книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

SECTION VI

Drugs for Inflammatory and Related Disorders

Learning Objectives

Answer questions about histamine

Use knowledge of H1 antagonists to describe their appropriate use

HISTAMINE

λHistamine is an autacoid present at high levels in the lungs, skin, and the gastrointestinal tract and is released from mast cells and basophils by type I hypersensitivity reactions, drugs, venoms, and trauma.

λHistamine receptors are of the serpentine family, with seven transmem- brane–spanning domains with G-protein–coupled second messenger effectors.

–H1 activation

º↑ capillary dilation (via NO) →↓ BP

º↑ capillary permeability →↑ edema

º↑ bronchiolar smooth muscle contraction (via IP3 and DAG release)

º↑ activation of peripheral nociceptive receptors →↑ pain and pruritus

º↓ AV nodal conduction

–H2 activation

º↑ gastric acid secretion →↑ gastrointestinal ulcers

º↑ SA nodal rate, positive inotropism, and automaticity

H1 ANTAGONISTS

λMechanism of action:

–H1 antagonists act as competitive antagonists of histamine and therefore may be ineffective at high levels of histamine.

–Vary in terms of both pharmacologic and kinetic properties, but all require hepatic metabolism and most cross the placental barrier.

221

Section VI λ Drugs for Inflammatory and Related Disorders

Table VI-1-1.Properties of Major Antihistamines

λUses:

–Allergic reactions: hay fever, rhinitis, urticaria

–Motion sickness, vertigo

–Nausea and vomiting with pregnancy

–Preoperative sedation

–OTC: sleep aids and cold medications

–Acute EPSs

λSide effects:

–Extensions of M block and sedation (additive with other CNS

Chapter Summary

λHistamine is an autacoid released from mast cells and basophils by type I hypersensitivity reactions or under the influence of drugs, venoms, or trauma. Histamine receptors are the G-protein–coupled, seven-transmembrane type.

Three different receptors are recognized: the well-characterized H1 and H2 types and an H3 variant.

λThe sequence of reactions leading to H1 and H2 activation is presented.

λH1 antagonists are competitive inhibitors with varying pharmacologic and kinetic properties. All require hepatic metabolism and cross the placental barrier.

λThe H1 antagonists are used to treat allergic reactions, motion sickness, vertigo, nausea and vomiting in pregnancy, and preoperative sedation, and are in over-the-counter sleeping pills.

λThe adverse effects are excess M block and sedation. Table VI-1-1 summarizes the properties of some of the major type 1 antihistamines.

222

Section VI λ Drugs for Inflammatory and Related Disorders

H2 Antagonists (e.g., Cimetidine, Ranitidine, Famotidine)

λMechanisms of action:

–Suppress secretory responses to food stimulation and nocturnal secretion of gastric acid via their ability to decrease (indirectly) the activity of the proton pump.

–Also partially antagonize HCl secretion caused by vagally or gastrininduced release of histamine from ECL-like cells (GI mast cells)

–No effects on gastric emptying time

λUses:

–PUD (overall less effective than proton pump inhibitors)

–Gastroesophageal reflux disease (GERD)

–Zollinger-Ellison syndrome

λSide effects:

–Cimetidine is a major inhibitor of P450 isoforms → drug interaction via ↑ effects

–Cimetidine →↓ androgens → gynecomastia and ↓ libido

Proton Pump Inhibitors

λMechanism of action:

–Omeprazole and related “–prazoles” are irreversible, direct inhibitors of the proton pump (K+/H+ antiport) in the gastric parietal cell

λUses:

–More effective than H2 blockers in peptic ulcer disease (PUD)

–Also effective in GERD and Zollinger-Ellison syndrome

–Eradication regimen for H. pylori

Misoprostol

λMechanism of action: PGE1 analog, which is cytoprotective →↑ mucus and bicarbonate secretion and ↓ HCl secretion

λUses: Previously for NSAID-induced ulcers, but PPIs are now used

Sucralfate

λMechanism of action: polymerizes on gastrointestinal luminal surface to form a protective gel-like coating of ulcer beds. Requires acid pH (antacids may interfere)

λUses: ↑ healing and ↓ ulcer recurrence

Bismuth Subsalicylate

λMechanism of action: like sucralfate, binds selectively to ulcer, coating it, and protecting it from acid and pepsin

λCombined with metronidazole and tetracycline to eradicate H. pylori (BMT regimen)

224

Section VI λ Drugs for Inflammatory and Related Disorders

Chapter Summary

λThe H2 histamine antagonists (e.g., cimetidine and ranitidine) are used to suppress the secretion of gastric acid. The mechanism of action is illustrated in Figure VI-2-1. The clinical uses and adverse effects are discussed.

λOmeprazole and the other “–prazole” proton-pump inhibitors are more powerful inhibitors of gastric secretion than are the antagonists. Their clinical uses and adverse reactions are considered.

λMisoprostol is a cytoprotective prostaglandin E1 analog.

λSucralfate forms a protective gel, covering gastrointestinal ulcers. Bismuth subsalicylate behaves similarly.

λAntacids neutralize preformed protons.

λFigure VI-2-2 illustrates the number of complex factors impinging upon the emetic (vomiting) center. The antiemetic drugs are listed.

226

Learning Objectives

Demonstrate understanding of drug actions on 5HT receptors

Describe treatment options for migraine headaches

λSerotonin (5-hydroxytryptamine, 5HT) is an autacoid synthesized and stored in gastrointestinal cells, neurons, and platelets. Metabolized by MAO type A, its metabolite 5-hydroxyinolacetic acid (5HIAA) is a marker for carcinoid.

λOf the seven receptor subtype families, all are G-protein coupled, except 5HT3, which is coupled directly to an ion channel.

DRUG ACTIONS ON 5HT RECEPTORS

5HT1(a–h)

λFound in the CNS (usually inhibitory) and smooth muscle (excitatory or inhibitory)

λDrug: buspirone

–Partial agonist at 5HT1a receptors → anxiolytic (generalized anxiety disorder [GAD])

λDrug: sumatriptan and other triptans

–Agonist at 5HT1d receptors in cerebral vessels →↓ migraine pain

–Side effects of “–triptans”: possible asthenia, chest or throat pressure or pain

5HT2(a–c)

λFound in CNS (excitatory)

λIn periphery, activation → vasodilation, contraction of gastrointestinal, bronchial, and uterine smooth muscle, and platelet aggregation

λDrugs:

–Olanzapine and other atypical antipsychotics: antagonist at 5HT2a receptors in CNS →↓ symptoms of psychosis

–Cyproheptadine

º5HT2 antagonist used in carcinoid, other gastrointestinal tumors, and postgastrectomy; also used for anorexia nervosa; serotonin syndrome

ºHas marked H1-blocking action: used in seasonal allergies

227