Pharmacology and Drug Reactions




(1)
University of Florida, College of Medicine, Gainesville, FL, USA

(2)
Private Practice:, Orlando, FL, USA

 




7.1 Anti-Infective Medications



A. Antibiotics


Side effects (SE) listed are either most common or serious


Penicillins (PCNs)





  • Binds and inactivates bacterial enzymes (PCN-binding proteins) involved in peptidoglycan synthesis → inhibits bacterial cell wall synthesis


  • Contains β-lactam ring; drug excretion via kidneys; specific types of PCNs:



    • PCNs with β-lactamase inhibitor: amoxicillin and clavulanate (Augmentin)


    • Penicillinase-resistant PCNs: dicloxacillin, methicillin, oxacillin


  • Spectrum: gram-positive (GP) bacteria and spirochetes


  • Treats: erysipeloid, anthrax, strep/staph infections, cat/dog/human bites


  • SE: morbilliform eruption, angiodema, anaphylaxis, hemolytic anemia, interstitial nephritis, acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN)


  • Contraindication (CI): hypersensitivity to any β-lactam antibiotic; pregnancy category B


Cephalosporins





  • Contains β-lactam ring with same mechanism as PCNs; 10% cross-reactivity w/ PCNs


  • Spectrum of bacterial coverage based upon generation of cephalosporin:



    • 1st generation: GP > gram-negative (GN); 2nd generation: GP = GN; 3rd generation: GP < GN; 4th generation: GP, GN (little activity against β-lactamase)


  • Adverse effects: AGEP, morbilliform eruption (serum sickness associated w/ cefaclor)


  • CI: same as with PCNs; pregnancy category B

Minocycline treatment of choice for CARP (confluent and reticulated papillomatosis of Gougerot-Carteaud)


Tetracyclines (TCNs)





  • Binds bacterial ribosomal unit (30s) → blocks bacterial protein synthesis


  • Spectrum: GP/GN bacteria, Chlamydia, Mycoplasma, rickettsia, spirochetes (syphilis, Lyme disease), certain mycobacteria (leprosy); different types of TCNs:



    • Doxycycline: excreted in GI tract, so can use in renal failure patients; photosensitivity


    • Tetracycline: most common to cause fixed drug eruption and may cause onycholysis, contraindicated in patients < 9 y/o due to brown discoloration of gingival third of teeth; photosensitivity


    • Minocycline: side effect includes blue-black pigmentation of skin/teeth (green-gray discoloration of mid-portion of teeth), drug-induced LE, autoimmune hepatitis


    • Demeclocycline: most phototoxic (then doxycycline)


  • ↓ Absorption with Fe/Ca2+; pregnancy category D


Macrolides





  • Binds bacterial ribosomal unit (50s) → blocks protein synthesis; alternative for PCN-allergic patients; spectrum: GP/GN bacteria, spirochetes, atypical mycobacteria


  • Adverse effects: cholestatic hepatitis (estolate form of erythromycin), nausea, diarrhea


  • Inhibits cytochrome p450: ↑ levels of p450 substrates like cyclosporine, anticonvulsants, warfarin, digoxin, benzodiazepines, HMG-CoA reductase inhibitors, theophylline (latter combination can cause cardiac arrhythmias); erythromycin + lovastatin → rhabdomyolysis; clarithromycin + CCBs → bradycardia, hypotension


  • Pregnancy category C (clarithromycin), category B (erythromycin, azithromycin)


Fluoroquinolones (FQs)





  • Inhibits bacterial DNA gyrase; spectrum: GN bacteria, strep/staph, certain mycobacteria


  • Adverse effects: tendon rupture, cartilage damage in joints, ↑ LFTs, nephrotoxicity


  • Contraindication: pregnancy and children (due to deposition of drug in cartilage)


  • ↓ Absorption with antacids, iron, sucralfate; inhibits CYP1A2 so ↑ levels of following drugs taken concomitantly: warfarin, aminophylline, theophylline; may also ↑ levels of procainamide; if taken with cyclosporine may increase renal toxicity


  • Pregnancy category C


Clindamycin





  • Binds bacterial ribosomal unit (50s) → blocks protein synthesis


  • Spectrum: GP and anaerobic bacteria


  • SE: pseudomembranous colitis (oral form); pregnancy category B

Only drug bactericidal to M. leprae


Rifampin (Rifampicin)





  • Inhibits RNA synthesis by inhibiting DNA-dependent RNA polymerase


  • Spectrum: mycobacteria (tuberculosis and leprosy)


  • SE: orange-red discoloration of urine/tears, ↓ OCP efficacy; pregnancy category C


Aminoglycosides





  • Binds bacterial ribosomal unit (30s) → blocks protein synthesis; used mainly in topical form


  • Spectrum: aerobic GN bacteria; SE (oral): ototoxicity, nephrotoxicity; pregnancy category D


Sulfonamides





  • Sulfamethoxazole and sulfasalazine; interferes with bacterial folic acid synthesis (needed for nucleic acid synthesis) by inhibiting dihydropteroate synthetase


  • Spectrum: GP/GN bacteria, Chlamydia, Nocardia


  • SE: hemolytic anemia (especially if G6PD deficient), nephrotoxicity, hepatotoxicity, TEN, Stevens-Johnson syndrome (SJS), AGEP, photosensitivity


  • Contraindication: hypersensitivity to medication, pregnancy (3rd trimester)


  • Pregnancy category C (D in third trimester)


Dapsone





  • Antibacterial and anti-inflammatory (mainly toward neutrophils by inhibition of myeloperoxidase); sulfone family (related to sulfonamides); spectrum: mycobacteria


  • Treats: leprosy, dermatitis herpetiformis, autoimmune blistering diseases, erythema elevatum diutinum, pyoderma gangrenosum


  • SE: hemolytic anemia (esp if G6PD deficient), cholestatic jaundice, methemoglobinemia, agranulocytosis (2-12 weeks after continuous treatment), motor peripheral neuropathy, acute psychosis, dapsone hypersensitivity syndrome, photosensitivity


  • Pregnancy category C


Vancomycin





  • Inhibits bacterial cell wall synthesis; only given intravenously; spectrum: GP bacteria


  • SE: red man syndrome, anaphylaxis, TEN, ototoxicity, phlebitis at IV site


  • Pregnancy category B


Metronidazole (Flagyl)





  • Forms toxic metabolites in bacteria, which inhibit nucleic acid synthesis


  • Spectrum includes anaerobes and protozoaSE: hypersensitivity, glossitis, disulfiram-like reaction (with alcohol) pregnancy category B


  • Pregnancy category C


Clofazimine (Lamprene)





  • Unclear mechanism; used for leprosy, erythema nodosum leprosum, DLE; category C


Linezolid





  • Inhibits protein synthesis but unique in that blocks initiation of protein production in bacteria


  • Reserve antibiotic used for serious infections caused by gram positive bacteria that are resistant to other antibiotics


  • SE (long term use): bone marrow suppression and thrombocytopenia


  • Pregnancy category C


B. Antifungals





Table 7-1:
Oral Antifungal Drugs






















































Name

Mechanism of Action

Characteristics

TRIAZOLES

Itraconazole (Sporanox)

Blocks ergosterol synthesis by inhibiting 14α-demethylase

Fungistatic, lipophilic, needs acidic milieu for absorption

SE: ↑ LFTs, ↓ WBC, ↑ TG, nephrotoxicity, CHF worsening

Tx: dimorphic fungi, aspergillosis, candidiasis, superficial dermatophytes, onychomycosis, sporotrichosis

Voriconazole

Inhibits cyt p450 (↑ levels of digoxin, cyclosporine, etc)

Category C

SE: visual disturbances

Fluconazole

Inhibits cyt p450 (↑ levels of digoxin, cyclosporine, etc)

Category C

Fungistatic, crosses blood-brain barrier

Tx: candidiasis, pityriasis versicolor (PV), cryptococcosis, histoplasmosis, superficial dermatophytes, coccidioidomycosis

IMIDAZOLES

Ketoconazole

Inhibits 14α-demethylase

Category C

Fungistatic, lipophilic, needs acidic milieu for absorption,

↑ absorption with food, inhibits cytochrome p450

SE: fulminant hepatitis (rare), ↑ LFTs (15%), gynecomastia

Tx: dermatophytes, candidiasis, dimorphic fungi, PV

ALLYLAMINES

Terbinafine (Lamisil)

Inhibits squalene epoxidase (1st step of ergosterol synthesis)

Category B

Fungicidal, biotransformed in liver, does NOT inhibit cyt p450

SE: nausea, metallic taste, liver damage, drug-induced LE

Tx: onychomycosis, tinea corporis, tinea pedis

POLYENES

Amphotericin B

Binds ergosterol and forms membrane pores

Category B

SE: acute reaction after infusion (fever, chills, nausea, tachypnea), nephrotoxicity, agranulocytosis, seizures, arrhythmias

OTHERS

Caspofungin

Inhibits synthesis of glucan (fungal cell wall)

Category C

IV administration

Tx: candidiasis and aspergillosis

Griseofulvin

Disrupts microtubule function (metaphase arrest)

Category C

Fungistatic, ↑ absorption w/ fatty meal, induces cytochrome p450 (may ↓ warfarin level), resistance seen in T. rubrum

SE: headache, paresthesias, photosensitivity, drug-induced LE, worsens acute intermittent porphyria

Tx: dermatophytes (NOT yeast or bacteria)


C. Antivirals (Table 7.2)





Table 7-2:
Oral Antiviral Drugs






















































Name

Mechanism of action

Spectrum, category

Miscellaneous

Acyclovir

Phosphorylated by viral thymidine kinase to acyclovir monophosphate, which blocks viral DNA polymerase → stops viral DNA synthesis

Herpes simplex virus (HSV), varicella-zoster virus (VZV)

Pregnancy category B

SE: IV infusion associated with reversible obstructive nephropathy, rarely may see severe CNS changes (ie. seizures)

Valacyclovir

Prodrug of acyclovir, same mechanism of action (viral thymidine kinase-dependent activity)

HSV, VZV, cytomegalovirus (CMV)

Category B

Better bioavailability than acyclovir

SE: TTP/HUS* seen in advanced HIV disease and transplant patients taking high doses

Penciclovir

Phosphorylated by viral thymidine kinase (similar mechanism to acyclovir)

HSV, VZV

Low bioavailability so typically used in topical form

Famciclovir

Prodrug of penciclovir with same mechanism as above

HSV, VZV

Category B

Better bioavailability than penciclovir

Gancyclovir

Phosphorylated by viral thymidine kinase; same mechanism as above

CMV (retinitis and CMV prophylaxis in transplant pts)

Category C

Better activity against CMV than acyclovir; ↓ oral bioavailability

SE: neutropenia, bone marrow suppression, mucositis, thrombocytopenia, seizures hepatic dysfunction

Foscarnet

Noncompetitive inhibition of viral DNA polymerases;

analogue of pyrophosphate

Does not require phosphorylation so active against acyclovir-resistant viruses

CMV (retinitis), resistant HSV, resistant VZV

Category C

Only IV form; active against infections resistant to acyclovir, famciclovir, ganciclovir

SE: penile ulcerations or erosions, nephrotoxicity

Cidofovir

Nucleoside analogue, inhibits viral DNA polymerase, independent of thymidine kinase activation

CMV

Category C

IV only; active against infections resistant to ganciclovir/foscarnet

SE: renal proteinuria, renal toxicity, ↑ creatinine

Amantadine, Rimantadine

Inhibit uncoating of viral DNA within infected host cells (prevents replication)

Influenza A/C, rubella

Category C

SE: anticholinergic symptoms, ataxia and photosensitivity

*TTP: thrombotic thrombocytopenic purpura*HUS: hemolytic uremic syndrome




Table 7-3:
Antiretroviral Drugs




































Name

Mechanism of Action

Characteristics

Nucleoside/nucleotide reverse transcriptase inhibitors

Zidovudine (AZT)

Thymidine analog, inhibits HIV reverse transcriptase (RT)

SE: melanonychia, mucocutaneous pigmentation, bone marrow suppression, lipodystrophy

Pregnancy category C

Didanosine (ddI)

Pyrimidine analog, similar to AZT

SE: pancreatitis, optic neuritis, peripheral neuropathy, lactic acidosis; category B

Abacavir (ABC)

Nucleoside RT inhibitor

SE: hypersensitivity reaction (can be fatal upon rechallenge)

Category C

Tenofovir

Nucleotide analogue, inhibits RT

Peripheral wasting, cushingoid appearance

Category B

Protease inhibitors

Indinavir, Ritonavir, Lopinavir

Block HIV-1 protease enzymes

SE: lipodystrophy (buffalo hump), gynecomastia, periungual pyogenic granulomas, paronychia, hepatotoxicity


D. Anti-Parasitic Drugs





Table 7-4:
Anti-Parasite Drugs
























































Name

Mechanism of Action

Comment

Pyrethrin

Natural extract of chrysanthemum; neurotoxic to lice (not ovicidal)

Contraindicated (CI) if allergy to chrysanthemums

Permethrin

Synthetic pyrethrin; disables nerve cell Na + transport channels in parasites → resulting in paralysis

Pediculicidal and ovicidal

2 strengths: 1% (OTC), 5% (Rx)

CI: allergy to chrysanthemums

Lindane

Chlorinated hydrocarbon; blocks neural transmission by interfering with GABA→ respiratory/muscular paralysis in parasites

Used for scabies, pubic lice, head lice, and body lice

SE: ICD, CNS symptoms (ie. seizures)

Malathion

Organophosphate cholinesterase inhibitor

Flammable; used in scabies, head lice

Ivermectin

Blocks glutamate-gated chloride channels → paralysis of parasite

Used for strongyloidiasis, onchocerciasis, Norwegian scabies

Crotamiton

Scabicide; unknown mechanism

SE: contact dermatitis

Precipitated sulfur (6%)

Unclear mechanism of action

Scabies in pregnant women and infants < 2 years of age

Thiabendazole, Albendazole

Inhibits fumarate reductase (helminth-specific enzyme)

Used in cutaneous larva migransSE: dizziness, drowsiness, jaundice

Na + stibogluconate,

meglumine antimoniate

Pentavalent antimonial; unclear mechanism

Treatment for leishmaniasis

SE: pancreatitis, hepatitis, renal failure, prolong QT interval

Pentamidine

Inhibits protozoal DNA/RNA/phospholipid/protein synthesis

Used for trypanosomiasis and leishmaniasis

Diethylcarbamazine (DEC)

Piperazine derivative, unknown mechanism

Mazzotti reaction pt with onchocerciasis treated with DEC → fever, hypotension, tachycardia

Used for filariasis, onchocerciasis


7.2 Immunosuppressant Drugs



A. Topical Immunosuppressants



Topical Glucocorticoids





  • Topical form: inhibits epidermal mitosis and DNA synthesis, ↓ collagen cross-linking


  • Vasoconstriction directly proportional to anti-inflammatory potency of agent


  • SE: atrophy, striae, acneiform eruption, hypertrichosis, hypopigmentation


  • Tachyphylaxis: efficacy of topical lost over time, and structurally different steroid required


  • Pregnancy category C


Topical Calcineurin Inhibitors





  • Includes pimecrolimus (Elidel®) and tacrolimus (Protopic®)


  • Binds FK506-binding protein, which then inhibits calcineurin (phosphatase) and subsequently blocks T cell activation; calcineurin typically activated by calcium and calmodulin (bound together), which subsequently causes dephosphorylation of nuclear factor of activated T cells (NFAT) and T cell activation


B. Oral Immunosuppressants



Oral Glucocorticoids





  • Anti-inflammatory, anti-mitotic, immunosuppressive and vasoconstrictive properties; forms complex with intracellular receptors and modulates transcription of certain genes


  • Effects:



    • ↓ Circulating lymphocytes/eosinophils/monocytes, ↓ macrophage response to lymphokines, ↓ Ab production, ↓ synthesis of proinflammatory molecules, ↓ fibroblast production of collagen


    • ↑ Neutrophils, ↑ blood glucose (stimulates gluconeogenesis), ↑ protein catabolism, ↑ plasma fatty acids/ketone body formation, ↑ acid/pepsin secretion in stomach


  • Side effects



    • Cutaneous: atrophy, telangiectasias, striae, poor wound healing


    • Musculoskeletal: osteoporosis (decrease intestinal calcium absorption, inhibit osteoblasts, increase bone resorption by osteoclasts and increase calcium excretion by kidneys)


    • Other: ↑ appetite, peptic ulcers, pancreatitis, Cushing’s syndrome, hyperglycemia, hypertriglyceridemia, sodium retention, cataracts, glaucoma, ↑ risk of infection, hypertension, hirsutism, HPA axis suppression, failure to thrive, aseptic necrosis of femoral head (MRI best modality to evaluate), muscle weakness, psychosis, pseudotumor cerebri


  • Short-acting glucocorticoids → cortisone and hydrocortisone



    • Greatest mineralocorticoid activity; lowest glucocorticoid activity


  • Intermediate and long-acting glucocorticoids → methylprednisolone, triamcinolone, dexamethasone, betamethasone



    • Virtually no mineralocorticoid activity; dexamethasone/betamethasone with highest glucocorticoid activity


  • Dosing



    • Single morning dose ↓ risk of HPA suppression


    • Divided daily dosing may ↑ anti-inflammatory efficacy but also ↑ systemic toxicity


    • Alternate day dosing reduces all complications except osteoporosis and cataracts


Azathioprine (Imuran) (Figure 7.1)





  • Purine analog which blocks purine synthesis (S phase specific); active metabolite is 6-mercaptopurine (6-MP) which is converted to either inactive or active metabolite (6-thioguanine) via one of three enzymatic pathways (TPMT, HPRT, XO):


A327767_2_En_7_Fig1_HTML.gif


Figure 7.1:
Metabolic pathway for azathioprine

TPMT: thiopurine methyltransferaseHPRT: hypoxanthine phosphoribosyltransferaseXO: xanthine oxidase





  • If XO or TPMT activity inhibited, HPRT becomes primary pathway causing excess toxic purine analogs, which can cause bone marrow suppression; can occur if azathioprine used with allopurinol (which blocks XO) or in patients with genetically low TPMT levels


  • Excreted by kidneysCheck TPMT levels before starting medication


  • SE: bone marrow suppression, hypersensitivity syndrome, teratogenicity, lymphoproliferative malignancies (latter only documented in rheumatoid arthritis)


  • Pregnancy category D


Methotrexate (Figure 7.2)





  • Antimetabolite and antifolate drug; inhibits dihydrofolate reductase (DHFR) involved in folic acid pathway, which is necessary for DNA/RNA synthesis (via purine and thymidylate synthesis); S phase specific

DHF: dihydrofolateTHF: tetrahydrofolate



A327767_2_En_7_Fig2_HTML.gif


Figure 7.2: 
Metabolic pathway inhibited by methotrexate





  • Renal excretion; liver biopsy at cumulative dose of 3.5 grams unless high risk; treat acute toxicity with leucovorin; caution in patients with ↑ alcohol intake, diabetes, or renal failure


  • SE: hepatotoxicity, pancytopenia, teratogenicity (egg and sperm), acute pneumonitis (idiosyncratic), pulmonary fibrosis, ± lymphoma


  • ↑ Pancytopenia risk with concomitant use of: NSAID, dapsone, TMP/SMX, or no folate supplementation; ↑ MTX levels with concomitant use of TCN, phenytoin, phenothiazine, barbiturate, NSAID, salicylate, sulfonamide


  • Pregnancy category C


Mycophenolate Mofetil (Cellcept)





  • Inhibits de novo purine synthesis by inhibiting inosine monophosphate dehydrogenase (IMPDH); T and B cells particularly affected; excreted by kidneys


  • After ingestion, active metabolite is mycophenolic acid; deactivated by liver but ‘reactivated’ by both epidermis and GI tract


  • SE: nausea, vomiting, reversible dose-related bone marrow toxicity, progressive multifocal leukoencephalopathy, pure red cell aplasia


  • Caution in peptic ulcer disease; of note, not hepatotoxic or nephrotoxic


  • Pregnancy category D


Cyclophosphamide (Cytoxan)





  • Nitrogen mustard derivative; cell cycle DNA cross-linkages at any point in cycle


  • SE: teratogenicity, ↑ lymphoma, ↑ leukemia, ↑ bladder cancer, ↑ SCC, bone marrow suppression, hemorrhagic cystitis (mesna decreases toxicity), azoospermia, pulmonary fibrosis, alopecia, hyperpigmentation of skin/nails


  • Treatment of choice for Wegener’s granulomatosis


  • Pregnancy category D


Apremilast (Otezla)





  • Selective immunosuppressant: phosphodiesterase-4 (PDE4) inhibitor which causes increased cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA) and other downstream effectors, resulting in inhibition of proinflammatory cytokine transcription, neutrophil degranulation, chemotaxis and adhesion to endothelial cells; used for both psoriasis and psoriatic arthritis


  • SE: nausea, diarrhea, depression, weight loss

Calcineurin: a phosphatase activated in presence of calmodulin and calcium by cyclophilin


Cyclosporine (CsA)





  • Inhibits T cell activity by binding to cyclophilin, which subsequently blocks cyclophilin’s ability to activate calcineurin; calcineurin regulates NFAT and IL-12, which results in overall inability to produce/release IL-12


  • Treatment for psoriasis, pyoderma gangrenosum, severe atopic dermatitis, autoimmune bullous disorders


  • SE: nephrotoxicity, reversible HTN, gingival hyperplasia, hyperlipidemia, ↑ K and ↓ Mg, ↑ uric acid, paresthesias, hypertrichosis, lymphoma


  • Metabolized by cytochrome p450 3A4: inhibitors of cytochrome cause ↑ CsA levels (ie. diltiazem, nicardipine, verapamil, ketoconazole, fluconazole, itraconazole, erythromycin); inducers of p450 enzymes result in ↓ CsA levels (rifampin, phenobarbital, phenytoin, carbamazepine)


  • Check BP regularly; if renal creatinine above 30% of baseline, dose should be reduced


  • ↑ Risk for renal toxicity: aminoglycosides, NSAIDs, amphotericin B and vancomycin


  • Pregnancy category C


Hydroxyurea



Aug 7, 2017 | Posted by in Dermatology | Comments Off on Pharmacology and Drug Reactions
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