Week 14
CHAPTER 36: DRUG ABUSE: BASIC
CONSIDERATIONS
CHAPTER 36 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Define drug abuse.
2. Discuss addiction.
3. Describe tolerance and cross-tolerance.
4. Differentiate between physical and psychologic dependence.
5. Describe drug abuse treatment program.
6. Describe the role of the Controlled Substances Act.
CHAPTER 36 OUTLINE
I. Introduction—Expertise on drug abuse may be applied to diagnosis and treatment of acute toxicity, diagnosis and treatment of secondary medical complications of drug abuse, facilitating drug withdrawal, and educating and counseling drug abusers
II. Definitions
A. Drug Abuse—Using a drug in a fashion inconsistent with medical or social norms (culturally defined); with different degrees of severity
B. Addiction—A disease process characterized by the continued use of a specific psychoactive substance despite physical, psychologic, or social harm
C. Other Definitions
1. Tolerance—State in which a particular dose elicits a smaller response than it formerly did (with increased tolerance, need higher and higher doses)
2. Cross-tolerance—Tolerance to one drug confers tolerance to another
3. Psychologic dependence—An intense subjective need for a particular psychoactive drug
4. Physical dependence—A state in which an abstinence syndrome will occur if drug use is discontinued
5. Cross-dependence—Ability of one drug to support physical dependence on another drug
6. Withdrawal syndrome—Constellation of signs and symptoms that occurs in physically dependent individuals when they discontinue drug use
III. Diagnostic Criteria for Substance Abuse and Substance Dependence—Criteria set forth in DSM-IV, substance dependence (equated with addiction) more severe disorder than substance abuse; being physically dependent on a drug is not the same as being addicted
IV. Factors Contributing to Drug Abuse—Drug abuse is end result of progressive involvement with drugs
A. Reinforcing Properties of Drugs—Experience that is pleasurable and reduces the intensity of unpleasant experiences
B. Physical Dependence—Degree determined largely by dosage size and duration of use; can contribute to compulsive drug use
C. Psychologic Dependence—Feel sense of well-being is dependent upon continued drug use; a sense of “craving” when drug unavailable
D. Social Factors—Play an important role in development of drug abuse; desire for social status and approval is common reason for initiating drug use
E. Drug Availability—Availability of the drug makes its use more common
F. Vulnerability of the Individual—Differences in individuals to be prone to drug abuse; individuals are usually impulsive, have low tolerance for frustration and are rebellious against social norms; additional factors may include depressive disorders, anxiety disorders, antisocial personality, and genetics
V. Approaches to Modifying Drug-Using Behavior—Ideal goal is complete cessation of drug use (total abstinence is only outcome for success); however, changes in drug use from compulsive to moderate is beneficial; techniques to help: (1) therapy directed at resolving emotional problems, (2) substitution of alternative rewards, (3) threats and external pressure to discourage drug use, and (4) use of pharmacologic agents to modify effects of abused drugs; two methods not successful have been prolonged hospitalization and traditional individual psychotherapy without other therapy
VI. The Controlled Substances Act—1970 act
A. Record Keeping—Mandatory and reported to DEA every 2 years
B. Drug Enforcement Administration Schedules—Schedule I has highest potential for abuse and no approved medical use in U.S.
C. Prescriptions—Only physicians registered with DEA can prescribe controlled drugs
1. Schedule II—Oral only in emergencies and followed with written within 72 hours; cannot be refilled
2. Schedules III and IV—Oral or written; can be refilled up to 5 times and within 6 months of original order
3. Schedule V—May be dispensed without a prescription if: drug is dispensed by pharmacist; amount limited; recipient is at least 18 years of age; the pharmacist writes and initials record indicating date, name and amount of drug with name and address of recipient; state and local laws do not prohibit dispensing these drugs without a prescription
D. Labeling—Schedules II, III, and IV must contain federal law caution and symbols of C-II, C-III, or C-IV used
E. State Laws—State laws may be more stringent than those of federal; more severe takes precedence
VII. Key Points
CHAPTER 88 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Discuss the use of amphotericin B.
2. Describe the adverse effects of amphotericin B.
3. Discuss systemic antifungal agents and their mechanism of action.
4. Describe the environment that ketoconazole requires for dissolution and absorption.
5. Discuss treatment of superficial mycoses.
CHAPTER 88 OUTLINE
I. Drugs for Systemic Mycoses—Systemic mycoses are divided into two categories: opportunistic infections (seen primarily in debilitated or immunocompromised host) and nonopportunistic infections (uncommon but can occur in any host)
A. Amphotericin B (Fungizone)—An important but dangerous drug; against broad spectrum of pathogenic fungi and drug of choice for most systemic mycoses; highly toxic with renal damage significant; only for infections that are progressive and potentially fatal
1. Mechanism of action—Binds to components of fungal cell membrane (ergosterol), increasing permeability; may be fungicidal or fungistatic; much of toxicity attributed to sterols
2. Microbial susceptibility and resistance—Active against broad spectrum of fungi, some protozoa
3. Therapeutic uses—Drug of choice for systemic mycoses; treatment prolonged (6–8 weeks); administered by IV only
4. Pharmacokinetics—Not effective with oral administration, only IV; don’t know how eliminated
5. Adverse effects—Serious adverse effects
a. Effects associated with intravenous infusion—Frequently produces fever, chills, rigors, nausea, and headache
b. Nephrotoxicity—Direct toxicity on kidney; renal impairment occurs in about everyone; do not use with other nephrotoxic drugs; check kidney function weekly; monitor intake and output; reduce drug if creatinine rises above 3.5 mg/dL
c. Hypokalemia—May need potassium supplements
d. Other effects—Infusion may be associated with delirium, hypotension, hypertension, wheezing, hypoxia, and other effects
6. Drug interactions
a. Nephrotoxic drugs—Avoid
b. Flucytosine—Potentiates the antifungal actions of drug, can reduce dosage, therefore decreasing risk of toxicity with combination
B. Ketoconazole (Nizoral)—Oral alternative to amphotericin B for less severe systemic mycoses
1. Mechanism of action—Inhibits synthesis of ergosterol (component of fungal cytoplasmic membrane); fungistatic at low concentrations and fungicidal at high concentrations
2. Antifungal spectrum—Most systemic mycoses and superficial infections
3. Therapeutic uses—Alternative to amphotericin B; less toxic and only slightly less effective; responses are slow; good for long-term suppression (see Table 86-1 in the text)
4. Pharmacokinetics—Weak base that requires acid environment for dissolution and absorption; needs normal GI pH; if increased pH, not well absorbed; most bound to plasma proteins; hepatic metabolism
5. Adverse effects—Well tolerated; common problems are N/V; give with food; more serious effects involve liver; can get mild effects also
a. Hepatotoxicity—Rare but potentially severe; can be fatal; discontinue at first sign of injury; do not use with history of liver damage; notify MD with symptoms
b. Endocrine effects—Inhibits steroid synthesis; males get gynecomastia, decreased libido and reduced potency and sterility at high doses; females get menstrual irregularities
6. Drug interactions
a. Drugs that raise gastric pH—Decrease absorption; give no sooner than 2 hours after ketoconazole; do not use proton pump inhibitors with ketoconazole
b. Terfenadine (Seldane) and astemizole (Hismanal)—These nonsedating antihistamines can become excessive because of inhibiting metabolizing enzymes and can cause fatal cardiac dysrhythmias
c. Rifampin—Reduces plasma levels of ketoconazole; need increased dosage of ketoconazole
C. Itraconazole (Sporanox)—Member of azole family; active against broad spectrum of fungal pathogens; similar to ketoconazole; administered orally; absorption greatly enhanced with food; distributed to lipophilic tissues (not CSF); hepatic metabolism and renal excretion; well tolerated; rare hepatitis and other minor effects; elevates levels of cyclosporine, digoxin, sulfonylureas, warfarin, terfenadine, astemizole, and cisapride; phenytoin, isoniazid, and rifampin can reduce plasma levels
D. Fluconazole (Diflucan)—Azole antifungal agent; same as ketoconazole; well absorbed (90%); widely distributed to tissues (including CSF); long half-life (30 hours); can inhibit hepatic drug-metabolizing enzymes to increase drug levels (warfarin, phenytoin, and cyclosporine)
E. Miconazole (Monistat IV when given IV)—Azole family; primarily for topical treatment of superficial mycoses; if given IV, severe adverse effects; enhances warfarin, so need to reduce warfarin dosage
F. Flucytosine (Ancobon)—For serious infections caused by Candida and Cryptococcus neoformans (narrow antifungal spectrum); used in combination with amphotericin B; resistance is common; monitor renal function
II. Drugs for Superficial Mycoses—Superficial mycoses caused by two groups of organisms (Candida species and dermatophytes)
A. Overview of Drug Therapy—Preferred for mild to moderate infections
1. Dermatophytic infections (ringworm)—Defined by location (tinea pedis, tinea corporis, tinea cruris, and tinea capitis); know when to use non-drug therapies in addition to drugs
2. Candidiasis—Vulvovaginal common in about 25% women of child-bearing age; can be treated now in 1–3 days; oral single dose used also; oral candidiasis (thrush) usually treated with topical therapy of nystatin or clotrimazole (see Table 86-3 in the text)
3. Onychomycosis (fungal infection of the nails)—Difficult to eradicate and requires prolonged therapy; topical not effective; usually a cosmetic problem, so treatment optional
B. Azoles: Clotrimazole, Ketoconazole, Others—Active against broad spectrum of pathogenic fungi; inhibits biosynthesis of ergosterol
1. Clotrimazole
a. Therapeutic uses—Drug of choice for dermatophytic infections and candidiasis of skin, mouth, and vagina
b. Adverse effects—Applied to skin causes stinging, erythema, edema, urticaria, pruritus, and peeling, but incidence is low; oral preparations cause gastric distress
2. Ketoconazole (Nizoral)—Oral and topical; same as clotrimazole but toxic via oral route
3. Miconazole—Topical and systemic use; drug of choice for cutaneous and vaginal candidiasis; mild adverse effects
4. Fluconazole (Diflucan)—Oral therapy of vulvovaginal candidiasis, oropharyngeal candidiasis, and onychomycosis
5. Newer azole drugs
a. Econazole (Spectazole)—Topical only for ringworm and superficial candidiasis
b. Oxiconazole (Oxistat) and sulconazole (Exelderm)—Broad-spectrum antifungal drugs for topical treatment of tinea infections; not absorbed systemically
c. Butoconazole, terconazole, and tioconazole—Only for topical treatment of vulvovaginal candidiasis; not recommended for use in first trimester of pregnancy
C. Griseofulvin—Orally administered for superficial mycoses; inactive against systemic infections
1. Mechanism of action—Deposited in keratin precursor cells of skin, hair, and nails and replaced by fungus-free tissue; inhibits fungal mitosis
2. Therapeutic uses—Not active against Candida species, only dermatophytic infections; responds quickly (3–8 weeks for skin; up to one year for toenail treatment); can get mild reactions from use but not to be used with patients with porphyria or hepatocellular disease; does effect warfarin (may need increased dosage)
D. Polyene Antibiotics
1. Amphotericin B (Fungizone)—Broad-spectrum antifungal for IV or topical use; drug of choice for systemic mycoses
2. Nystatin—Treatment of candidiasis; drug of choice for chemotherapy of intestinal candidiasis and candida of skin, mouth, esophagus, and vagina; used orally or topically; oral causes GI disturbance
3. Other drugs for superficial mycoses
a. Tolnaftate—Topical for variety of superficial mycoses (only dermatophytes); powders not as effective as creams, etc.
b. Haloprogin (Halotex)—Topical for dermatophytes and Candida species; especially for tinea pedis
c. Undecylenic acid—Topical for superficial dermatophyte mycoses
d. Ciclopirox olamine—For both dermatophytes and Candida species; absorption minimal, so no toxicity
e. Naftifine (Naftin)—New class of antifungal drugs (allylamines); approved for topical use; inhibits squalene eposidase and inhibits synthesis of ergosterol
f. Terbinafine (Lamisil)—Same family as naftifine
CHAPTER 90: DRUGS FOR HIV INFECTION AND
RELATED OPPORTUNISTIC INFECTIONS
CHAPTER 90 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Discuss the pathophysiology involved in the patients who are HIV-positive.
2. Describe the three different phases of the HIV infection.
3. Discuss the therapies used for persons with HIV infection.
4. Distinguish the therapies for persons who are at various stages of HIV infection.
5. Discuss the factors that increase the risk for hematologic dysfunction.
6. Describe the adverse effects related to the various drug therapies for patients with HIV infection.
7. Discuss the evaluation methods to indicate status of the immune system.
8. Discuss treatment modalities for prophylaxis and treatment of common opportunistic infections in patients with AIDS.
CHAPTER 90 OUTLINE
I. Introduction—HIV causes AIDS; HIV promotes immunodeficiency by killing CD4 T lymphocytes (CD4 T cells); patients are at risk for opportunistic infections and certain neoplasms; it has become a global epidemic since identified in 1981; new treatment such as protease inhibitors and triple-drug therapy has caused dramatic advances; no cure; patients have to be educated about transmission
II. Pathophysiology
A. Characteristics of HIV—A retrovirus; lacks self-replication; obligate intracellular parasite; RNA as genetic material rather than DNA; reverse transcriptase is enzyme for process of transcribing RNA to DNA; two types of HIV (HIV-1, which is found worldwide, and HIV-2, which is found mainly in West Africa)
1. Target cells—CD4 T cells (helper T lymphocytes), which are essential for immune system; with CD4 T cell kill, immune system undergoes progressive decline and person becomes more susceptible to opportunistic infections; CD4 provides point of attachment for HIV; cell dies in 1.25 days; most CD4 T cells reside in lymph nodes and other lymphoid tissues; HIV also infects macrophages and microglial cells
2. Structure of HIV—See Figure 88-1 in the text; the outer envelope of HIV contains glycoproteins needed for attachment to host cells (gp 41 and gp 120 subunits)
3. Replication cycle of HIV—See Figure 90-2 in the text and the 10 steps of replication
4. Replication rate—Replicates rapidly during all stages of the infection; initial phase is massive replication (acute retroviral syndrome); usually remain asymptomatic for about 10 years
5. Mutation and drug resistance—Mutates rapidly; resistance related to total viral load
B. Transmission HIV—Present in all body fluids of infected persons; transmission via intimate contact with blood, semen, and vaginal secretions; disease can be transmitted by sexual contact, transfusion, and accidental needle sticks
C. Clinical Course of HIV Infection—A triphasic clinical course; initial phase of massive replication where people experience flu-like acute retroviral syndrome, the immune system’s counter attack; the middle phase characterized by prolonged clinical latency; during late phase, CD4 T cells drops below critical level; HIV damages many cell types especially those of immune and nervous systems, and many patients experience peripheral neuropathies
III. Classification of Antiretroviral Drugs—Two major classes of antiretroviral drugs: reverse transcriptase inhibitors (nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors) and protease inhibitors
IV. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
A. Zidovudine (Retrovir, Azidothymidine, AZT)—Combined with other drugs, reduces viral load, increases CD4 T cell counts, delays onset of disease symptoms, and reduces symptom severity
1. Mechanism of antiviral action—AZT inhibits HIV replication of suppressing synthesis of viral DNA; is converted intracellularly to active form (ZTP); ZTP blocks viral DNA synthesis by inhibiting reverse transcriptase and by becoming incorporated into the growing strand of viral DNA
2. Therapeutic use—HIV infections: penetrates CNS better than most antiretroviral drugs, so valuable for relieving cognitive symptoms; should be combined with at least one other antiretroviral agent
3. Adverse effects
a. Anemia and neutropenia—Principal toxic effects; may need multiple transfusions; increased risks with advanced HIV infection, deficiencies in vitamin B12, and folic acid and with concurrent use of drugs that are myelosuppressive, nephrotoxic, or toxic to circulating blood cells; determine hematologic status before treatment and every 4 weeks
b. Lactic acidosis—With severe hepatomegaly and hepatic steatosis
c. Other adverse effects—GI effects occur on occasion; may get CNS effects and myopathy
4. Drug interactions—Increased risk if taking myelosuppressive, nephrotoxic, or directly toxic drugs to circulating blood cells; examples include ganciclovir, dapsone, pentamidine, pyrimethamine, TMP-SMZ, amphotericin B, flucytosine, vincristine, vinblastine, and doxorubicin
5. Preparation, dosage, and administration—Available in capsules and syrup for oral therapy and solution for IV; avoid rapid infusion
B. Other NRTIs
1. Didanosine (Videx, dideoxyinosine, or ddT)—Actions and uses: for HIV infection and should be combined with at least one other antiretroviral drug; adverse effects: pancreatitis, which can be fatal is major dose-limiting factor; watch for symptoms; history of pancreatitis, alcoholism, and use of IV pentamidine increase risk; other milder effects occur; take drug 1 hour before meals or 2 hours after, chew tablets or manually crush them and put in at least 1 ounce of water; powder should be put in 4 ounces of water (no fruit juice)
2. Zalcitabine (Hivid)—Actions and uses: approved for combined use with another antiretroviral agent to treat patients with HIV infection or those who have shown significant clinical or immunologic deterioration; food delays absorption and reduces amount absorbed; adverse effects: peripheral neuropathy and less common pancreatitis and stomatitis; drug interactions: don’t combine with other drugs causing peripheral neuropathy and pancreatitis (zalcitabine, didanosine, and stavudine)
3. Stavudine (Zerit)—Actions and uses: known also as d4T, is analog of thymidine; converted to active form after uptake by cells; suppresses HIV replication by causing premature termination of growing DNA strand and by competing with natural nucleoside triphosphates; adverse effects: peripheral neuropathy and pancreatitis (low incidence of 1%), which can be fatal; drug interactions: combination with other antiretroviral agents)
4. Lamivudine (Epivir)—Known also as 3TC, is analog of cytidine; converted to active form after uptake and suppresses HIV like other antiretroviral agents; combine with other agents; minimal side effects (insomnia and headache)
5. Abacavir—Approved only for HIV infections
V. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)—Are not naturally occurring nucleosides; bind to active center of reverse transcriptase, causing direct inhibition
A. Nevirapine (Viramune)—Mechanism of action: binds directly to HIV reverse transcriptase and disrupts active center of enzyme; only for HIV-1; does not affect human DNA polymerase; pharmacokinetics: 90% absorbed with oral administration (food doesn’t matter); very lipid-soluble; hepatic metabolism with urine and feces excretion; resistance: develops rapidly if drug used alone; therapeutic use: for HIV-1; adverse effects: most common reaction is rash, which can be severe or even life-threatening; start with low dosage and gradually increase; drug interaction and administration: induces hepatic cytochrome P450, so increases metabolism of other drugs
B. Other NNRTIs—Efavirenz and delavirdine
VI. Protease Inhibitors—Most effective antiretroviral drugs available; in combination with other drugs, viral levels are reduced to levels not detected by current assays; all inhibit cytochrome P450, making drug dosing a challenge; resistance also a problem; cross-resistance only within classification; never use alone, preferably use two other drugs
A. Group Properties
1. Adverse effects—Hyperglycemia/diabetes; fat redistribution; hyperlipidemia; increased bleeding in hemophiliacs; elevation of serum transaminase
2. Drug interactions—P450 inhibitors; P450 inducers; P450 substrates; and Protease inhibitor combinations
B. Saquinavir (Invirase)—Low bioavailability makes it less useful than other protease inhibitors
1. Soft gelatin formulation—Mechanism of action: protease catalyzes final step in HIV protease, which cleaves the bonds in the polyproteins, which would allow for HIV to mature; inhibitors prevent the cleaving process so virus remains immature and noninfectious; pharmacokinetics: poor bioavailability (4%) due to poor absorption and extensive first-pass effect; food increases bioavailability; highly protein-bound (98%); elimination by cytochrome P450; excreted in feces primarily; therapeutic use: for HIV only; use in combination; not first-line drug; adverse effects: well tolerated; side effects are headache, nausea, diarrhea, and abdominal pain; may cause diabetes (no definitive link established); drug interaction and administration: inhibits cytochrome P450 drug-metabolizing enzymes, which causes increase in drug levels; use of terfenadine and astemizole (two antihistamines) can be fatal in combination; also avoid cisapride and ergot alkaloids; drugs that induce cytochrome P450 (rifampin, rifabutin, etc.) can accelerate metabolism of saquinavir, which is low to begin with, so avoid these; agents that inhibit P450 (ritonavir, ketoconazole, and grapefruit juice) can slow metabolism of saquinavir, increasing levels and enhancing therapeutic effects; always take with food to increase absorption
2. Hard gelatin formulation—Lower bioavailability
C. Other Protease Inhibitors
1. Indinavir (Crixivan)—Action and use: inhibits HIV protease; combine with another drug or two; pharmacokinetics: moderate bioavailability (30%) on empty stomach; administering with high fat, protein, or caloric meal decreases absorption by 70%; liver dysfunction prolongs half-life; adverse effects: well tolerated; major adverse effect is nephrolithiasis (hydrate well with 48 ounces water daily); risk of diabetes; can get GI intolerance, blurred vision, dizziness, rash, metallic taste, or thrombocytopenia; drug interaction and administration: inhibits cytochrome P450, which decreases metabolism of other drugs (astemizole, terfenadine, cisapride, triazolam, midazolam, and ergot alkaloids); didanosine decreases absorption of indinavir; rifampin and rifabutin induces cytochrome P450; levels can be increased by ketoconazole; maximize absorption with water on empty stomach or with skim milk, coffee, tea, or low-fat meal; do not give with large meal; protect medication from moisture
2. Ritonavir (Norvir)—Action and use: an HIV protease inhibitor; for HIV-1 and HIV-2; approved for adults and children; combined with at least one reverse transcriptase inhibitor; adverse effects: common during initial weeks of therapy and then fade; oral solution can be mixed with chocolate milk, Ensure, or Advera to improve taste; drug interaction and administration: powerful inhibitor of cytochrome P450 drug-metabolizing enzymes, which decreases metabolism of these drugs; can decrease levels of other drugs (ethinyl estradiol, zidovudine, clarithromycin, sulfamethoxazole, and theophylline); start with low dosage and increase
3. Nelfinavir (Viracept)—Action and uses: for adults and children in those as young as 2 years old; combine with at least one reverse transcriptase inhibitor; adverse effects: diarrhea only adverse effect of note; may pose risk of diabetes; administration: do not mix with acidic foods or juices; can mix powder with water, milk, formula, soy formula, etc.
4. Amprenavir—Similar to other protease inhibitors
VII. Management of HIV Infection—Improvement with multidrug therapy (usually a protease inhibitor plus two NRTIs); patients usually take three drugs for HIV and additional drugs for opportunistic infections; therefore, drug interactions and side effects very significant; 2000 guidelines from the U.S. government made recommendations
A. Diagnosis—Several tests: enzyme-linked immunoadsorbent assay (ELISA) and Western blot
1. Viral load (plasma HIV RNA)—Treatment primarily determined by this—see guidelines in Table 90-7 in the text
2. CD4 T cell counts—Not predictive of viral load measurements but do tell how much damage HIV has done; as therapy takes effect, CD4 T counts rise
3. HIV drug resistance—Significant concern in HIV therapy; usually emerges over the course of treatment; two types of assays employed (phenotypic and genotypic)
1. Symptomatic HIV disease—Patients should receive maximally effective antiretroviral therapy; three drugs (one protease inhibitor plus two NRTIs); alternative consists of one NNRTI plus two NRTIs, but this is less effective; goal is to achieve maximal and sustained suppression of HIV replication as evidenced by reduction of plasma HIV RNA to levels not detected; combination decreases risk of resistance; use plasma HIV RNA to monitor therapy; complex therapy; multiple drug and food interactions make it difficult to develop effective therapy (Table 90-8 in the text)
2. Asymptomatic HIV disease—More complex to determine treatment during asymptomatic phase; weigh benefits and risks
3. Acute HIV disease—All patients with primary acute HIV disease should receive maximally effective antiretroviral therapy (one protease inhibitor plus two NRTIs); early and aggressive interventions offer multiple benefits (may decrease extent to which HIV disseminates throughout body, preserve immune system function, slow progression of HIV disease, decrease rate of mutation, may decrease risk of emergence of drug-resistant virion, and may possibly eradicate HIV before it gets firmly established); drawbacks to aggressive treatment include reduction in quality of life due to drug toxicity, blunting early immune response, and emergence of drug-resistant HIV if treatment fails
4. Changing the regimen—Four reasons to change therapy
a. Treatment failure—most compelling reason; failure indicated by plasma HIV RNA failing to drop by 10-fold in first 4 weeks, plasma HIV RNA failing to drop to undetectable levels within 4–6 months, rebounding of HIV RNA after falling to undetectable level, CD4 T counts continuing to drop, and clinical disease progressing; determine cause if possible
b. Treatment with a suboptimal regimen—Noted by failure to suppress HIV RNA to undetectable levels; treatment with one drug is considered suboptimal; replace old drugs with new
c. Drug toxicity—Replace drug with one from same group and of equal efficacy
d. Noncompliance—Multiple reasons
D. Treatment of Pregnant Patients—Basic principles: follow same guidelines for managing HIV infection in nonpregnant adults; balance benefits with risk; since danger to fetus is greatest in first trimester, may need to discontinue treatment during that time; little data available regarding treatment for women in general; zidovudine only drug proved to decrease risk of HIV transmission to fetus by 70%–80%; but treatment with all drugs or no drugs; Reducing Perinatal HIV Transmission (mother-to-child transmission during perinatal period primarily during delivery; need to reduce risk by minimizing viral load with HAART)
E. Treatment of Adolescent Patients—Same principles guide adolescents as adults; information limited; treat only with drugs that have documented testing
F. Treatment of Infants and Young Children—AIDS is seventh leading cause of death in kids 1–14 in U.S.; treat with combination
G. Postexposure Prophylaxis—One-time exposure does carry risk; can be decrease by prophylactic drugs
VIII. Prophylaxis and Treatment of Opportunistic Infections—With advanced HIV, persons are vulnerable to infections; risk greatest among patients with <200 CD4 T cell count
A. Pneumocystis carinii Pneumonia (PCP)—Most common opportunistic infection and leading cause of death among those with AIDS; clinically very nonspecific symptoms
1. Treatment of active PCP—Trimethoprim plus sulfamethoxazole (TMP-SMZ) is treatment of choice; effective in 90% of patients; improvement seen in 4–8 days; if severely immunocompromised, then intravenous pentamidine preferred; there are other alternatives that are less effective
2. Prophylaxis of PCP—Recommended for all with CD4 T count <200 and for those with previous PCP; preferred treatment is TMP-SMZ or an alternative of aerosolized pentamidine
B. Cytomegalovirus (CMV) Retinitis—One of most common complications of AIDS patients; if CD4 T counts <50, then very vulnerable; if untreated, loss of vision can occur; need induction phase to decrease viral load then maintenance therapy for life; even with therapy, blindness can occur; one of three agents usually used (ganciclovir, cidofovir, and foscarnet); maintenance therapy very expensive (wholesale cost is $9113/year for the IV ganciclovir)
1. Ganciclovir (Cytovene) is drug of choice for CMV retinitis; dose-limiting toxicities are neutropenia and thrombocytopenia
2. Foscarnet (Foscavir) less well tolerated than ganciclovir and much more expensive; IV twice/day for induction then one/day for maintenance; dose-limiting toxicities are nephrotoxicity, electrolyte imbalance, genital ulceration, and fluid overload
3. Cidofovir (Vistide)—A new IV drug for CMV retinitis; longer half-life; kidney damage is dose-limiting toxicity; must give probenecid and IV hydration with therapy
4. Fomivirsen
C. Mycobacterium tuberculosis and Mycobacterium avium Complex—Slow growing microbes requiring prolonged drug therapy; always treated with multiple drugs
1. Mycobacterium tuberculosis—Four drug regimen (isoniazid plus rifampin plus pyrazinamide plus ethambutol), then switched to two-drug protocol (isoniazid plus rifampin) 2 months later
2. Mycobacterium avium Complex (MAC)—Two microbes; infection begins in lungs or GI tract, then disseminates to blood, bone marrow, liver, spleen, lymph nodes, brain, kidneys, and skin; use either azithromycin or clarithromycin plus at least one other drug (usually ethambutol); other drugs may need to be added; after acute infection, prophylaxis with either azithromycin or clarithromycin
D. Toxoplasma Encephalitis—A protozoan that is usually benign except in immunocompromised host; infection can be lethal; appears like encephalitis and usually late in disease; treatment of choice is pyrimethamine plus sulfadiazine; other alternatives to sulfadiazine are available; lifelong maintenance required
E. Cryptococcal Meningitis—A fungus that usually manifests as meningitis; treatment of choice is amphotericin B infused daily for 2 or more weeks; may combine oral flucytosine with the amphotericin B
F. Varicella-Zoster Virus Infection (VZV)—Can cause chickenpox and herpes zoster, known also as shingles or simply zoster; preferred treatment for shingles is high-dose oral acyclovir (800 mg 5 times/day for 7–10 days); if disseminated VZV, then intravenous acyclovir
G. Herpes Simplex Virus Infection—Common among patients with HIV disease
H. Candidiasis—HIV-infected patients develop Candida species
A. Obstacles to Vaccine Development—Very difficult; widespread variation of HIV strains; don’t prevent infection, just attenuate it
B. Current Status of Vaccine Development—One vaccine approved for phase III clinical trails
X. Keeping Current—Numerous Web site locations
XI. Key Points
XII. Summary of Major Nursing Implications
A. Nucleoside Reverse Transcriptase Inhibitors
B. Non-Nucleoside Reverse Transcriptase Inhibitors
C. Protease Inhibitors
D. Implementation: Administration
CHATPER 91: DRUG THERAPY OF SEXUALLY
TRANSMITTED DISEASES
CHAPTER 91 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Discuss the major sexually transmitted diseases.
2. Describe the various treatment modalities for sexually transmitted diseases.
CHAPTER 91 OUTLINE
I. Introduction—Sexually transmitted diseases (STDs) are defined as infectious or parasitic diseases that are transmitted primarily through sexual contact; see Table 91-1 in the text
II. Chlamydia Trachomatis Infections—Most common cause of bacterial STD in U.S.; can cause genital tract infections, proctitis, cojunctivitis, lymphogranuloma venereum, and neonatal ophthalmia and pneumonia (see Table 91-1 in the text)
A. Characteristics—Common; symptoms are mild but disease not benign; cause sterility in women
B. Adults and Adoledscents—Uncomplicated disease, use single dose of azithromycin or 7 days of doxycycline (ofloxacin as alternative)
C. Infection in Pregnancy—Use erythromycin for 7 days (not erythromycin estolate because of liver damage); amoxicillin as substitute; treat male partner
D. Infants—About one-half get infection during birth process; infants at risk for conjunctivitis and pneumonia; need systemic erythromycin; can also use topical erythromycin, tetracycline, or silver nitrate
E. Children—Sexual abuse most likely cause; treatment depends on age and weight
F. Lymphogranuloma Venereum (LGV)—A unique strain of C. trachomatis; transmission strictly by sexual contact; common in tropical countries and does occur in U.S.; begins as a papule, spreads to lymph nodes, drains; treatment with doxycycline; erythromycin as substitute
III. Gonococcal Infection
A. Characteristics—Gonorrhea is caused by Neisseria gonorrhoeae (gram-negative diplococcus); usually by sexual contact and also by infected exudates; in males burning sensation and puslike discharge, whereas in females, commonly asymptomatic; can lead to sterility; with oral sex, mouth and throat can become infected; with anal sex, rectum can become infected; can get bacteremia in both sexes causing cutaneous lesions, arthritis, and meningitis or endocarditis (rare); drug of choice is now ceftriaxone as single IM dose; if disseminated gonorrhea, need parenteral therapy
B. Treatment—Large number also infected with C. trachomatis (use doxycycline and azithromycin)
1. Urethral, cervical, and rectal infections—Cefixime, ceftriaxone, ciprofloxacin, and ofloxacin are agents of choice
2. Pharyngeal infection—More difficult
3. Conjunctivitis—Ceftriaxone 1 g IM, and wash eyes with saline
4. Pregnancy—Single 1 g of ceftriaxone or spectinomycin (2 g)
5. Disseminated gonococcal infection—Secondary to gonococcal bacteremia
6. Neonatal infection—Acquired from infected mother during birthing process; initial symptom is conjunctivitis, then other structures involved, then blindness; prevented by topical drug immediately postpartum (erythromycin, tetracycline, or silver nitrate)
7. Children—Sexual abuse most likely cause
IV. Nongonococcal Urethritis (NGU)—Diagnosed by presence of polymorphonuclear leukocytes and negative culture for N. gonorrhoeae; especially in sexually active adolescent girls; drug of choice is doxycycline for 7 days; use erythromycin plus metronidazole for pregnant women and young children
V. Pelvic Inflammatory Disease (PID)—A syndrome that includes endometritis, pelvic peritonitis, tubo-ovarian abscess, and inflammation of the fallopian tubes; infertility can result; symptoms include abdominal pain, vaginal discharge and fever; need broad coverage; combination therapy (cefotaxime or cefotetan or combined with doxycycline as IV therapy or outpatient with cefoxitin IM with probenecid PO followed by oral doxycycline for 14 days)
VI. Acute Epididymitis—Either sexual or nonsexual acquisition; see fever and pain in the back of the testicles; treat with ofloxacin for 10 days
VII. Syphilis—Caused by spirochete Treponema pallidum; penicillin is drug of choice
A. Characteristics—Three stages: primary stage (after incubation period of 1–4 weeks develop chancre); secondary stage (in 2–6 weeks after chancre with T. pallidum in bloodstream and spreads; symptoms of skin lesions and flulike symptoms); tertiary syphilis develops 5–40 years later with almost any organ involved; neurosyphilis is common
B. Treatment—Penicillin G is drug of choice for all stages of syphilis; dosage and form changes with stage of disease
VIII. Acquired Immunodeficiency Syndrome—AIDS caused by HIV
IX. Chancroid—Caused by Haemophilus ducreyi; transmission by sexual contact; infection is painful, ragged ulcer at site of inoculation; lymph nodes swollen; recommended treatments are erythromycin, ceftriaxone, and azithromycin
X. Trichomoniasis—Caused by Trichomonas vaginalis; in women infection asymptomatic or thin watery vaginal discharge and itching/burning; in males no symptoms; treat with single dose of metronidazole (Flagyl); do not use drug during first trimester; treat male partners
XI. Bacterial Vaginosis—Results from alteration in vaginal microflora; may not be transmitted sexually; malodorous vaginal discharge; treatment either oral with metronidazole (Flagyl) or intravaginal with metronidazole or clindamycin
XII. Herpes Simplex Infections
A. Characteristics—Virus type 2 (HSV-2); in U.S., genital herpes has reached epidemic proportions; symptoms develop 6–8 weeks after contact; in females or males get blisters or vesicles; can get systemic symptoms; within days get painful ulcer-like sores; symptoms resolve in 2–3 weeks; virus remains latent; can’t eliminate virus; avoid sexual contact during infectious times; use condom
B. Neonatal Infection—Transmitted to infant either in utero or during delivery; if acquired in utero can result in abortion or fetal malformation; at delivery can result in neurologic damage and death; do cesarean section to protect infant
C. Treatment—Acyclovir, famciclovir, and valacyclovir
XIII. Genital and Anal Warts (Condyloma Acuminatum)—Caused by human papillomaviruses (HPVs); some types of warts associated with genital carcinoma; use condom to minimize risk; warts can be removed (cryotherapy), but virus remains; podophyllin can be used to remove warts also
XIV. Proctitis—Primarily from receptive anal intercourse
XV. Pediculosis Pubis and Scabies—Lice and mites; intense itching; topical permethrin can eliminate organisms
XVI. Key Points
CHAPTER 98 OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Describe the three major classes of anticancer drugs.
2. Differentiate between cell-cycle–specific and cell-cycle–nonspecific anticancer drugs.
3. Discuss the indications for bifunctional alkylating agents.
4. Describe the use of antimetabolites as anticancer agents.
5. Describe specific adverse effects of selective anticancer agents.
6. Discuss the use of glucocorticoids in the treatment of cancer.
7. Describe the role of hormones in the selection of cancer therapy.
CHAPTER 98 OUTLINE
I. Introduction to the cytotoxic drugs—Three major classes (cytotoxic agents, hormones and hormone antagonists, and biologic response modifiers); cytotoxic drugs are the largest group and are subdivided into alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, topoisomerase inhibitors, and miscellaneous cytotoxic drugs
A. Mechanism of Cytotoxic Action—See Table 98-2 in the text for principal mechanisms
B. Cell-Cycle Specificity—From one mitotic division to the next
1. Cell-cycle–specific drugs—Toxic only to cells passing through particular phase of cell cycle; known as schedule-dependent drugs
2. Cell-cycle–nonspecific drugs—Drugs act at any phase; usually alkylating agents and most antitumor antibiotics; increase cell kill when used with phase-specific drugs
D. Toxicity—Especially to proliferating cells (bone marrow, hair follicles, GI epithelium, and germinal epithelium); see Chapter 97
E. Dosage, Handling, and Administration
1. Dosage and administration—Complex process requiring specialized training
2. Handling of cytotoxic drugs—Drugs are usually mutagenic, teratogenic, and carcinogenic with direct contact causing injury
3. Administration of vesicants—Extravasation of vesicants cause severe injury; use only good IV flow veins without previous irradiation
II. Alkylating Agents—Nitrogen mustards, nitrosoureas, and others (see Table 98-1 in the text)
A. Shared Properties
1. Mechanism of action—Highly reactive with DNA; may have one (monofunctional agents) or two reactive sites (bifunctional agents that form cross-links); very toxic to proliferating cells; can be administered in single bolus
2. Resistance—Common
3. Toxicities—Injure cells that have high growth fraction; nausea and vomiting occur with all agents; especially with cisplatin; all are vesicants so must be given IV
B. Properties of Individual Alkylating Agents
1. Nitrogen mustards
a. Cyclophosphamide (Cytoxan, Neosar) is bifunctional agent against broad spectrum of neoplastic diseases (Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma and solid tumors of the head, neck, ovary, and breast; drug most widely used; it is a prodrug that undergoes conversion to active form in liver; is not a vesicant so can be given orally (give with food); major dose-limiting toxicity is bone marrow depression with severe nausea, vomiting, and alopecia common; acute hemorrhagic cystitis possible; hydrate well
b. Mechlorethamine (Mustargen)—Bifunctional used for Hodgkin’s disease and non-Hodgkin’s lymphomas; powerful vesicant; in blood converted to inactive forms; bone marrow depression severe with other toxicities including nausea, vomiting, alopecia, diarrhea, stomatitis, amenorrhea, and sterility
c. Chlorambucil (Leukeran)—Safest nitrogen mustard; bone marrow depression major dose-limiting toxicity; drug of choice for chronic lymphocytic leukemia, and used for Hodgkin’s disease, non-Hodgkin’s lymphomas, and ovarian cancers; oral
d. Melphalan (Alkeran)—A bifunctional agent well tolerated; has caused leukemia; not a vesicant; severe nausea/vomiting rare; drug of choice for palliative therapy of multiple myeloma and for carcinoma of ovary and breast
e. Ifosfamide (Ifex)—Derivative of cyclophosphamide; for refractory germ-cell cancer of testes; toxicities include bone marrow depression and hemorrhagic cystitis (give mesna and hydration); IV administration
2. Nitrosoureas—Bifunctional alkylating agents against broad spectrum of diseases
a. Carmustine (BCNU)—Crosses blood-brain barrier, so used to treat primary and metastatic tumors of the brain, as well as Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma, malignant melanoma, hepatoma, and adenocarcinoma of stomach, colon, and rectum; get delayed bone marrow depression; severe nausea and vomiting and also injury to liver, kidneys and lungs has been reported; either topical (implanting wafer) or IV administration
b. Lomustine (CCNU)—Similar to carmustine; can also be used for melanomas and carcinomas of breast, lung, and colon; IV administration; need to check renal function carefully
c. Streptozocin (Zanosar)—Differs significantly; selective uptake by pancreas islet cells; primary use for pancreatic metastasis; watch for kidney damage; minimal bone marrow depression; IV administration
3. Additional alkylating agents
a. Cisplatin (Platinol)—Not a true alkylating agent but kills by performing cross-linkages between and within strands of DNA; primary for testicular cancer; also used for cancer of ovary, bladder, head, and neck; damages kidney (counter with hydration, diuretic, and amifostine); bone marrow suppression; damages hearing and is neurotoxic
b. Carboplatin (Paraplatin)—Analog of cisplatin; only for initial and palliative therapy for ovarian cancer but has been used in small-cell cancer of lung, squamous cell cancer of head and neck and endometrial cancer; given by IV infusion; similar adverse effects with addition of anaphylactic reaction (use epinephrine, glucocorticoids, and antihistamines)
c. Busulfan (Myleran)—Also a bifunctional agent use limited to bone marrow; for chronic myelogenous leukemia with 90% remission rate; administration is oral
d. Temozolomide (Temodar)—Oral therapy for anaplastic astrocytoma that has relaspsed
III. Antimetabolites—Disrupt critical metabolic processes; act during cycles
A. Folic Acid Analog: Methotrexate—Acts by preventing conversion of folic acid to active form; this is only one for cancer treatment (others used for bacterial infections and malaria)
1. Mechanism of action—Inhibits dihydrofolate reductase; leucovorin rescue enhances effects of methotrexate but affects normal cells also (potentially fatal if right dose at right time is not given)
2. Resistance—Occurs because of decreased uptake of methotrexate, increased synthesis of dihydrofolate reductase and synthesis of modified form of dihydrofolate reductase with reduced affinity for methotrexate
3. Pharmacokinetics—Orally, IM, IV, and intrathecally administered
4. Therapeutic uses—Neoplastic diseases, severe psoriasis, and RA
5. Toxicity—Dose-limiting toxicities are bone marrow depression, pulmonary infiltrates, and fibrosis and oral and GI ulceration (death from perforation or hemorrhagic enteritis); nausea and vomiting can occur shortly after administration; high doses cause injury to kidney (urine should be alkalinized and give fluids); avoid pregnancy
B. Pyrimidine Analogs (cytosine, thymine, uracil) can inhibit biosynthesis of pyrimidines, inhibit biosynthesis of DNA and RNA, and disrupt nucleic acid function
1. Cytarabine (Cytosar-U)—Also known as Ara C; suppresses further DNA synthesis; resistance (occurs from several mechanisms); pharmacokinetics (IV, SC, or intrathecal for administration; liver deamination; excreted in urine); therapeutic uses (acute myelogenous leukemia and combined with other drugs for therapy); toxicity (bone marrow suppression, nausea, vomiting and fever with stomatitis, liver injury, and conjunctivitis have occurred)
2. Fluorouracil (Adrucil)—Fluorinated derivative of uracil; to treat solid tumors; is converted to active form only in cells going through cell cycle, but drug lacks phase specificity; resistance (by decreased activation of fluorouracil and production of altered thymidylate synthetase that has low affinity for FdUMP; therapeutic uses (solid tumors; palliative therapy of carcinomas of colon, rectum, breast, stomach, and pancreas; employed topically to treat premalignant keratoses); pharmacokinetics (by IV with continuous infusion more effective and less toxic than bolus; enters CNS with ease; hepatic metabolism); toxicity (bone marrow depression and oral and GI ulceration; other effects include alopecia, hyperpigmentation, and neurologic deficits)
3. Capecitabine (Xeloda)—Prodrug form of fluorouracil for metastatic breast cancer, 20% experience 50% reduction in tumor size
4. Floxuridine (FUDR)—Is converted to FdUMP in body; for metastatic carcinoma of colon; given by intra-arterial infusion
5. Gemcitabine (Gemzar)—A nucleoside analog that inhibits DNA synthesis; converted to two active forms (gemcitabine diphosphate and gemcitabine triphosphate); therapeutic use (adenocarcinoma of pancreas as first-line therapy and for those previously treated with floxuridine); toxicity (fairly well tolerated; 70% have mild nausea and vomiting; high incidence of elevated serum transaminases, proteinuria, hematuria, pain, fever, and other less common effects)
C. Purine Analogs—Bases employed for biosynthesis of nucleic acids
1. Mercaptopurine—A prodrug that undergoes conversion to active form within cells; is S-phase–specific; resistance includes reduced activation of the drug and accelerated deactivation; pharmacokinetics (administered orally with erratic absorption; metabolized by liver; drug interactions include allopurinol); therapeutic uses (lymphocytic leukemia and acute and chronic myelogenous leukemia in adults); toxicity (bone marrow depression, can get hepatic dysfunction, nausea, vomiting, oral and GI ulceration; is mutagenic and levels increased with allopurinol)
2. Thioguanine—Like mercaptopurine; for acute lymphocytic and myelogenous leukemias; not interactive with allopurinol; less severe reactions than with mercaptopurine; may see jaundice
3. Pentostatin (Nipent)—Analog of adenosine; suppresses DNA synthesis; only approved indication is hairy cell leukemia; adverse effects are bone marrow depression, CNS depression, with N/V, rash, and fever; very costly drug ($1400); give by IV bolus or infusion
4. Fludarabine (Fludara)—Analog of adenosine; approved only for chronic lymphocytic leukemia; cell kill from inhibiting DNA replication
5. Cladribine (Leustatin)—Adenosine analog with unique combination of actions; inhibits DNA synthesis and DNA repair; highly effective (drug of choice) against hairy cell leukemia (HCL) and effective for chronic lymphocytic leukemia non-Hodgkin’s lymphomas, acute myeloid leukemia and mycosis fungoides; dose-limiting is myelosuppression; administer continuous IV over 7 days
IV. Antitumor Antibiotics—Cytotoxic drugs originally isolated from Streptomyces; only used to treat cancers not infections; directly act with DNA; all given parenterally
A. Dactinomycin (Actinomycin D)—Mechanism of action (planar molecule that kills cells through intercalation with DNA, which then prevents RNA and protein synthesis; drug is phase-nonspecific); pharmacokinetics (IV infusion; rapidly cleared from blood; does not cross blood-brain barrier; biliary and renal excretion); therapeutic uses (Wilms’ tumor and rhabdomyosarcoma as well as choriocarcinoma, Ewing’s sarcoma, Kaposi’s sarcoma, and testicular cancer); toxicity (dose-limiting from bone marrow depression, oral and GI mucositis; can get N/V, diarrhea, alopecia, folliculitis and dermatitis in irradiated areas); extremely corrosive to soft tissue
B. Doxorubicin (Adriamycin, Rubex)—Against broad spectrum of neoplastic diseases; however, very cardiotoxic; mechanism of action (intercalates with DNA and causes strand scission); pharmacokinetics (IV infusion, doesn’t cross blood-brain barrier; metabolized by liver, biliary excretion); therapeutic uses (for solid tumors and disseminated cancers); toxicity (cardiotoxic with both acute and delayed injury (congestive heart failure often unresponsive to treatment requiring total dose not to exceed 550 mg/m2 over person’s lifetime); there is new drug (dexrazoxane) that seems to protect heart by binding to iron and preventing interaction with doxorubicin, but problems were intensified suppression of myelosuppression and reduced anticancer effects of doxorubicin; can also get red urine and sweat, extravasation, bone marrow suppression, alopecia, stomatitis, anorexia, pigmentation of extremities; another new drug, dexrazoxane (Zinecard), can protect heart from doxorubicin; must already have received 300 mg/m2
C. Daunorubicin, liposomal (DaunoXome)—A new formulation of daunorubicin to increase delivery to tumor cells and decrease uptake to normal cells; shares many of properties of doxorubicin; give as 1-hour infusion; only indication for use is HIV-related Kaposi’s sarcoma
D. Epirubicin (Ellence)—Adjunct for breast cancer
E. Idarubicin (Idamycin)—Analogue of daunorubicin and doxorubicin; only approved for acute myelogenous leukemia in adults; is cardiotoxic
F. Valrubicin (Valstar) for localized cancer of the bladder; but first choice of therapy for bladder cancer is bacille
G. Mitoxantrone (Novantrone)—Less toxic than daunorubicin or doxorubicin; intercalates of DNA and promotes DNA strand breakage; get blue-green urine, skin, and sclera
H. Bleomycin (Blenoxane)—Contains mixture of glycopeptides; causes severe injury to lungs; for broad spectrum of tumors; administration by SC, IV, or IM
I. Mitocycin (Mutamycin)—Prodrug; bifunctional, or trifunctional alkylating agent; labeled for use with adenocarcinoma of stomach and pancreas and has been used for other tumors; do get bone marrow depression
J. Plicamycin (Mitramycin)—Highly toxic and restricted for testicular carcinoma; major risk of hemorrhage
V. Mitotic Inhibitors—Act at M phase to prevent cell division; two groups: vinca alkaloids and taxoids
A. Vinca alkaloids
1. Vincristine (Oncovin, Vincasar)—Blocks mitosis during metaphase; pharmacokinetics (must be given IV; enters tissues rapidly; poor CNS penetration; hepatic metabolism and biliary excretion; 12% eliminated by kidney); therapeutic uses (bone-marrow sparing, so good for combination therapy for numerous tumors); toxicity (peripheral neuropathy is major dose-limiting toxicity; nearly all experience some motor and sensory nerves; little toxicity to bone marrow; severe local injury; alopecia in 20% of patients)
2. Vinblastine (Velban, Velsar, Alkaban)—Analog of vincristine; difference is this drug is very toxic to bone marrow; less severe neurotoxicity
3. Vinorelbine (Navelbine)—Semisynthetic vinca alkaloid similar to vincristine and vinblastine; approved only for nonsmall-cell lung cancer; profound bone marrow depression
B. Taxoids
1. Paclitaxel (Taxol)—Acts during late G2 to promote formation of stable microtubule bundles; for Kaposi’s sarcoma and metastatic ovarian and breast cancers; other investigational uses; toxicity (severe hypersensitivity reactions, requires pretreatment with glucocorticoid, both histamine receptor antagonists; dose-limiting toxicity is bone marrow depression)
2. Docetaxel (Taxotere)—Similar to paclitaxel; additionally, causes fluid retention
VI. Topoisomerase Inhibitors
A. Topotecan—Enzyme that relieves torsional strain in DNA and prevents repair of DNA; used for metastatic cancer of ovary refractory to cisplatin and other drugs; infuse over 30 minutes for 5 consecutive days, wait for 16 days, and repeat for 4 cycles; very costly (each course >$2500); get bone marrow suppression
B. Irinotecan (Caamptosar)—Impairs DNA replication; for metastatic cancer of colon or rectum that has progressed despite treatment with fluorouracil; also being studied for advanced cancers; infuse and treat weekly; 4-week course is $4000; severe diarrhea can occur (early and late) and must be treated; numerous side effects
C. Etoposide (VePesid)—Derived from podophyllotoxin, a naturally occurring plant alkaloid; prevents resealing of DNA strand breaks; only for refractory testicular cancer and small-cell cancer of the lung; given orally and IV; most of drug eliminated in urine; bone marrow depression
D. Teniposide (Yumon)—Analog of etoposide and shares same action; only approved for refractory acute lymphoblastic leukemia of childhood; slow IV infusion; bone marrow depression is dose-limiting toxicity; secondary leukemias develop within 8 years of initial drug exposure
VII. Miscellaneous Cytotoxic Drugs
A. Asparaginase (Elspar)—An enzyme that is limited almost exclusively to leukemic lymphoblasts; administered as IV or IM; used only for lymphocytic leukemia usually in combination with other drugs; severe adverse effects including coagulation deficiencies, injury to liver, pancreas, and kidney plus CNS depression; hypersensitivity occurs
B. Pegaspargase (Oncaspar)—Modified form of asparaginase with fewer hypersensitivity reactions but otherwise similar
C. Hydroxyurea (Hydrea)—On S-phase for chronic myelocytic leukemia
D. Mitotane (Lysodren)—Analog of two insecticides (DDD and DDT); palliative therapy of inoperable adrenocortical carcinoma
E. Procarbazine (Matulane)—Cell-cycle–nonspecific; advanced Hodgkin’s disease; risk of HTN with sympathomimetic drugs, tricyclic antidepressants, and tyramine-rich foods
F. Dacarbazine (DTIC-Dome)—Prodrug activated by liver; for metastatic malignant melanoma but only 20% rate; given by IV; bone marrow suppression is dose-limiting toxicity
G. Docetaxel (Taxotere)—Similar to paclitaxel; only approved for locally advanced or metastatic breast cancer; neutropenia develops in virtually all patients; severe fluid retention can occur; hypersensitivity can also occur
H. Hydroxyurea (Hydrea)—Inhibits DNA replication (S-phase specific); absorbed after oral administration; used for chronic myelocytic leukemia and recurrent inoperable carcinoma of ovary; dose-limiting toxicity is bone marrow suppression; get CNS depression plus other usual effects
I. Altretamine (Hexalen)—For palliative therapy of persistent or recurrent ovarian cancer; absorbed well but undergoes rapid hepatic metabolism; central neurotoxicity occurs
VIII. Hormones and Hormone Antagonists—Least toxic of all anticancer drugs; highly specific drugs; 6 basic categories (glucocorticoids, androgens/antiandrogens, estrogens/antiestrogens, aromatase inhibitors, progestins, and gonadotropin-releasing hormone analog
A. Glucocorticoids—Used in combination with other drugs; useful for lymphoid tissue cancers; long-term treatment causes adverse effects; also helps to treat adverse effects of cancer therapy
B. Antiestrogens
1. Tamoxifen (Nolvadex)—Most widely prescribed anticancer agent in world; for breast cancer and being investigated for prevention of breast cancer; binds to estrogen receptors preventing activation of estradiol; adverse effects are N/V, hot flushes, menstrual irregularities; helps preserve bone in postmenopausal women; increases risk of endometrial cancer; use for breast cancer as additive therapy and for prevention of breast cancer in women at high risk
2. Raloxifene (Evista)—A SERM similar to tamoxifen without risk of endometrial cancer
3. Toremifene (Fareston)—For metastatic breast cancer with ER—positive tumors or if status of ER is unknown
C. Aromatase Inhibitors—For breast cancer in postmenopausal women; deprive breast cancer cells of estrogen
1. Anastrozole (Arimidex)—For postmenopausal women with advanced breast cancer; deprives cancer of estrogen; generally well tolerated with only 3.3% discontinuing drug for side effects
2. Letrozole (Femara)—Similar to anastrozole
3. Exemestane (Aromasin)—Oral therapy for advanced breast cancer in postmenopausal women where disease progresses after tamoxifen
IV. D. Drugs for Prostate Cancer
1. Gonadotropin-releasing hormone agonists (Gn-RH)—Suppress production of androgens by testes; only two available
a. Leuprolide (Lupron)—Synthetic analog of gonadotropin-releasing hormone (also known as luteinizing hormone-releasing hormone); for advanced carcinoma of prostate as alternative to orchiectomy; given SC daily, or IM either monthly or every 3 months; mechanism of action (suppresses androgen production by testes; initially may get increase of testosterone, then decline; referred to as chemical castration; adrenal androgens not affected); adverse effects (hot flashes most common, impotence and loss of libido occur; if have vertebral metastases or preexisting obstruction of urinary tract, treatment may be intolerable)
b. Gosereline (Zoladex)—Like leuprolide; unique administration with pellet implanted by SC in upper abdominal wall
2. Androgen receptor blockers—Three are available; only for cancer of prostate; should be combined with orchiectomy or chemical castration
a. Flutamide (Eulexin)—Take with Gn-RH in patients with metastatic prostate cancer; it helps prevent cancer cells from undergoing increased stimulation in initial phase of Gn-RH therapy; orally administered; adverse effects include gynecomastia, N/V, and diarrhea; toxic hepatitis has occurred on rare basis; monitor liver function
b. Bicalutamide (Casodex)—Like flutamide; breast pain most common adverse effect; if combined with leuprolide get hot flashes
c. Nilutamide (Nilandron)—Like other two androgen receptor blockers; used only for advanced prostate cancer patients who have undergone orchiectomy; prolonged progression-free survival; not well tolerated with significant and frequent adverse effects
3. Estrogens—Diethylstilbestrol diphosphate (Stilphostrol); second-line drugs for treating prostate cancer; suppress production of androgens; get fluid retention, hypercalcemia, depression, thromboembolic disorders, and gynecomastia
4. Estramustine (an estrogen mustard)—Hybrid molecule of estradiol and nor-nitrogen mustard; palliative therapy of advanced prostate cancer
5. Androgens—Therapeutic use (palliative therapy in women with advanced or metastatic carcinoma of breast but is not first-line drug; 50%–60% get objective responses, and benefits last 12–14 months; adverse effects (virilization common due to high dosages; can get hypercalcemia)
6. Progestins—Two are used to treat cancer (medroxyprogesterone acetate and megestrol acetate); for advanced endometrial carcinoma and megestrol used for advanced breast cancer; about 30% get objective response and survival for about 2 years; tumors with positive progesterone respond better; adverse effects include fluid retention and non-fluid weight gain; hypercalcemia may occur if bone metastases prevent; not for first 4 months of pregnancy
IX. Biologic Response Modifiers: Immunostimulants—Alter host responses to cancer;
A. Interferon Alfa-2a and Interferon Alfa-2b—naturally occurring proteins with complex antiviral, anticancer, and immunomodulatory actions; used for solid tumors and hematologic malignancies
1. Description—Glycoproteins
2. Mechanism of action—Enhancement of host immune responses and direct antiproliferative effects on cancer cells
3. Antineoplastic uses—Hairy cell leukemia chronic myelogenous leukemia, malignant melanoma, and AIDS-related Kaposi’s sarcoma
4. Pharmacokinetics—By IM or SC; peaks in 4–8 hours
5. Adverse effects—Multiple effects with flu-like symptoms which usually decrease with continued therapy; long-term or high-dose therapy cause bone marrow depression
B. Aldesleukin (Interleukin-2)—Used for advanced renal carcinoma; must be given where intensive care facility available with cardiopulmonary or intensive care medicine specialist available; similar to human interleukin-2; given IV; almost all experience significant toxicity with 4% fatality; patients get capillary leak syndrome
C. Levamisole (Ergamisol)—Can help restore immune responses that are depressed; only for additional therapy following surgical resection of stage III colon cancer when used with fluorouracil; mild adverse effects
D. BCG Vaccine—Freeze dried preparation of attenuated Mycobacterium bovis is approved for primary and relapsed carcinoma in situ of bladder; for bladder cancer drug administered directly into bladder; risk of systemic infection including fatal septic shock; must be handled with care; urine must be disinfected with equal volume of 5% hypochlorite before flushing
X. Miscellaneous Anticancer Drugs
A. Bisphosphonates (i.e., Alendronate, Pamidronate)—Discussed in Chapter 70 to treat osteoporosis and Paget’s disease and for women with breast cancer because of helping prevent metastases and prolonging life
B. Trastuzumab (Herceptin)—For metastatic breast cancer patients who failed to respond to other drugs or in combination with paclitaxel as first-line therapy; adverse effects include cardiac damage seen as ventricular dysfunction and congestive heart failure and also see flu-like symptoms
C. Rituximab (Rituxan)—Low-grade B-cell non-Hodgkin’s lymphoma but can get hypersensitivity reactions
D. Thalidomide (Thalomid)—Causes severe birth defects; only for erythema nodosum leprosum (complicated form of leprosy) in U.S. as approval; however, research demonstrated benefit with multiple myeloma, leukemia, and various solid tumors (renal cell carcinoma, AIDs-related Kaposi’s sarcoma, brain cancers, breast, ovary, prostate, and colon cancers)—must comply with safeguards with drug because of teratogenesis
XI. Special Interest Topics—Angiogenesis Inhibitors: No Flow-No Grow
A. Angiogenesis stimulated by tumors releasing growth factors; current research regarding inhibiting factors; drugs are less toxic, tumor resistance does not develop and can prolong life without causing tumor regression
XII. Key Points
CHAPTER 102: HERBAL SUPPLEMENTS
CHAPTER 102
OBJECTIVES
At the conclusion of this chapter, the student will be able to:
1. Define herbal medicine.
2. Identify the adverse drug interactions between herbal medicines and prescribed medications.
3. Describe the most common oral formulations of herbal preparations.
4. Discuss the medicinal usage of herbs.
5. Describe the Dietary Supplement Health and Education Act.
CHAPTER 102 OUTLINE
I. Introduction—Herbal medicine is defined as use of plant-derived products to promote health and relieve symptoms of disease; some are helpful; some are harmful and can be deadly; most common form of alternative medicine; more visits to alternative medicine practitioners than to primary care physicians in 1997; German Commission E provides more information on herbal products
II. Limited Regulation: The Dietary Supplement Health and Education Act
A. Core Provisions—Dietary Supplement Health and Education Act of 1994 exempts vitamins, minerals, and botanical products; if not sold as drug can be sold as dietary supplement; do not have to prove safety or effectiveness to FDA
B. Package Labeling—Must be labeled as dietary supplement and state no claims to diagnose, treat, cure, or prevent disease but can refer to benefiting specific areas of health (i.e., urinary health, cardiovascular health)
C. Adverse effects—Product is assumed safe until proven otherwise
D. Impurities, Adulterants, and Variability—labels might not identify what is in the product; no regulation of actual content
E. Comments—Untested by proper research procedures; JAMA article in 1998 commented on the need to test alternative treatments just as with other drugs
III. Adverse Interactions with Conventional Drugs
A. Concerns—Increased toxicity and decreased therapeutic effects; some interactions have been identified (e.g., ginkgo biloba, feverfew, and garlic suppress platelet aggregation, so interacts with antiplatelets and anticoagulants)
IV. Oral Formulations
A. Teas, Infusions, and Decoctions—Aqueous extracts, from steeping plant
B. Tinctures and Fluid Extracts—Plant in water and alcohol and processing
C. Solid Extracts—Removed residual fluid; most concentrated
D. Glycerites—Glycerin instead of alcohol, less potent, shorter shelf-life
V. Standardization of Herbal Products
A. Herbal crops—Can vary from year to year, so potency will also vary; need for standardization to decrease variability by preparing three-step process in which the manufacturer prepares extract of plant parts, analyzes the extract for one or two known ingredients, and dilutes or concentrates extract so that end product has predetermined amount; benefit of standardization (permits accurate dosing and allows extrapolation of data in clinical trails); problem with standardization (may destroy active ingredient; unidentified other products still there)
VI. Dosage—Dosing is imprecise; must be standardized to be relatively similar
VII. Commonly Used Medicinal Herbs
A. Aloe—Aloe vera, Aloe barbadensis; for topical therapy primarily; actions (anti-inflammatory and
analgesic effect; promotes healing of burns, moisturizes skin, and has mild
antimicrobial action); effectiveness (fresh
aloe gel for minor burns and abrasions; laxative effectiveness well
established); adverse effects (on
skin devoid of adverse effects except for mild hypersensitivity; oral use can
cause severe diarrhea); comments (enzyme
activity may not survive processing; best source for skin is fresh aloe leaves)
B. Black Cohosh—Cimicifuga racemosa; for acute symptoms of menopause and PMS; actions (suppresses release of
luteinizing hormone, which correlates with relief of menopausal symptoms); effectiveness (evaluated extensively
in Germany, where it has been documented to relieve menopausal symptoms; no
more than 6 months use); adverse effects
(stomach upset on rare occasions; not for use during pregnancy); interactions with conventional drugs (may
potentiate hypotensive effects of antihypertensive drugs and hypoglycemic
effects); comments (used in U.S. by
native Americans; be sure not to confuse with blue cohosh)
C. Echinacea—Echinacea
angustifolia, E. purpurea, E. pallida; used orally (to stimulate
immune function, suppress inflammation, and treat viral infections) or
topically (to treat wounds, burns, eczema, psoriasis, and herpes simplex
infections); actions (several active
ingredients; actions from combination of actions); effectiveness (anecdotal reports support concept on stimulation of
immune system function); adverse effects
(few adverse effects including fever, nausea, and vomiting; rarely,
allergic reaction); interactions with
conventional drugs (compromise therapy for TB, cancer, and HIV infections
and may oppose effects of immunosuppressant drugs)
D. Feverfew—Tanacetum
parthenium; for prophylaxis and treatment of migraine, relieves fever,
stimulates menstruation, reduces stomach upset and suppresses inflammation
along with topical application for infection and toothache; actions (parthenolide blocks formation
of gene transcription for activation and proliferation of certain inflammatory
cells); effectiveness (clinical
studies and history indicate positive for migraines as preventative, not as
effective for treatment); adverse
effects (well tolerated; may get GI effects; chewing leaves can cause
ulceration; allergic reaction if allergic to ragweed); comments (research underway to evaluate nuclear transcription
factor and relate to inflammatory process)
E. Garlic—Allium
sativum; for CV effects; actions (from
sulfides in garlic oil; interferes with cholesterol synthesis in liver;
antiplatelet from inhibiting thromboxane synthesis; decrease in BP may be from
increased activity of nitric oxide synthetase, which ultimately vasodilates); effectiveness (favorable effects on BP
and plasma lipids; cooked garlic not effective; few products contain adequate
allicin); adverse effects (unpleasant
taste, bad breath, heartburn, flatulence, and other GI); interactions with conventional drugs (antiplatelet effects and
drugs related to bleeding); comments
(may benefit patients with mild hypertension and hypercholesterolemia)
F. Ginger Root—Zingiber officinale; to suppress nausea and vomiting, improves
appetite, anti-inflammatory, and analgesic properties; actions (mechanism unclear, possible blockade of serotonin); effectiveness (evidence supports
prevention and treatment of motion sickness, morning sickness, and
postoperative nausea; for patients with rheumatoid arthritis, helps reduce pain
and improve joint mobility and decrease swelling/morning stiffness); adverse effects (well tolerated;
caution with pregnancy); interactions
with conventional drugs (antiplatelet or anticoagulant drugs); comments (best source is supermarket;
chew slices or make tea)
G. Ginkgo—Ginkgo
biloba; to improve memory, sharpen concentration, and promote clear
thinking; to counter erectile dysfunction from antidepressants; prepared by
acetone extraction of leaves yielding flavenoids and terpenoids; actions (multiple biologic effects from
improved blood flow); effectiveness (studies
support benefits of cognitive improvement and other processes because of
decreased blood flow); adverse effects
(well tolerated; some GI effects; suppresses coagulation ); comments (dried leaves are shipped to
Europe for processing)
H. Goldenseal—Hydrastis
canadensis; treat bacterial, fungal, and protozoal infections and
gallbladder inflammation); actions
(several active ingredients that have several effects; effects incompletely
understood); effectiveness (bacteriostatic
or bactericidal to many pathogens); adverse
effects (relatively nontoxic at therapeutic doses; can stimulate uterus, so
not for pregnancy); comments
(standardized preferred; often sold with echinacea)
I. Kava—Piper
methysticum; relieve anxiety, promote sleep, and relax muscles; natural
alternative to benzodiazepines; actions
(alpha-pyrones or kava-lactones with unknown mechanism); effectiveness (studies in Europe show kava relaxes skeletal muscles
and relieves tension and anxiety; cognitive function improves; taken for weeks
before anxiolytic effects develop); adverse
effects (can impair vision and cause muscle incoordination and scaly skin);
interactions (intensifies other CNS
depressants) comments (has
mind-altering properties)
J. Ma Huang—Ephedra
sinica; sympathomimetic and CNS stimulant actions (like ephedrine to reduce appetite, increase energy, and
suppress symptoms of allergies, influenza, and colds; activates adrenergic
receptors); effectiveness (relieves
symptoms of allergies, colds, and flu and bronchospasm for asthma patients;
does suppress appetite); adverse effects
(ephedra potentially dangerous because of CV stimulation; limit amount and
avoid use in those with CV, thyroid, and diabetic conditions); interactions (potentiates CNS
stimulants, with MAOIs can cause hypertensive crisis; counters antihypertensive
agents); comments (controversy over
the regulation of it; should have informative labels)
K. St. John’s Wort—Hypericum perforatum; used to relieve mild to moderate depression;
see Chapter 31
L. Saw Palmetto—Serenoa repens, Sabal
serrulata; relieves urinary symptoms associated with BPH; actions (unknown; does have
antiandrogenic activity); effectiveness (studies
in U.S. and Europe support relief of urinary problems associated with BPH); adverse effects (well tolerated; can be
GI effects or headaches; causes false negative for PSA levels; pregnant women
should not use); interactions (do
not combine with finasteride); comments
(urologists may recommend as first-line therapy for BPH)
M. Valerian—Valeriana
officinalis; sedative preparation to promote sleep; actions (may increase availability of GABA like benzodiazepines); effectiveness (objective evidence
limited but used for years in other countries; helps with falling asleep but
not for staying asleep); adverse effects
(well tolerated but may have daytime drowsiness, dizziness, depression,
dyspepsia, and pruritus); interactions
(does not potential CNS depressant effects of alcohol); comments (was used as tranquilizer through WWII until more
effective sedatives found)
VIII. Key Points