Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

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Glucocorticoids 7

Learning Objectives

Describe mechanism of action and adverse effects of commonly used glucocorticoid medications

Table VI-7-1. Synthetic Derivatives of Cortisol

		Glucocorticoid		Mineralocorticoid
Drugs		Activity		Activity		Duration
Cortisol,	1		1		Short
hydrocortisone
Prednisone	4		0.3		Medium
Triamcinolone	5		0		Intermediate
Betamethasone	25		0		Long-acting
Dexamethasone	30		0		Long-acting

λMechanisms of action:

–Cellular effects

º↓ leukocyte migration

º↑ lysosomal membrane stability →↓ phagocytosis

º↓ capillary permeability

–Biochemical actions

ºInhibit PLA2 (via lipocortin expression) →↓ PGs and ↓ LTs

º↓ expression of COX 2

º↓ platelet-activating factor

º↓ interleukins (e.g., IL-2)

λUses: antiinflammatory and immunosuppressive

λSide effects:

–Suppression of ACTH: cortical atrophy, malaise, myalgia, arthralgia, and fever—may result in a shock state with abrupt withdrawal

–Iatrogenic cushingoid syndrome → fat deposition, muscle weakness/ atrophy, bruising, acne

–Hyperglycemia due to ↑ gluconeogenesis → increased insulin demand and other adverse effects

–Osteoporosis: vertebral fractures—aseptic hip necrosis

Clinical Correlate

Minimize Steroidal Toxicity

λAlternate-day therapy; local application (e.g., aerosols)

λDose-tapering to avoid cortical suppression

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Section VI λ Drugs for Inflammatory and Related Disorders

–↑ gastrointestinal acid and pepsin release → ulcers, gastrointestinal bleeding

–Electrolyte imbalance: Na+/water retention → edema and hypertension, hypokalemic alkalosis, hypocalcemia

–↓ skeletal growth in children

–↓ wound healing, ↑ infections (e.g., thrush)

–↑ glaucoma, ↑ cataracts (via ↑ sorbitol)

–↑ mental dysfunction

Chapter Summary

λSynthetic derivatives of cortisol are often used to manage inflammatory conditions or to promote immunosuppression. This chapter discusses the duration of action of several antiinflammatory steroids, their cellular effects and biochemical actions, as well as the many and severe adverse effects.

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Drugs Used for Treatment of Asthma

Learning Objectives

Describe the mechanism of action of beta-receptor agonists, muscarinicreceptor blockers, glucocorticoids, and anti-leukotrienes in asthma

Compare the uses and side-effects of theophylline, cromolyn, and nedocromil

λAsthma is an inflammatory disease associated with bronchial hyperreactivity (BHR), bronchospasm, ↑ mucus secretion, edema, and cellular infiltration.

λEarly asthmatic responses (EAR) lasting from 30 to 60 minutes are associated with bronchospasm from the actions of released histamine and leukotrienes.

λLate asthmatic responses (LAR) involve infiltration of eosinophils and lymphocytes into airways → bronchoconstriction and inflammation with mucous plugging.

λManagement of asthma includes bronchodilators to provide short-term relief and antiinflammatory agents that reduce bronchial hyperactivity and protect against cellular infiltration.

Bronchoconstriction

++ +

Acetylcholine Adenosine Leukotrienes

–	–		–	–
Ipratropium	Theophylline		“Lukasts”	Zileuton
	Bronchodilation
	+	Theophylline
		Theophylline
	cAMP		–
	cAMP	Phosphodiesterase
Adenylyl Cyclase		Phosphodiesterase
Adenylyl Cyclase

AMP

ATP +

Beta Agonists

Figure VI-8-1. Drug Actions on Bronchiolar Smooth Muscle

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Section VI λ Drugs for Inflammatory and Related Disorders

BETA-RECEPTOR AGONISTS

λBeta-2 selective drugs (albuterol, metaproterenol, terbutaline) are widely used for relief of acute bronchoconstriction and in prophylaxis of exer- cise-induced asthma (see Figure VI-8-1).

λLonger-acting drugs (e.g., salmeterol) may decrease nighttime attacks (prophylaxis only) and permit dosage reduction of other agents.

λAerosolic forms have low potential for systemic toxicity but may cause anxiety, muscle tremors, and cardiovascular toxicity with overuse.

MUSCARINIC-RECEPTOR BLOCKERS

λIpratropium and tiotropium used via inhalation cause bronchodilation

in acute asthma, especially in COPD patients, and they may be safer than β agonists are in patients with cardiovascular disease.

λThey are the drugs of choice in bronchospasm caused by β blockers.

λThere are minor atropine-like effects.

THEOPHYLLINE

λBronchodilates via inhibition of phosphodiesterase (PDE) →↑ cAMP and also by antagonism of adenosine (a bronchoconstrictor)

λMainly adjunctive; regular use may decrease symptoms, but narrow therapeutic window predisposes to toxicity → nausea, diarrhea, CV (↑ HR, arrhythmias) and CNS excitation

λMany drug interactions; toxicity ↑ by erythromycin, cimetidine, and fluoroquinolones

λAminophylline IV sometimes used in bronchospasm or status asthmaticus

CROMOLYN AND NEDOCROMIL

λPrevent degranulation of pulmonary mast cells and ↓ release of histamine, PAF, and LTC4 from inflammatory cells

λProphylactic use:

–↓ symptoms and bronchial hyperactivity (BHR), especially responses to allergens

–Minimal systemic toxicity but may cause throat irritation and cough

–Relieved by a β2 agonist

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Chapter 8 λ Drugs Used for Treatment of Asthma

GLUCOCORTICOIDS

λBlock mediator release and ↓ BHR via ↓ PGs, LTs, and inflammatory interleukins (ILs)

λSurface-active drugs (budesonide, flunisolide) used via inhalation for both acute attacks and for prophylaxis

λMay cause oropharyngeal candidiasis (prevented with spacers and gargling)

λLow dosage may also prevent the desensitization of β receptors that can occur with overuse of β2 agonist

λPrednisone (oral) and IV steroids generally reserved for severe acute attacks

ANTILEUKOTRIENES

λZafirlukast and montelukast are antagonists at LTD4 receptors with slow onset of activity used prophylactically for many forms of asthma, including antigen, exercise, or drug-induced (e.g., ASA).

λZileuton is a selective inhibitor of lipoxygenases (LOX), ↓ formation of all LTs. It has a more rapid onset (1–3 hours) and is adjunctive to steroids.

Chapter Summary

λThe management of asthma involves the use of bronchodilators to relieve short-term effects and antiinflammatories to reduce bronchial hyperactivity and protect against cellular infiltration.

λβ2-selective agonists are used for the relief of acute bronchoconstriction and as a prophylaxis in exercise-induced asthma. Longer-acting β-adrenoceptor agonists can be used prophylactically to decrease nighttime attacks. The mechanisms responsible for their effects are shown in Figure VI-8-1, which illustrates the action of antiasthmatic drugs.

λThe roles of muscarinic receptor blockers, theophylline, cromolyn, nedocromil, glucocorticoids, and antileukotrienes in the treatment of asthma are discussed. Their modes of action are also illustrated in Figure VI-8-1.

Clinical Correlate

All asthmatics need a short-acting beta-2 agonist for acute attacks. For phophylaxis, glucocorticoids are most often used.

Clinical Correlate

For COPD (emphysema, chronic bronchitis), multiple bronchodilators are used including beta-2 agonists and

M blockers.

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