Deja Review Pharmacology, 2nd Edition

CHAPTER 11. Miscellaneous Topics in Pharmacology

 

IMMUNOSUPPRESSIVE AGENTS

 

What are the main targets of immunosuppressive agents?

Inhibition of gene expression; inhibition of lymphocyte signaling and activation; depletion of proliferating lymphocytes; inhibition of cytokine action; depletion of specific immune cells; blockade of costimulation; blockade of cell adhesion and migration; inhibition of complement activation

Which agents are signaling inhibitors of B-/T-cell proliferation?

Cyclosporine A, tacrolimus, and sirolimus

What is the mechanism of action of cyclosporine A?

Complexes with cyclophilin to inhibit calcineurin, thereby decreasing interleukin (IL)-2, which is the main inducer for activation of T lymphocytes

What are the main therapeutic indications of cyclosporine A?

Prevention of organ rejection in heart, kidney, and liver transplants

What are the adverse effects of cyclosporine A?

Nephrotoxicity; hepatotoxicity; cytomegalovirus (CMV) infections; hypertension; hyperkalemia; hirsutism; glucose intolerance; gingival hyperplasia; tremor; upper respiratory infections; anemia; leukopenia; thrombocytopenia

Name three medications that can cause gingival hyperplasia:

 

  1. Cyclosporine
  2. Phenytoin
  3. Nifedipine

 

What major hepatic enzyme metabolizes cyclosporine A?

CYP 3A4

Cyclosporine A becomes more effective as an immunosuppressant when combined with what class of drugs?

Glucocorticoids

FK506 is also known as?

Tacrolimus

What are the main therapeutic indications of tacrolimus?

Prevention of organ rejection in liver and kidney transplants

What is the mechanism of action of tacrolimus?

It inhibits calcineurin by binding to FK binding protein (FKBP) rather than cyclophilin, cyclosporin’s target protein. It inhibits the signaling pathway coupling cell receptor activation of IL-2 gene transcription (IL-2 synthesis).

What is the mechanism of action of sirolimus?

It blocks IL-2 receptor signaling required for cell activation and proliferation. It forms a complex with the immunophilin FKBP, it does not affect calcineurin activity, but inhibits the kinase mTOR, which is necessary for cell growth and proliferation.

What are the adverse effects of tacrolimus?

Nephrotoxicity; neurotoxicity; hypertension; headache; tremor; rash; hyperglycemia; hyperkalemia; anemia; leukocytosis; thrombocytopenia

Which murine monoclonal antibody interferes with T-lymphocyte function by binding to CD3 glycoprotein?

Muromonab-CD3 (OKT3)

Give examples of cytotoxic agents used in immunosuppressive therapy:

Azathioprine, mycophenolate mofetil, methotrexate, leflunomide, hydroxychloroquine, cyclophosphamide

Which cytotoxic agents used in immunosuppressive therapy are pro-drugs?

Azathioprine, mycophenolate mofetil, leflunomide

Which cytotoxic immunosuppressant is an alkylating agent?

Cyclophosphamide

Which immunosuppressant is a derivative of 6-mercaptopurine, antagonizes purine metabolism, and is cytotoxic to lymphocytes?

Azathioprine

Which immunosuppressant inhibits inosine monophosphate dehydrogenase, thereby inhibiting de novo guanosine nucleotide synthesis?

Mycophenolate mofetil

Which immunosuppressive agents are cytokine inhibitors?

Etanercept, infliximab, adalimumab, certolizumab, thalidomide, anakinra

Which cytokine inhibitor is not a tumor necrosis alpha (TNF-α) inhibitor?

Anakinra (It is an interleukin-1 [IL-1] receptor antagonist.)

Give two examples of immunosuppressive agents that inhibit costimulation:

 

  1. Abatacept
  2. Belatacept

 

Give two examples of immunosuppressive agents that block cell adhesion:

 

  1. Natalizumab
  2. Efalizumab

 

Give an example of an immunosuppressive agent that blocks complement action:

Eculizumab

AGENTS FOR OBESITY

 

What anorexiant works by increasing dopamine and norepinephrine levels in the brain?

Phentermine

What anorexiant works by blocking reuptake of serotonin, norepinephrine, and dopamine into presynaptic nerve terminals in the brain?

Sibutramine

What are the adverse effects of phentermine and sibutramine?

Tachycardia; hypertension; headache; insomnia; dry mouth; constipation

What drugs should be avoided in patients taking sibutramine?

Monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); dextromethorphan

What popular name was given to the combination regimen fenfluramine and phentermine and why was it eventually pulled off of the market?

Fen-phen (combination of fenfluramine and phentermine); pulmonary hypertension and heart valve abnormalities. Fenfluramine was removed from the markets in 1997 in the United States because of these side effects.

What antiobesity agent inhibits gastric and pancreatic lipase, thereby inhibiting breakdown of dietary fat?

Orlistat

What are the adverse effects of orlistat?

Oily spotting; abdominal discomfort; flatus with discharge; fatty stools; fecal urgency; increased defecation

What vitamin supplementation is recommended in patients taking orlistat?

Fat-soluble vitamins

What are the fat-soluble vitamins?

A; D; E; K

AGENTS FOR OSTEOPOROSIS

 

Give examples of medications that belong to the bisphosphonate drug class:

Alendronate; risedronate; etidronate; pamidronate; ibandronate

What is the mechanism of action of the bisphosphonates?

Inhibition of osteoclast-mediated bone resorption

Which bisphosphonate can only be administered intravenously?

Pamidronate

What must patients be counseled on regarding oral bisphosphonate therapy?

Take medication with a full glass of water and stay in a sitting or standing position for 30 minutes following administration to prevent esophageal irritation.

Intravenous pamidronate can also be used to treat what conditions?

Hypercalcemia of malignancy; osteolytic bone lesions associated with multiple myeloma or metastatic breast cancer

What selective estrogen receptor modulator can increase bone density in women without increasing the risk for endometrial cancer?

Raloxifene

How is calcitonin administered?

Intranasally

What is the source of medically used intranasal calcitonin?

Salmon

How much calcium should a postmenopausal woman take daily?

Calcium should be taken with what other supplement to enhance its absorption?

Vitamin D

What recombinant N-terminal 34-amino-acid sequence of parathyroid hormone stimulates osteoblast function, increases gastrointestinal (GI) calcium absorption, and increases renal tubular reabsorption of calcium?

Teriparatide

AGENTS FOR ERECTILE DYSFUNCTION

 

What prostaglandin ET(PGE1) analog is injected into the corpus cavernosum and causes increased arterial inflow and decreased venous outflow to and from the penis, respectively?

Alprostadil

What is the mechanism of action of sildenafil?

Enhances the vasodilatory effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE-5) which allows for increased cyclic guanosine monophosphate (cGMP) levels (cGMP causes smooth muscle relaxation in the corpus cavernosum)

Name two other PDE-5 inhibitors used in the treatment of erectile dysfunction:

 

  1. Tadalafil
  2. Vardenafil
  3. Udenafil
  4. Avanafil

 

What are the adverse effects of sildenafil?

Headache; dizziness; color vision disturbances; hypotension

Sildenafil is contraindicated in patients taking what type of medications?

Nitrates (potentiates hypotension)

AGENTS FOR RHEUMATOID ARTHRITIS

 

For the following disease-modifying antirheumatic drugs (DMARDs), give the mechanism of action:

Glucocorticoids

Decrease production of inflammatory mediators; suppression of neutrophil migration

Etanercept

Recombinant tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1; binds TNF and inhibits its interaction with cell surface receptors

Infliximab

Chimeric monoclonal antibody that binds to human TNF-α, thereby interfering with its activity

Leflunomide

Inhibits dihydro-orotic acid dehydrogenase, thereby inhibiting pyrimidine synthesis

Anakinra

IL-1 receptor antagonist

Gold salts

Inhibit phagocytosis and lysosomal enzyme activity of macrophages

Methotrexate

Inhibits dihydrofolate reductase; increases adenosine levels (this is methotrexate’s anti-inflammatory mechanism of action)

Hydroxychloroquine

Interferes with lysosomal function; inhibits chemotaxis of neutrophils and eosinophils

Penicillamine

Depresses circulating rheumatoid factor (RF); depresses T-lymphocyte activity

What is RF?

IgM directed against IgG

What other disease is penicillamine used to treat?

Wilson disease

What are the adverse reactions for the following DMARDs?

Glucocorticoids

Acne; insomnia; edema; hypertension; osteoporosis; cataracts; glaucoma; psychosis; increased appetite; hirsutism; hyperglycemia; muscle wasting; pancreatitis; striae; redistribution of body fat to abdomen, back, and face

Etanercept

Hypersensitivity; headache; local injection site reactions; respiratory tract infection; positive antinuclear antibody (ANA); activation of latent tuberculosis

Infliximab

Headache; rash; nausea; diarrhea; urinary tract infection; infusion reactions; arthralgia; upper respiratory infection; activation of latent tuberculosis

Leflunomide

Pregnancy category X; hepatotoxicity; rash; alopecia

Anakinra

Local injection site reactions; headache; infection

Gold salts

Nephrotoxicity; dermatitis; alopecia; eosinophilia; leukopenia; thrombocytopenia; hematuria; nausea; vomiting

Methotrexate

Mucositis; nausea; vomiting; diarrhea; nephrotoxicity; leukopenia; thrombocytopenia; hepatotoxicity; pneumonitis; crystalluria

Hydroxychloroquine

Cardiomyopathy; alopecia; visual disturbances; anorexia; nausea; vomiting; diarrhea; aplastic anemia; agranulocytosis; hemolysis in G6PD deficiency; cinchonism; exacerbation of porphyria

Penicillamine

Vasculitis; alopecia; hypoglycemia; thyroiditis; eosinophilia; hemolytic anemia; thrombotic thrombocytopenic purpura (TTP); hepatotoxicity; proteinuria

AGENTS FOR GOUT

 

What two categories do gout patients fall into pathophysiologically?

 

  1. Overproducers
  2. Underexcretors

 

Which drug is a xanthine oxidase inhibitor?

Allopurinol

What biochemical process is the enzyme xanthine oxidase involved in?

Purine metabolism

Which two drugs require dosage reductions when given concomitantly with allopurinol (because they are metabolized by xanthine oxidase)?

 

  1. 6-Mercaptopurine
  2. Azathioprine (reduce to 25% of normal dose)

 

What is the most common side effect of allopurinol?

Skin rash

Name other potential side effects of allopurinol:

Nausea; vomiting; renal impairment; acute tubular necrosis; agranulocytosis; Stevens-Johnson syndrome

Name three uricosuric agents:

 

  1. Probenecid
  2. Sulfinpyrazone
  3. High-dose aspirin

 

Define uricosuric:

Enhancing renal excretion of uric acid

What is the mechanism of action of probenecid?

Inhibits proximal tubular resorption of uric acid

Probenecid inhibits the tubular secretion of what antibiotic and is sometimes given in combination to prolong its half-life?

Penicillin

How is acute gout treated?

Colchicine; nonsteroidal anti-inflammatory drugs (NSAIDs)

Why is allopurinol not used in the treatment of an acute gout attack?

May actually precipitate acute gouty arthritis and therefore perpetuate the acute gout attack (used for prevention and not treatment of gout attacks)

What is the mechanism of action of colchicine?

Increases depolymerization of microtubules; decreases leukocyte motility; decreases phagocytosis in joints and lactic acid production, thereby reducing deposition of urate crystals

What are the adverse effects of colchicine?

Nausea; vomiting; diarrhea; abdominal pain; agranulocytosis; aplastic anemia; bone marrow suppression; alopecia; myopathy; arrhythmia; hepatotoxicity

RETINOIDS

 

Retinoic acid shares a similar structure and function with what fat-soluble vitamin?

Vitamin A

13-cis-Retinoic acid is also known as what drug?

Isotretinoin (Accutane)

What is the major therapeutic indication of isotretinoin?

Acne

Isotretinoin belongs in what pregnancy risk factor category?

Pregnancy category X. This drug should not be used in pregnant patients under any circumstances. Fetal isotretinoin syndrome involves fetal craniofacial, cardiac, and CNS defects.

What is the mechanism of action of isotretinoin?

Decreases sebaceous gland size and reduces sebum production; regulates cell proliferation and differentiation; decreases hyperkeratinization; decreases androgen levels; decreases Propionibacterium acnes levels (bacterium associated with acne)

Hypervitaminosis A can damage what major organ?

Liver

All-trans-retinoic acid (ATRA) is also known as what drug?

Tretinoin

What is the major therapeutic indication of ATRA?

Induction of remission in patients with acute promyelocytic leukemia (APL)

What is the mechanism of action of tretinoin (when used for acne)?

Binds to nuclear receptors and inhibits clonal proliferation and granulocyte differentiation

HERBAL MEDICATIONS

 

Does the United States Food and Drug Administration (FDA) regulate herbal medications?

No

Are herbal medications considered “drugs” by FDA standards?

No, considered “nutritional supplements”

What herbal medication is used for migraine and fever?

Feverfew

What herbal medication is used for “jet lag”?

Melatonin

What herbal medication is used for depression?

St. John’s wort

What herbal medication is used for benign prostate hyperplasia (BPH)?

Saw palmetto

What herbal medication is used for anxiety?

Kava kava

What herbal medication is used for Alzheimer disease?

Gingko biloba

What herbal medication is used for hypercholesterolemia?

Garlic

What herbal medication is used for the common cold?

Echinacea

What herbal medication is used for hepatitis?

Milk thistle

What herbal medication is used to treat hot flushes in menopause?

Black cohosh

Is St. John’s wort a metabolic enzyme inducer or inhibitor?

Inducer

What herbal supplements should one use with caution when using warfarin concomitantly?

The G4 supplements: garlic, ginger, gingko, and ginseng. These substances may interact with warfarin, and some, especially gingko which has antiplatelet effects, may increase bleeding risk. Ginseng may decrease warfarin’s effects.

SUBSTANCE ABUSE AND TOLERANCE

 

What are the physiologic effects of heroin?

Euphoria; decreased motor function; respiratory depression; miosis

What are some of the signs/symptoms of heroin withdrawal?

Nausea; vomiting; muscle aches; yawning; lacrimation; rhinorrhea; diarrhea; sweating; fever; mydriasis; piloerection; insomnia

What is another name for piloerection?

Goose bumps

How can heroin overdose lead to death?

Acute respiratory depression

What drug is used for the treatment of heroin abuse?

Methadone (jo,-receptor agonist)

What drug is used to treat respiratory depression during an opioid overdose?

Naloxone

What drug is used to counteract the sympathetic effects of heroin withdrawal?

Clonidine

What is the mechanism of action of cocaine?

Blocks reuptake of dopamine, serotonin, and norepinephrine

What is the mechanism of action of amphetamines?

Ultimately, they increase the release of catecholamines from presynaptic nerve endings.

What are the physiologic effects of cocaine and amphetamines?

Euphoria; reduced inhibitions; reduced sleep; reduced appetite; tachycardia; sweating; increased alertness; pupillary dilation

What are the withdrawal signs/symptoms of cocaine and amphetamines?

Depression; increased sleep; increased drug cravings; bradycardia; dysphoria

What are the physiologic effects of marijuana?

Analgesia; increased appetite; impairment of short-term memory; antiemetic; altered perception of time and space; change in motor and postural control

What is the active psychotropic component of marijuana?

Delta-9-tetrahydrocannabinol (Δ9-THC)

What medication is a synthetic form of THC formulated in sesame oil and is used as an appetite stimulant in AIDS patients and as an antiemetic during chemotherapy in cancer patients?

Dronabinol

What are the signs/symptoms of marijuana withdrawal?

Restlessness; irritability; agitation; insomnia; nausea

Is overdose of marijuana fatal?

No

Give examples of hallucinogenic drugs:

Methylenedioxymethamphetamine (MDMA; has hallucinogenic properties, yet is usually classified as a stimulant); mescaline; psilocybin; lysergic acid diethylamide (LSD); phencyclidine (PCP)

MDMA is also known as?

Ecstasy

Ecstasy can be neurotoxic to which type of neurons?

Serotonergic neurons

What is a major side effect of LSD?

Flashbacks

Is overdose of LSD fatal?

No

Does LSD have reinforcing effects?

No

What drug class does PCP and ketamine belong to?

Dissociative anesthetics

Is overdose of PCP fatal?

Yes, it is potentially fatal.

Does PCP have reinforcing effects?

Yes

What types of ocular disturbances are seen in PCP intoxication?

Vertical and horizontal nystagmus

TOXICOLOGY

 

Name the antidote for each type of poisoning:

Atropine

Acetylcholinesterase inhibitors

Arsenic, gold

Dimercaprol

Lead, mercury

Dimercaprol; succimer; penicillamine

Acetylcholinesterase inhibitors

Atropine with pralidoxime

Acetaminophen

N-acetylcysteine

Benzodiazepines

Flumazenil

β-Blockers

Glucagon

Copper

Penicillamine

Carbon monoxide

Oxygen (hyperbaric)

Digoxin

Digoxin immune Fab

Heparin

Protamine

Iron

Deferoxamine; deferasirox

Theophylline

β-Blockers

Warfarin

Vitamin K; fresh frozen plasma (FFP)

Thrombolytics

Aminocaproic acid; tranexamic acid

Opioids

Naloxone

What are the signs and symptoms of arsenic poisoning?

“Rice water” stools; GI discomfort; seizures; pallor; skin pigmentation; alopecia; bone marrow suppression; stocking glove neuropathy

What are the signs and symptoms of iron poisoning?

Bloody diarrhea; shock; coma; dyspnea; necrotizing gastroenteritis; hematemesis

What are the signs and symptoms of lead poisoning?

Nausea; vomiting; diarrhea; tinnitus; encephalopathy; anemia; neuropathy; nephropathy; infertility; hepatitis

What are the signs and symptoms of mercury poisoning?

Ataxia; auditory loss; visual loss; chest pain; pneumonitis; nausea; vomiting; renal failure; shock

What are the signs and symptoms of tricyclic antidepressant (TCA) poisoning?

Hyperthermia; coma; convulsions; cardiotoxicity; mydriasis; constipation; prolonged QT interval

What are the signs and symptoms of SSRI poisoning (must be when used concomitantly with other serotonergic agents such as MAOIs or TCAs)?

Tachycardia; hypertension; seizures; hyperthermia; agitation; muscle rigidity; hallucinations

CLINICAL VIGNETTES

 

A 66-year-old man with a past medical history of stable angina well controlled with oral nitroglycerin comes in for a regular check up to his primary care physician’s office. After you politely ask about his wife he replies, “Well, she’s not too happy with me lately.” After some gentle prodding you elicit a history of erectile dysfunction. He asks you about a medication he saw on TV, Viagra (sildenafil). You inform him that because he takes nitrates he cannot also take this medication due to potentially fatal interactions. What alternative medication might you suggest for this patient?

The phosphodiesterase inhibiting properties of sildenafil cause vasodilation, allowing increased blood flow to maintain an erection. However, when used concomitantly with another vasodilating drug such as nitroglycerin, blood pressures may fall to levels insufficient to perfuse vital organs, especially in someone with preexisting heart disease. Therefore, an alternative agent must be used to treat this man’s erectile dysfunction. Alprostadil is a less popular medication than sildenafil since it must be injected directly into the corpus cavernosa, but it does not have the systemic effects seen with sildenafil, making it a viable alternative to treat this patient’s condition.

A 74-year-old woman undergoes a bone scan to evaluate her bone density. Her T-score comes back at –2.7. What is the mechanism of the class of medications that are first-line therapy for this woman’s medical condition?

This patient has osteoporosis, defined as a T-score of less than -2.5. Studies have found the most benefit in early preventative treatment in women with the highest risk for fracture, that is, those with lower (more negative) T-scores. Bisphosphonates are generally first-line therapy for osteoporosis. Bisphosphonates work by binding to hydroxyapatite crystal in bone and inhibiting osteoclast-mediated bone resorption.

A 53-year-old man presents to your office with a warm, swollen right metacarpal phalangeal joint. He notes that this pain began suddenly, and is exquisitely painful. What are your options for immediate treatment for this man’s pain, as well as long-term management for his condition?

This is a classic presentation of gout, seen most commonly in older men. It is caused by an accumulation of uric acid crystals in a joint or tendon. Acute management involves NSAIDs, colchicine, or steroids (local or systemic). Long-term management includes life-style modifications to decrease purine breakdown such as decreased intake of red meat and alcohol. Allopurinol, a xanthine oxidase inhibitor, may be helpful as well.