Pharmacology Notes

Rabeprazole increases serum levels and potentially increases the toxicity of benzodiazepines when taken concurrently.

Histamine H2-Receptor Antagonists
Th ere are two types of histamine receptors: histamine (H1) and histamine (H2). Th e second of these mediates the acid secretion from gastric parietal cells and is inhibited by the H2-receptor-blocking drugs. These drugs may be preferred to other antiulcer agents because of their convenience and lack of effect on GI motility. H2-receptor antagonists are listed in Table 15-2.

Mechanism of Action
Cimetidine was the fi rst H2-receptor antagonist approved for clinical use. It blocks the H2 receptor on the parietal cells of the stomach, thus decreasing gastric acid secretion.

Indications
H2-receptor antagonists are used to promote healing of gastric and duodenal ulcers, and hypersecretory states such as Zollinger-Ellison syndrome. Prototypes of H2-receptor antagonists include cimetidine, famotidine, nizatidine, and ranitidine. Th ey are a remarkably safe group of drugs.

• Cimetidine is available OTC for the treatment of acute gastric ulcer, duodenal ulcer, and gastroesophageal refux. It is also used in the treatment of Zollinger-Ellison syndrome. 

• Famotidine is the most potent H2-receptor antagonist. Aft er a 40-mg dose, mean nocturnal gastric acid secretion is reduced by 94 percent for up to 10 hours. It is recommended for the short-term treatment of mucosal ulcers of the GI tract. Famotidine is absorbed incompletely. It should be used in a lower dosage and at longer dosing intervals in patients with severe renal insuffi ciency. 

• The newest H2-receptor antagonist, nizatidine, may be used to treat and prevent recurrence of duodenal ulcers. It is also used for gastric ulcers, and gastroesophageal refl ux. More than 90 percent of an oral dose is excreted in the urine within 12 hours, and 60 percent as unchanged drug. Therefore, it should be used in reduced dosage in patients with severe renal insuffi ciency.

• Ranitidine is a more potent drug. It is fi ve to ten times more potent than cimetidine. Ranitidine requires a less frequent dosing schedule than cimetidine. It is an H2-receptor antagonist indicated for the short-term treatment of duodenal ulcers and the management of hypersecretory conditions such as Zollinger-Ellison syndrome. Th e pharmacokinetic profi le of ranitidine is similar to that of cimetidine.

Adverse Effects
The list of adverse reactions is long, but the incidence is low. Among the adverse eff ects associated with all four drugs are headache, dizziness, malaise, myalgia, nausea, diarrhea, constipation, rashes, pruritus, and impotence. Adverse effects, such as unusual bleeding, fever, sore throat, hallucinations, or skin rash should be reported promptly, and the therapy must be discontinued.

Contraindications and Precautions
Histamine H2 antagonists should be avoided in patients with a known hypersensitivity, and during lactation or pregnancy. Th ese agents are used cautiously in patients with hepatic or renal dysfunction. Cimetidine is used used cautiously in elderly patients because they may cause confusion, and a dosage reduction may be needed. Cimetidine, famotidine, and ranitidine are pregnancy category B drugs, while nizatidine is a pregnancy category C drug.

All of these drugs should be used cautiously during pregnancy and lactation.

Drug Interactions
Cimetidine increases the risk of decreased white blood cell counts with antimetabolites and alkylating agents. It also increases serum levels and risk of toxicity of warfarin-type anticoagulants, phenytoin, beta-adrenergic blocking agents, alcohol, quinidine, lidocaine, theophylline, chloroquine, and diazepam. Nizatidine increases serum salicylate levels with aspirin. Ranitidine also increases the eff ects of warfarin and toxicity of lidocaine. Ranitidine decreases the eff ectiveness of diazepam and its clearance.

Antacids
There are differences in the types of antacids, in terms of their contents, neutralizing capacity, duration of action, side eff ects, and cost. These must be considered when choosing an antacid for therapeutic use. Antacids are OTC drugs. The most widely used antacids are sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide.

Mechanism of Action
Antacids neutralize hydrochloric acid and raise gastric pH, thus inhibiting pepsin (a gastric enzyme). Antacids reduce the concentration and total load of acid in the gastric contents. By increasing gastric pH, antacids also inhibit pepsin activity. In addition, they strengthen the gastric mucosal barrier.

Indications
These agents are used widely for the relief of heartburn, dyspepsia, and medical treatment of peptic ulcer. Th e primary role of antacids in the management of acid-peptic disorders is the relief of pain. Nonsystemic antacids (magnesium or aluminum substances) are preferred to systemic antacids such as sodium bicarbonate for intensive ulcer therapy because they avoid the risk of alkalosis. Liquid antacid forms have a greater buff ering capacity than tablets. However, tablets are more convenient to carry. Antacid mixtures such as aluminum hydroxide with magnesium hydroxide provide more even, sustained action than single-agent antacids, and permit a lower dosage of each compound.

Adverse Effects
Constipation can occur in patients using calcium carbonate and aluminum containing antacids. Diarrhea is a common adverse effect of magnesium- and sodium-containing antacids. If diarrhea occurs, the patient may alternate the antacid mixture with aluminum hydroxide. Hypophosphatemia and osteomalacia can occur with long-term use of aluminum hydroxide, but patients, such as alcoholics. Calcium carbonate usually is avoided because it causes acid rebound, hypercalcemia, vomiting, metabolic alkalosis, confusion, and renal calculi. It may also delay pain relief and ulcer healing.

Contraindications and Precautions
Antacids are contraindicated in patients with severe abdominal pain of unknown cause, and during lactation. Sodium bicarbonate is contraindicated in patients with hypertension, congestive heart failure (CHF), severe renal disease, and edema. It should not be used for ulcer therapy. All antacids should be used cautiously in elderly patients and renally impaired patients. Chronic administration of calcium carbonate-containing antacids should be avoided because of hypercalcemia. Calcium carbonate and magnesiumcontaining antacids should be used cautiously in patients with severe renal disease.

Drug Interactions
Because antacids alter gastric pH and affect absorption of ingested substances, they have a high potential for drug interactions. To ensure consistent absorption and therapeutic effi cacy, orally administered drugs should be given 30 to 60 minutes before antacids. Th ese agents bind with tetracycline and inhibit its absorption, reducing its therapeutic efficacy.
Antacids may destroy the coating of enteric-coated drugs, leading to premature drug dissolution in the stomach. Antacids may interfere with the absorption of many drugs, including cimetidine, ranitidine, digoxin, isoniazid, iron products, anticholinergics, and phenothiazines

Peptic ulcer refers to a lesion located in either the stomach (gastric ulcer) or in the duodenum (small intestine) . In general, ulcers occur whenever there is an increase in acid secretion or a decrease in mucosal resistance. Mucosal injury in the acid peptic diseases includes gastric ulcer, duodenal ulcer, and gastroesophageal refl ux disease, which are mediated by gastric acid. Hydrochloric acid is secreted by parietal cells in the body of the stomach. It is regulated by adjacent endocrines, such as gastrin, or by histamine, somatostatin, and prostaglandin E2. Gastrin is a relatively weak stimulant of the parietal cells. It acts primarily to cause the release of histamine, which is the most potent stimulus of acid secretion, and acts as the common mediator. Histamine antagonists inhibit acid secretion that is stimulated by gastrin and acetylcholine, as well as histamine. There are a number of causes of peptic ulcer, including:

• Family history

• Smoking tobacco

• Alcohol

• Coffee

• Stress

• Infection with Helicobacter pylori (H. pylori)

• Blood group O

• Anti-infl ammatory drugs (aspirin, NSAIDs, and glucocorticoids)

A wide variety of prescription and OTC medications are available for the treatment of peptic ulcer. These drugs include: antacids, H2-receptor antagonists, proton pump inhibitors, and antibiotics. Antibiotics treat peptic ulcers caused by Helicobacter pylori

The digestive system, sometimes called the gastrointestinal tract, alimentary tract, or gut, consists of a long hollow tubule. The digestive tract secretes substances used in the process of digestion into the canal. Th e growth of the body depends upon the consumption, absorption, and metabolism of food. Th is system also involves the elimination of waste. The digestive system is subject to many disorders, some of which are very common. Numerous drugs are used to treat these varying conditions.

Th ere are three groups of medications that may meet the treatment goals for angina pectoris.
1. Nitrates
2. β-Adrenergic Blockers
3. Calcium Channel Blockers

Calcium Channel Blockers
Calcium channel blockers are considered third-choice agents in the treatment of stable angina, certain dysrhythmias, and hypertension.

Mechanism of Action
Calcium channel blockers are a type of drug that block the entry of calcium into smooth muscle cells as well as myocytes. They produce arterial vasodilation and thereby reduce arterial blood pressure. They also reduce myocardial contractility, resulting in reduction of myocardial oxygen consumption.

Indications
Calcium channel blockers are used to treat exertional angina that is not controlled by nitrates, and in combination with beta-blockers. This combination provides the most effective therapy. They are considered the drug of choice in the treatment of angina at rest. Diltiazem and verapamil will reduce the heart rate. Nifedipine, amlodipine, and felodipine are among the most potent calcium-blocking agents. β-blockers are recommended as the first-line treatment of angina pectoris, but if they are not tolerated, calcium channel blockers can be administered. Diltiazem and verapamil can be used, but they have the disadvantage of depressing contractility more than dihydropyridines do. The therapeutic goal in medication use is to reduce the
frequency and intensity of anginal attacks without suppressing the cardiac action too much.

Adverse Effects
Common adverse effects related to the use of calcium channel blockers include: fl ushing, headaches, dizziness, hypotension, ankle edema, constipation, and palpitations. Combinations of nitrates, β-blockers, and calcium channel blockers are oft en preferred for treatment of angina pectoris, because these agents have fewer adverse eff ects.

Contraindications and Precautions
Calcium channel blockers are contraindicated in patients with a history of hypersensitivity to these drugs, hypotension, or cardiogenic shock. The major contraindications to combination therapy are associated with the use of β-blockers and calcium channel blockers, which may cause excessive
cardiac depression. Calcium channel blockers should be used with caution during pregnancy (category C) and lactation, and in patients with congestive heart failure, hepatic or renal dysfunction, and hypotension.

Drug Interactions
Calcium channel blockers increase risk of orthostatic hypotension with prazosin. Increased blood pressure may occur with aspirin, bismuth subsalicylate, or magnesium salicylate. Some calcium channel blockers increase serum levels and toxicity of cyclosporine.

Beta-adrenergic Blockers
Beta-adrenergic blockers (β-blockers) block the beta 1 receptor site. Beta-blockers decrease the eff ects of the sympathetic nervous system by blocking the release of the catecholamines epinephrine and norepinephrine, thereby decreasing the heart rate and blood pressure.

Mechanism of Action
Beta blockers reduce oxygen demand, both at rest and during exertion, in the myocardium, and prevent myocardial infarction (IM).

Indications
Th e beta-blockers reduce the frequency and severity of exertional angina that is not controlled by nitrates. Th erefore, these are an important part of therapy for angina pectoris. Combined therapy with nitrates is oft en preferred in the treatment of angina pectoris, because of a decrease in the side eff ects of both agents.

Adverse Effects
Beta-blockers have few adverse eff ects on the respiratory and cardiovascular systems. Common adverse eff ects of these drugs include dyspnea, bronchospasm, hypotension, bradycardia, and hypoglycemia. These agents may also cause insomnia and depression.

Contraindications and Precautions
β-blockers are contraindicated in patients with a known hypersensitivity to these agents. β-blockers are also contraindicated for use in patients with asthma, congestive heart failure, heart block, bradycardia, and diabetes mellitus. These drugs should be avoided in patients with cardiogenic shock, pulmonary edema, and peripheral vascular disease.β-adrenergic blockers should be used with caution in patients prone to non-allergenic bronchospasm (e.g., chronic bronchitis, emphysema), major surgery, stroke, renal disease, or hepatic disease. β-blockers are used cautiously in elderly patients, patients with diabetes mellitus, and in patients prone to hypoglycemia.

Drug Interactions
These agents may interact with atropine and other anticholinergics, NSAIDs, insulin, sulfonylureas, lidocaine, verapamil, prazosin, and terazosin.

Nitrates
Nitrates were the fi rst agents used to relieve angina. Th is group of drugs reduces myocardial ischemia, but may cause hypotension. Nitrates are still an important part of antianginal therapy.

Mechanism of Action
Nitrates primarily are eff ective in the venous circulation by relaxing vascular smooth muscle and reducing the left ventricle’s work. Th ese agents are administered to dilate the blood vessels and stop attacks of angina

Indications
Nitrates are used in the treatment of angina as coronary vasodilators. Nitrate preparations should be based on onset of action, duration of action, and patient compliance. Nitrate preparations are available in sublingual tablets, nitroglycerin spray bottles, topical nitroglycerin ointments, and transdermal patches. The sublingual route is the most common route of administration for nitroglycerin. This agent begins to work rapidly and lasts for about an hour. Th is is an ideal preparation for acute anginal pain.

Administration should begin as soon as the pain begins, and should not be delayed until the pain is severe. If one tablet is not sufficient, one or two additional tablets should be taken at fi ve-minute intervals. For persistent pain, the patient should see a physician, because he or she may have signs of a myocardial infarction. Th e shelf life of nitroglycerin is longer in a dark, tightly closed container. Aft er the container is opened, the drug is eff ective for approximately 30 days, and the date on which it was opened should be written on the container. Th irty days aft er the container is opened, the medication should be discarded and replaced with a new bottle.

Transdermal patches contain a reservoir of nitroglycerin. Th is agent is slowly released for absorption through the skin  The patches are slow in onset and are not eff ective for an ongoing anginal attack. The application site of the patch should be rotated daily to prevent irritation.

Topical ointment can also be used on the skin by using an applicator, and covering it with plastic wrap held in place with adhesive tape. The sites should be rotated to prevent local irritation.

Adverse Effects
Abrupt discontinuation of long-acting nitroglycerin preparations may cause angina. Vasodilation can lead to orthostatic hypotension, tachycardia, headache, dizziness, weakness, syncope, and blushing. Nitrate-induced headache is a result of the dilation of cerebral blood vessels. Nitrates may also increase intraocular and intracranial pressure. Continuous exposure to nitrates may lead to tolerance. Large doses of nitrate drugs can produce methemoglobinemia (the presence of methemoglobin in the blood).

Contraindications and Precautions
These agents are contraindicated in patients with hypersensitivity to nitrates, severe anemia, head trauma, and increased intracranial pressure. Nitrates are also contraindicated in glaucoma, hypotension, hyperthyroidism, and alcoholism.

Safety during pregnancy (category C) and lactation is not established. Nitrate drugs should also be used cautiously in severe liver or kidney disease.

Drug Interactions
A combination of nitrates and sildenafi l (Viagra) can cause prolonged and potentially life-threatening hypotension. Sildenafi l therapy should therefore be contraindicated in patients who use nitrates. Beta-blockers, calcium channel blockers, vasodilators, and alcohol can enhance the hypotensive effect of nitrates. IV nitroglycerin may antagonize the eff ects of heparin.

Angina Pectoris
Angina pectoris is an episodic, reversible oxygen insufficiency. This condition is the most common form of IHD. Angina pectoris is applied to varying forms of transient chest pain that are attributable to insuffi cient myocardial oxygen. Atherosclerotic lesions that produce a narrowing of the coronary arteries are the major cause of angina. However, tachycardia (increased heart rate), anemia, hyperthyroidism, and hypotension can cause an oxygen imbalance. According to the American Heart Association, angina occurs more commonly in women than men. There are several types of angina: stable (classic), unstable, decubitus (nocturnal), and silent angina. The most common form is classic angina that may occur, with predictable frequency, from exertion (often from exercising), emotional stress, or a heavy meal. Classic angina is relieved by rest, nitroglycerin, or both.

Unstable angina is a medical emergency, and the patient must be treated in a hospital. It typically has a sudden onset, sudden worsening, and stuttering reoccurrence over days and weeks, and carries a more severe short-term prognosis than stable chronic angina. Unstable angina occurs during periods of rest. Signs of unstable angina include changes in blood pressure, transient heart murmur, and arrhythmias.

Decubitus angina is a condition characterized by periodic attacks of cardiac pain that occur when a person is lying down. It is also known as vasospastic angina. Decubitus angina occurs when the decreased myocardial blood fl ow is caused by spasms of the coronary arteries.

Silent angina is a condition that occurs in the absence of angina pain. One or more coronary arteries are occluded, but the individual remains asymptomatic.

Nocturnal angina is caused by coronary artery spasms and can be treated by calcium channel blockers and nitrates. It occurs during the REM
period of sleep.

• Treatment goals for angina include:

• Reducing the risk of sudden death

• Preventing myocardial infarction (MI)

• Increasing myocardial oxygen supply

• Reducing pain and anxiety associated with an angina attack

 Treatment for angina includes surgery and drug therapy. If the coronary arteries are signifi cantly occluded or blocked, coronary arterial bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) are performed. CABG is a procedure wherein a vein graft is surgically implanted to bypass the part of the occlusion in the coronary artery. PTCA reduces obstruction by means of invasive procedures requiring cardiac catheterization. Th e catheter contains an infl atable balloon that flattens the obstruction. Newer techniques use laser angioplasty.

Arteriosclerosis and Atherosclerosis
Arteriosclerosis is the term used to describe degenerative changes in small arteries, commonly occurring in older individuals and diabetics. Elasticity is lost, and the walls become thick and hard. The lumen gradually narrows and may become obscured. Th is leads to diff use ischemia and death in various tissues, such as those of the heart, kidneys, or brain.

Atherosclerosis is differentiated by the presence of atheromas (plaques consisting of lipids, cells, and cell debris, often with attached thrombi, which form inside the walls of large arteries). Atheromas form primarily in large arteries such as the aorta and the coronary arteries.

In ischemic heart disease (IHD)—[most commonly called coronary artery disease (including angina pectoris), and also referred to as coronary heart disease (CHD) or myocardial infarction (heart attack)]—, part of the heart muscle is damaged because of obstruction in an artery. Th e basic problem is insuffi cient oxygen for the needs of the heart muscle.

A common cause of disability and death, coronary artery disease may ultimately lead to heart failure, serious arrhythmias, or sudden death. Th ere are several factors that may aff ect functions that control myocardial oxygen demand

Anxiety disorders may be classified as

1. generalized anxiety disorder, 
2. panic disorder, 
3. obsessive-compulsive disorder, 
4. social anxiety disorder,
5. post-traumatic stress disorder. 

Click to view each type.