures somnolence
Pregabalin Same as above Partial seizures Renal elimination Same as above
Vigabatrin Inhibits GABA Partial seizures Renal elimination Drowsiness, dizziness, psy-
transaminase chosis, ocular effects

Miscellaneous
Valproate Blocks high-frequency Generalized tonic-clonic, Extensive protein binding Nausea, alopecia, weight
firing partial, and myoclonic and metabolism; many gain, teratogenic
seizures drug interactions
Lamotrigine Blocks Na+ and Ca2+ chan- Generalized tonic-clonic, Not protein-bound, exten- Dizziness, diplopia,
nels, decreases neuronal partial, myoclonic, and headache, rash
glutamate release absence seizures drug interactions
Levetiracetam Binds synaptic protein, Generalized tonic-clonic Well absorbed, extensive Dizziness, nervousness,
modifies GABA and and partial seizures depression, seizures
glutamate release interactions
Tiagabine Blocks GABA reuptake Partial seizures Extensive protein binding Dizziness, nervousness,
depression, seizures
drug interactions
Topiramate May block Na+ and Ca2+ Generalized tonic-clonic, Both hepatic and renal Sleepiness, cognitive slow-
channels; also increases absence, and partial sei- clearance ing, confusion, paresthesias
GABA effects zures, migraine
Zonisamide Blocks Na+ channels Generalized tonic-clonic, Both hepatic and renal Sleepiness, cognitive slow-
partial, and myoclonic clearance ing, poor concentration,
seizures paresthesias
228 PART V Drugs That Act in the Central Nervous System

DRUG SUMMARY TABLE: Skeletal Muscle Relaxants

Subclass Mechanism of Action Receptor Interactions Pharmacokinetics Adverse Effects

Depolarizing
Succinylcholine Agonist at ACh-N recep- Stimulates ANS ganglia Parenteral: short action, Muscle pain, hyperkalemia,
tors causing initial and M receptors inactivated by plasma increased intragastric and
twitch then persistent esterases intraocular pressure
depolarization

Nondepolarizing
d-Tubocurarine Competitive antagonists ANS ganglion block Parenteral use, variable Histamine release
Atracurium at skeletal muscle ACh-N (tubocurarine) disposition (mivacurium, tubocurarine)
Cisatracurium receptors
Mivacuriuma (pancuronium) (atracurium, cisatracurium) (atracurium) Muscle
Rocuronium relaxation is potentiated by
Vecuronium inhaled anesthetics,
(rocuronium, vecuronium) aminoglycosides and
- possibly quinidine
curium, pancuronium,
tubocurarine)

Centrally acting
Baclofen Facilitates spinal GABAB receptor Oral; intrathecal for severe Sedation, muscle weakness
inhibition of motor activation: pre- and spasticity
neurons postsynaptic
Cyclobenzaprine Inhibition of spinal Mechanism unknown Oral for acute muscle M block, sedation,
(many others; see text) stretch reflex spasm due to injury or confusion, and ocular
inflammation effects
Diazepam Facilitates GABA-ergic GABAA receptor Oral and parenteral for Sedation, additive with
transmission in CNS activation: postsynaptic acute and chronic spasms other CNS depressants

Tizanidine Pre- and postsynaptic α2 Agonist in spinal cord Oral for acute and chronic Muscle weakness, sedation,
inhibition spasms hypotension

Direct-acting
Dantrolene Weakens muscle Blocks RyR1 Ca2+ channels Oral for acute and chronic Muscle weakness
contraction by reducing in skeletal muscle
myosin-actin interaction hyperthermia
ACh, acetylcholine; ANS, autonomic nervous system; ChE, cholinesterase; M, muscarinic receptor; N, nicotinic receptor
a
Mivacurium is no longer available in the USA.
 CHAPTER 29 Antipsychotic Agents & Lithium 243

DRUG SUMMARY TABLE: Antipsychotics and Lithium

Mechanism of Clinical Pharmacokinetics
Subclass Action Effects Applications and Interactions Toxicities

Phenothiazines
Chlorpromazine Block of D2 Block α, M, and H1 Schizophrenia Oral and parenteral Extensions of α- and M
Fluphenazine receptors >> forms, hepatic metabo- receptor-blocking actions
Thioridazine 5-HT2 receptors decreased seizure (manic phase), lism, long half-life -
threshold antiemesis, preop tion, tardive dyskinesias,
sedation hyperprolactinemia
Thioxanthene
Thiothixene          

Butyrophenone
Haloperidol Block of D2 Some α Schizophrenia; bipo- Oral and parenteral Extrapyramidal dysfunc-
receptors >> M block and sedation lar disorder (manic tion (major)
5-HT2 receptors than phenothiazines phase), Huntington’s metabolism
chorea, Tourette’s
syndrome

Atypicals
Aripiprazole Block of 5-HT2 Some α block (clozap- Schizophrenia (posi- Oral and parenteral Agranulocytosis (clozap-
Clozapine receptors >> D2 ine, risperidone, zipra- tive and negative
Olanzapine receptors sidone) and M block metabolism gain (clozapine, olanzap-
Quetiapine (clozapine, olanzap- disorder (olanzapine, ine), hyperprolactinemia
Risperidone ine), variable H1 block risperidone), major -
Ziprasidone depression (aripip- gation (ziprasidone)
razole), agitation
in Alzheimer’s and
Parkinson’s

Lithium
  Uncertain, sup- No specific actions on Bipolar affective Renal elimination, Tremor, edema, hypothy-
presses IP3 and ANS receptors or spe- roidism, renal dysfunction
DAG signaling mood swings therapeutic window—
sedation (prophylaxis) monitor blood levels

by thiazides and
NSAIDs

Alternative drugs for bipolar affective disorder

Carbamazepine Unclear actions Ataxia and diplopia Valproic acid com- Carbamazepine forms Hematotoxicity and
Lamotrigine in bipolar (carbamazepine) petes with lithium as active metabolite induction of drug
Valproic acid first choice in bipo- (phase I); lamotrigine metabolism (carbamaze-
Chapter 24 for and headache lar disorder, acute and valproic acid form
antiepileptic (lamotrigine) conjugates (phase II)
drug mechanism used in acute phase weight gain, and inhibi-
distress, weight gain, and for prophylaxis tion of drug metabolism
alopecia (valproic acid) in depressive phase (valproic acid)

ANS, autonomic nervous system; DAG, diacylglycerol; 5-HT 2, serotonin type 2; IP 3, inositol trisphosphate NSAIDs, nonsteroidal anti-inflammatory
drugs.
 CHAPTER 35 Agents Used in Dyslipidemia 295

CHECKLIST

When you complete this chapter, you should be able to:

❑ Describe the proposed role of lipoproteins in the formation of atherosclerotic
plaques.
❑ Describe the dietary management of hyperlipidemia.
❑ List the 5 main classes of drugs used to treat hyperlipidemia. For each, describe the
mechanism of action, effects on serum lipid concentrations, and adverse effects.
❑ On the basis of a set of baseline serum lipid values, propose a rational drug
treatment regimen.
❑ Argue the merits of combined drug therapy for some diseases, and list 3 rational
drug combinations.

DRUG SUMMARY TABLE: Drugs for the Treatment of Hyperlipidemias

Toxicities, Drug
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Interactions

Statins
Atorvastatin, Inhibit HMG-CoA Atherosclerotic vascular Oral administration Myopathy, hepatic
simvastatin, reductase disease (primary and dysfunction, teratogen
rosuvastatin secondary preven- metabolism (CYP3A4,
CYP2C9) interacts with
syndromes P450 inhibitors/competitors
Fluvastatin, pravastatin, lovastatin: similar but somewhat less efficacious

Fibrates
Gemfibrozil, PPAR-α agonistsa Hypertriglyceridemia, low Oral administration Myopathy, hepatic
fenofibrate HDL cholesterol dysfunction, cholestasis

Bile acid-binding resins

Colestipol Prevents reabsorption Elevated LDL cholesterol, Oral administration Constipation, bloating
of bile acids from the pruritus
gastrointestinal tract of some drugs and vitamins
Cholestyramine, colesevelam: similar to colestipol

Sterol absorption inhibitor

Ezetimibe Reduces intestinal Elevated LDL cholesterol, Oral administration Rarely, hepatic
uptake of cholesterol phytosterolemia dysfunction, myositis
by inhibiting sterol
transporter NPC1L1

Niacin Decreases VLDL synthe- Low HDL cholesterol, Oral administration Gastrointestinal irritation,
sis and LDL cholesterol elevated VLDL and LDL flushing, hepatic toxic-
ity, hyperuricemia, may
HDL cholesterol reduce glucose tolerance
a
PPAR-α, peroxisome proliferator-activated receptor-alpha. Also responsible for TG-lowering effect of omega-3 fatty acids.
 CHAPTER 36 NSAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout 305

DRUG SUMMARY TABLE: NSAIDs, Acetaminophen, & Drugs for Rheumatoid Arthritis & Gout
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions

Salicylates
Aspirin Acetylation of COX-1 Analgesia, antipyretic, Duration of activity Gastrointestinal (GI) toxicity,
and COX-2 results in anti-inflammatory, is longer than nephrotoxicity, and increased
decreased prostaglandin and antithrombotic pharmacokinetic bleeding time at therapeutic levels
synthesis half-life of drug due
cancer to irreversible COX
inhibition hyperventilation, metabolic acidosis,
hyperthermia, coma in overdose

Nonselective NSAIDs
Ibuprofen Reversible inhibition of Analgesiaa, antipyretic, Rapid metabolism and GI toxicity, nephrotoxicity
COX-1 and COX-2 results and anti-inflammatory renal elimination
in decreased prostaglandin
synthesis arteriosus aspirin’s antithrombotic action
Many nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) available for clinical use. See Table 36–1

COX-2 inhibitor
Celecoxib Selective, reversible Analgesia, antipyretic, and Hepatic metabolism
inhibition of COX-2 anti-inflammatory
results in decreased risk of GI toxicity than nonselective
prostaglandin synthesis
than nonselective NSAIDs

Other analgesic
Acetaminophen Mechanism unknown, Analgesia, antipyretic Hepatic conjugation Hepatotoxicity in overdose
weak COX inhibitor (antidote is acetylcysteine)

chronic alcohol consumption,

which induces P450 enzymes

Disease-modifying antirheumatic drugs (DMARDs)

Methotrexate Cytotoxic to rapidly Anticancer, rheumatic Renal elimination Nausea, mucosal ulcers,
dividing immune cells disorders hematotoxicity, hepatotoxicity,
due to inhibition of teratogenicity
dihydrofolate reductase
Diverse array of DMARDs available for clinical use. See Table 36–2

Microtubule assembly inhibitor

Colchicine Inhibition of microtubule Chronic and acute gout, Oral drug Diarrhea, severe liver and kidney
assembly decreases familial Mediterranean damage in overdose
macrophage migration fever
and phagocytosis

Uricosurics
Probenecid Inhibition of renal Chronic gout, Oral drug Exacerbation of acute gout,
reuptake of uric acid prolongation of hypersensitivity reactions, inhibits
antimicrobial drug renal tubular secretion of weak
action acids such as methotrexate
Sulfinpyrazone: similar to probenecid

Xanthine oxidase inhibitors

Allopurinol Active metabolite Chronic gout, adjunct to Activated by xanthine GI upset, hypersensitivity
irreversibly inhibits cancer chemotherapy reactions, bone marrow
xanthine oxidase and suppression
lowers production of
uric acid
Febuxostat: reversible inhibitor of xanthine oxidase
a
Ketorolac is used as pure analgesic (not for anti-inflammatory effect).
 CHAPTER 38 Thyroid & Antithyroid Drugs 321

CHECKLIST

When you complete this chapter, you should be able to:

❑ Sketch the biochemical pathway for thyroid hormone synthesis and release and indicate
the sites of action of antithyroid drugs.
❑ List the principal drugs for the treatment of hypothyroidism.
❑ List the principal drugs for the treatment of hyperthyroidism and compare the onset and
duration of their action.
❑ Describe the major toxicities of thyroxine and the antithyroid drugs.

DRUG SUMMARY TABLE: Thyroid & Antithyroid Drugs

Toxicities, Drug
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Interactions

Thyroid preparations
Levothyroxine (T4) Activation of nuclear receptors Hypothyroidism T4 is converted to T3 in See Table 38–1 for symp-
Liothyronine (T3) results in gene expression target cells, the liver, and toms of thyroid excess
with RNA formulation and 3 is 10×
protein synthesis more potent than T4

Thioamides
Propylthiouracil (PTU) Inhibit thyroid peroxidase Hyperthyroidism Oral administration, Nausea, gastrointestinal
Methimazole reactions, iodine organifica- delayed onset of activity disturbances, rash,
tion, and peripheral conver- agranulocytosis, hepatitis,
sion of T4 to T3 hypothyroidism

Iodides
Lugol’s solution, Inhibit iodine organification Preparation for surgical Oral administration, acute Rare
potassium iodide and hormone release thyroidectomy onset of activity within
2–7 d
of thyroid gland

Radioactive iodine (131I) Radiation-induced destruc- Hyperthyroidism Oral administration Sore throat,
tion of thyroid parenchyma hypothyroidism

Beta blockers
Propranolol Inhibition of β receptors; Thyroid storm Rapid onset of activity Asthma, AV blockade,
inhibition of conversion of hypotension, bradycardia
T4 to T3
348 PART VII Endocrine Drugs

DRUG SUMMARY TABLE: Antidiabetic Agents

Clinical Toxicities, Drug
Subclass Mechanism of Action Applications Pharmacokinetics Interactions

Insulins
Regular insulin Activate insulin receptor Type 1 and type 2 Parenteral administration, Hypoglycemia, weight gain
diabetes short-acting
Rapid-acting: lispro, aspart, glulisine
Intermediate-acting: NPH
Long-acting: detemir, glargine

Biguanides
Metformin Decreased endogenous Type 2 diabetes Oral administration Gastrointestinal (GI)
glucose production disturbances, lactic acidosis
(rare)

Insulin secretagogues
Glipizide Increases insulin secretion Type 2 diabetes Oral administration Hypoglycemia, weight gain
from pancreatic beta cells
by closing ATP-sensitive
K+ channels
Glyburide, glimepiride: like glipizide, sulfonylurea drugs with intermediate duration of action
Chlorpropamide, tolbutamide: older sulfonylurea drugs, lower potency, greater toxicity; rarely used
Repaglinide, nateglinide: fast-acting insulin secretagogues

Alpha-glucosidase inhibitors
Acarbose Inhibit intestinal Type 2 diabetes Oral administration GI disturbances
α-glucosidases
Miglitol: similar to acarbose

Thiazolidinediones
Rosiglitazone Regulates gene expres- Type 2 diabetes Oral administration Fluid retention, edema,
sion by binding to PPAR-γ anemia, weight gain, bone
fractures in women, may worsen
heart disease and increase risk
of myocardial infarction
Pioglitazone: similar to rosiglitazone, possibly fewer cardiovascular adverse effects

Incretin-based drugs
Exenatide Analog of glucagon-like Type 2 diabetes Parenteral administration GI disturbances, headache,
peptide-1 (GLP-1) pancreatitis
activates GLP-1 receptors
Sitagliptin Inhibitor of the dipeptidyl Type 2 diabetes Oral administration Rhinitis, upper respiratory
peptidase-4 (DPP-4) that infections, rare allergic
degrades GLP-1 and other reactions
incretins

Amylin analog
Pramlintide Analog of amylin activates Type 1 and type 2 Parenteral administration GI disturbances,
amylin receptors diabetes hypoglycemia, headache

Glucagon
Glucagon Activates glucagon Severe hypoglycemia, Parenteral administration GI disturbances, hypotension
receptors β-blocker overdose

SGLT2 inhibitors
Canagliflozin, Inhibit renal glucose Type 2 diabetes Oral Osmotic diuresis, genital and
dapagliflozin absorption via SGLT2 urinary tract infections
PPAR-γ, peroxisome proliferator-activated receptor-gamma; SGLT, sodium-glucose co-transporter.
394 PART VIII Chemotherapeutic Drugs

CHECKLIST

When you complete this chapter, you should be able to:

❑
❑ Identify the characteristic pharmacodynamic and pharmacokinetic properties of isoniazid
and rifampin.
❑ List the typical adverse effects of ethambutol, pyrazinamide, and streptomycin.
❑
tuberculosis, and multidrug-resistant tuberculosis.
❑ Identify the drugs used in leprosy and in the prophylaxis and treatment of
M avium-intracellulare complex disease.

DRUG SUMMARY TABLE: First-Line Antimycobacterial Drugsa

Activity & Clinical Pharmacokinetics &
Drugs Mechanism of Action Uses Interactions Toxicities

Isoniazid (INH) Requires bioactivation; - Hepatotoxicity, peripheral

inhibits mycolic acid drug for LTBI and a neuropathy (use pyridox-
primary drug for use in inhibits metabolism of carbam-
expression of katG and combinations azepine, phenytoin and warfarin deficiency
inhA genes

Rifamycins Rash, nephritis, cholesta-

Rifampinb - an optional drug for LTBI, enterohepatic cycling with some
Rifabutin tance emerges rapidly a primary drug used in - flu-like syndrome with
Rifapentine when drug is used alone  combinations for active TB intermittent dosing
decreased efficacy of many drugs
(rifabutin less)

Ethambutol Inhibits formation of ara- -

binoglycan, a component ponent of many drug disturbances, reversible
of mycobacterial cell wall combination regimens for in renal dysfunction -
- active TB ache, confusion, hyper-
idly if drug is used alone uricemia, and peripheral
neuritis

Pyrazinamide Uncertain, but requires - -

bioactivation via hydro- ponent of many drug elimination (reduce dose in dence), hyperuricemia,
lytic enzymes to form combination regimens for dysfunction) myalgia, maculopapular
pyrazoic acid (active) active TB rash, porphyria, and

pregnancy

Streptomycin Binds to S12 ribosomal Ototoxicity,

subunit inhibiting protein when injectable drug nephrotoxicity
synthesis needed, or in treatment of
drug-resistant strains
a
Backup drugs include amikacin, aminosalicylic acid, ciprofloxacin, cycloserine, ethionamide, and levofloxacin.
b
Rifampin is also used for eradication of staphylococci and meningococci in carriers.
G6PDH, glucose-6-phosphate dehydrogenase; LTBI, latent tuberculosis infection.
450 PART VIII Chemotherapeutic Drugs

DRUG SUMMARY TABLE: Cancer Chemotherapy Drugs

Subclass Mechanism of Action Clinical Applications Acute Toxicities Chronic Toxicities

Alkylating agents
Cyclophosphamide Forms DNA cross-links, Breast cancer, ovarian cancer, Nausea and vomiting Myelosuppression, alopecia,
resulting in inhibition non-Hodgkin’s lymphoma, hemorrhagic cystitis
of DNA synthesis and chronic lymphocytic leukemia,
function neuroblastoma
Other major alkylating agents: mechlorethamine, procarbazine, busulfan, carmustine, lomustine, dacarbazine
Platinum analogs: cisplatin, carboplatin, oxaliplatin

Antimetabolites
Methotrexate Inhibits DHFR, resulting Breast cancer, head and neck Mucositis, diarrhea Myelosuppression
in inhibition of synthesis cancer, primary CNS lymphoma,
of thymidylate, purine non-Hodgkin’s lymphoma, bladder
nucleotides, serine, and cancer, choriocarcinoma
methionine
6-Mercaptopurine Inhibits de novo purine Acute myelogenous leukemia Nausea and vomiting Myelosuppression,
synthesis immunosuppression,
hepatotoxicity
5-Fluorouracil Inhibits thymidylate syn- GI cancers, breast cancer, head Nausea, mucositis, Myelosuppression,
thase, and its metabolites and neck cancer, hepatocellular diarrhea neurotoxicity
are incorporated into RNA cancer
and DNA, all resulting in
inhibition of DNA synthesis
and function and in RNA
processing
Other antimetabolites: cytarabine, gemcitabine

Vinca alkaloids
Vincristine Interferes with microtu- Acute lymphocytic leukemia, None Neurotoxicity with periph-
bule assembly, resulting Hodgkin’s and non-Hodgkin’s eral neuropathy, paralytic
in impaired mitosis lymphoma, Wilms’ tumor, ileus, myelosuppression,
neuroblastoma alopecia, inappropriate
ADH secretion
Other vinca alkaloids: vinblastine, vinorelbine

Podophyllotoxins
Etoposide Inhibits topoisomerase II, Lung cancer, non-Hodgkin’s Nausea, vomiting Alopecia,
resulting in DNA damage lymphoma, gastric cancer myelosuppression
Other podophyllotoxins: teniposide

Camptothecins
Topotecan Inhibits topoisomerase I, Small cell lung cancer, ovarian Nausea, vomiting, Myelosuppression
resulting in DNA damage cancer diarrhea
Other camptothecins: irinotecan

Taxanes
Paclitaxel Interferes with microtu- Breast, lung, ovarian, Nausea, vomiting, hypo- Myelosuppression,
bule disassembly, gastroesophageal, prostate, blad- tension, arrhythmias, peripheral sensory
resulting in impaired der, and head and neck cancers hypersensitivity neuropathy
mitosis
Other taxanes: docetaxel

(Continued )
 CHAPTER 54 Cancer Chemotherapy 451

DRUG SUMMARY TABLE: Cancer Chemotherapy Drugs (Continued )

Subclass Mechanism of Action Clinical Applications Acute Toxicities Chronic Toxicities

Anthracyclines
Doxorubicin Oxygen free radicals bind Lymphomas, myelomas, sarcomas, Nausea, arrhythmias Alopecia, myelosuppres-
to DNA causing strand and breast, lung, ovarian and thy- sion, cardiomyopathy,
breakage; inhibits topoi- roid cancers myelosuppression
somerase II; intercalates
into DNA
Other anthracyclines: daunorubicin, idarubicin, epirubicin, mitoxantrone
Other antitumor antibiotics: bleomycin, mitomycin

Tyrosine kinase inhibitors

Imatinib Inhibits bcr-abl tyrosine Chronic myelogenous leukemia, Nausea, vomiting Fluid retention with ankle
kinase and other receptor gastrointestinal stromal tumor and periorbital edema,
tyrosine kinases diarrhea, myalgias, heart
failure
Other tyrosine kinase inhibitors: dasatinib, nilotinib, sorafeniba, sunitiniba, and pazopaniba

Growth factor receptor inhibitors

Trastuzumab Inhibits the binding of HER-2/neu receptor-positive Nausea, vomiting, chills, Cardiac dysfunction
EGF to the HER-2/neu breast cancer fever, headache
growth receptor
Other growth factor receptor inhibitors: cetuximab, panitumumab, gefitinib, erlotinib

Vascular endothelial growth factor (VEGF) inhibitors

Bevacizumab Inhibits binding of VEGF Colorectal, breast, non-small cell Hypertensin, infusion Arterial thromboembolic
to its receptor, resulting lung, and renal cancer reaction events, gastrointestinal
in inhibition of tumor perforations, wound
vascularization healing complications,
proteinuria

Proteasome Inhibitors
Bortezomib Reversibly inhibits chymo- Multiple myeloma Hypotension, edema, GI Peripheral neuropathy,
trypsin-like activity of the upset cardiac dysfunction,
26S proteasome
Other proteasome inhibitor: carfilzomib

Hormone agonists
Prednisone See Chapter 39      

Hormone antagonists
Tamoxifen See Chapter 40      
Other hormonal antagonists: aromatase inhibitors, GnRH agonist and antagonists, androgen receptor antagonists (see Chapter 40)
DHFR, dihydrofolate reductase; EGF, epidermal growth factor; GnRH, gonadotropin-releasing hormone; VEGF, vascular endothelial growth factor.
a
These small molecules all inhibit VEGF-R2 and VEGF-R3 receptor tyrosine kinases (RTKs). In addition they each inhibit a different spectrum of multiple other RTKs.