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FITZ > Topical and Systemic treatments Chapter 190 > Flashcards

Topical and Systemic treatments Chapter 190 Flashcards

1
Q

Cytotoxic drug most active during the S phase

A

Antimetabolites

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2
Q

cytotoxic drugs independent of cell cycle

A

Alkylating agents

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3
Q

MoA of Methotrexate?

A

Competitive & irreversible inhibitor of dihydrofolate reductase -> inhibits folic acid metabolism

Partially inhibits thymidylate
synthetase -> reduces availability of purine nucleotides and thymidylate

Inhibits DNA methylation via
decreasing cellular levels of S-adenyl methionine

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3
Q

What drugs modulate the behavior of inflammatory and other cells through inhibition of cell growth and development?

A

Cytotoxic & Antimetabolic Drugs

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4
Q

PK of methotrexate?

A

● Oral MTX is absorbed rapidly through the GI tract
● In children, absorption is decreased by
concurrent ingestion of food and milk, but this is not true for adults
● 1/2 life: 4-5 hours
● Eliminated chiefly by
the kidneys hence decreases if GFR and tubular secretion can cause MTX toxicity

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5
Q

Indication of Methotrexate?

A

Chief indication: severe psoriasis & psoriatic arthritis

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6
Q

Off label uses for Methotrexate?

A
  • Dermatomyositis
  • Cutaneous lupus erythematosus
  • Scleroderma
  • Pemphigus vulgaris
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7
Q

Monitoring therapy for MTX?

A

● CBC and LFT: every 2-4 weeks for first few months (LFT should not be performed earlier than 5 days since last dose to avoid confounding results)
● Renal function test performed every 1-2 months or if with suspicion of altered renal function
● Liver biopsy after 3.5-4g total cumulative dose

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8
Q

Pregnancy category of MTX?

A

Category X

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9
Q

Absolute contraindications to MTX?

A

Pregnancy
Lactation
Leukemia, Leukopenia, thrombocytopenia

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10
Q

PK of Hydroxyurea

A

● Rapid onset of action, with tissue effects
noted within 5 hours
● at least 80% is
excreted by the kidney

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10
Q

Complications of MTX?

A

● Hematologic effects: most imp acute adverse effect of MTX is myelosuppression; neutropenia with life threatening bone marrow toxicity can occur
● GI effects: Nausea and vomiting - dose related; Folate supplement- reduces GI symptoms
● Hepatic effects: MTX is hepatotoxic, avoid in patients with liver disease and active alcoholics; dose reduction recommended 2-3x the normal transaminases level, d/c if with 5x increase than normal value
Mucosal & Cutaneous effects: Oral stomatitis & ulcerations; Skin ulceration may herald bone marrow suppression
● Mutagenicity & Teratogenicity: Category X, reliable contraceptive is a requisite; Men- wait 3 months since last dose; Women- wait after 1 complete menstrual cycle
● Pulmonary effects: Acute pneumonitis & pulmonary fibrosis
● Overdose: give Folinic acid within the first 24-36 hours; 15-25mg q6 for 6-10 doses

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11
Q

MOA of Hydroxyurea

A

● Impairs DNA synthesis through inhibition of ribonucleotide diphosphate reductase -> limits DNA bases available for synthesis -> strand breakage and cell death
● Most active in cells with a high
proliferative index
(preferentially concentrated in leukocytes)

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12
Q

Indications of Hydroxyurea

A

Chiefly used for tx of psoriasis

● Adjuvant tx in
metastatic melanoma & erythromelalgia

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13
Q

Dosing of Hydroxyurea

A

● 200-, 400-, 500-mg tablets
● Usual dose: 1-2g/day

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14
Q

Absolute CI to Hydroxyurea?

A

Hypersensitivity

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15
Q

most common AE of Hydroxyurea?

A

Most common adverse effect with hydroxyurea is myelosuppression
○ All patients on hydroxyurea develop megaloblastosis
○ 10%-35% of patients develop anemia; 7% develop leukopenia; 2%-3%
develop thrombocytopenia
○ Hydroxyurea should be discontinued if:
- Hgb declines by more than 3 g
- WBC declines to <4000 to 4500 cells/mm
- PC declines to <100,000

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16
Q

Pregnancy category of Hydroxyurea?

A

Category D

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17
Q

Rare but impt AE of Hydroxyurea?

A

● A rare but important adverse effect of hydroxyurea is fever with a flulike illness

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18
Q

Drug interactions w Hydroxyurea?

A

Drug Interactions:
○ - Few significant drug interactions
○ - Coadministration with other myelosuppressive agents and cytarabine ->
additive bone marrow toxicity.

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19
Q

MoA of Azathioprine?

A

Synthetic analog of purine bases

Prodrug metabolized to 6-mercaptopurine → 6-thioguanine via HGPRT → RNA/DNA synthesis & repair inhibition → immunosuppression

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20
Q

PK of Azathioprine?

A

Better bioavailability than 6-MP by mouth (equal parenterally)
→ 6-MP within RBCs → 3 competing pathways:
● Anabolized to active 6-TG via HGPRT
● Catabolized to inactive XO
● Catabolized to inactive
form by TPMT

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21
Q

Indications for Azathioprine?

A

Dermatomyositis
Pemphigus vulgaris
systemic lupus erythematosus

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22
Q

Most feared complication of Azathioprine

A

Acute severe neutropenia

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23
Absolute CI to Azathioprine
Hypersensitivity to Azathioprine Active or ongoing infection
24
Pregnancy Cat of Azathioprine?
Category D
25
complications of Azathioprine?
Myelosuppression (all cell lines) GI effects (MC leading to discontinuations ↑ Lymphoproliferative disease or skin CA
26
moa of THIOGUANINE?
Natural AZA metabolite Inhibits purine synthesis via purine analogs that inhibit DNA/RNA synthesis Preferential against T lymphocytes
27
Off label use for THIOGUANINE
Severe psoriasis
28
Dosing regimen of THIOGUANINE
40 mg tabs 80 mg 2x/week + 20 mg every 2-4 weeks with maximum 160 mg 3x/week TPMT assays to guide dosing Pulse dosing: 120 mg 2x/week or 160 mg 3x/week reduces BM toxicity
29
MC SE of Thioguanine
Myelosuppression
30
MOA of Cyclosporine?
Inhibits intracellular calcineurin → ↓ IL-2 & IFNγ, T lymphocytes Psoriasis
31
MOA of Mycophenolic Acid & Mycophenolate Mofetil?
MPA: Lipid soluble, weak organic acid Antifungal, antibacterial, antiviral, immunosuppressive Oral for moderate to severe psoriasis MMF: MPA derivative ↑ Bioavailability, tolerance, immunosuppression
32
MoA and Indication for Tacrolimus?
Macrolide that inhibits calcineurin by binding FK506 binding protein Oral: prevents transplant rejection Topical: Atopic Dermatitis
33
MoA for Thalidomide?
Nonpolar glutamic acid derivative Hypnosedative, immunomodulatory, neural/vascular effects Teratogenic (phocomelia) Effective and approved for Erythema Nodosum Leprosum Off label: Kaposi sarcoma, pyoderma gangrenosum, bullous pemphigoid, prurigo nodularis, uremic pruritus, Jessner lymphocytic infiltrate
34
Cyclophosphamide MOA?
From nitrogen mustard Alkylating agent crosslinking DNA Immunosuppressive & steroid sparing for autoimmune blistering disorders & systemic vasculitis Cell cycle-nonspecific B > T lymphocytes Suppressor > helper T cells
35
Indications for CYCLOPHOSPHAMIDE
Only in most serious diseases Vasculitis, CTD, Advanced CTCL + steroids in Pemphigus Vulgaris Mucous membrane pemphigoid, SJS/TEN Not routinely used with availability of safer immunosuppressives
36
Chlorambucil moa
From nitrogen mustard Alkylating agent crosslinking DNA
37
PK of Chlorambucil?
Oral bioavailability is 87% 99% protein bound Slower onset than cyclophosphamide
38
Indications for Chlorambucil
Should not be used in non malignant cases no US FDA approved indications Off label: Pemphigus vulgaris Bullous pemphigoid Pyoderma gangrenosum
39
Pregnancy Cat for Chlorambucil
Category D
40
MOA for Doxorubicin?
DNA intercalation → synthesis termination Specific to S phase of cell division
41
Agents that cause Alopecia
Agents: Doxorubicin, cyclophosphamide, vincristine
41
agents that cause Acneiform Eruption
Associated Agents: Actinomycin D, MTX, cisplatin.
41
Agents that cause Malformed nail plates/Dystrophy
Anthracyclines (Doxorubicin), taxanes (Paclitaxel, docetaxel)
41
Presentation of Acneiform eruptions?
Folliculitis with erythematous macules, papules, and pustules.
41
Agents that cause nail pigmentation?
Doxorubicin, vincristine, cyclophosphamide, MTX, 5-fluorouracil.
41
PK of Doxorubicin
Pegylated liposomal doxorubicin (PLD) has better tolerance than standard doxorubicin Prevents phagocytosis by RES
41
Indications for Doxorubicin
AIDS-related Kaposi sarcoma CTCL, MF, Sezary syndrome
42
Risks for Doxorubicin
Cardiotoxicity Infusion site reactions
43
MC complication of Doxorubicin
MC PLD SE: Myelosuppression Less cardiotoxicity with non liposomal doxorubicin + antiretrovirals = Hepatotoxicity Drug interactions: digoxin, cyclosporine, CCBs, ciprofloxacin
44
Indications for Doxorubicin?
AIDS-related Kaposi sarcoma CTCL, MF, Sezary syndrome
45
PK for Doxorubicin
Pegylated liposomal doxorubicin (PLD) has better tolerance than standard doxorubicin Prevents phagocytosis by RES
46
Risks for Doxorubicin
Cardiotoxicity Infusion site reactions
46
Complications for Doxorubicin
MC PLD SE: Myelosuppression Less cardiotoxicity with non liposomal doxorubicin + antiretrovirals = Hepatotoxicity Drug interactions: digoxin, cyclosporine, CCBs, ciprofloxacin
46
agent in Neutrophilic Eccrine Hidradenitis (NEH) and Syringosquamous Metaplasia
Cytarabine
47
Implicated agents in Acral Erythema
Cytarabine Doxorubicin Fluorouracil , MTX.
48
Implicated agents in Inflammation of Actinic Keratoses Cutaneous Hyperpigmentation
Systemic fluorouracil
49
Implicated agents in Cutaneous Hyperpigmentation
Bleomycin
50
Implicated agents in Radiation Recall Reaction
MTX
51
agents that cause Radiation Enhancement Reactions
Doxorubicin Dactinomycin
52
agents that cause Sclerotic Dermal Reactions
Bleomycin, Docetaxel
53
Agents that cause Raynaud Phenomenon
Bleomycin, vincristine, cisplatin
54
MoA of Acyclovir
Active form: acyclovir triphosphate → causes premature termination of
55
Indications for acyclovir
● Symptomatic primary or recurrent HSV1/2 infections ● Chronic suppression of HSV1/2 infections ● HSV encephalitis ● Primary VZV infection, including HIV associated acute retinal necrosis ● Herpes zoster (shingles) ● Prevention of perinatal and treatment of neonatal HSV infection ● HSV gingivostomatitis and orolabial cold sores (off-label) ● Prevention of HSV, CMV, or VZV reactivation in hematopoietic stem cell transplant and HIV patients (off-label) ● New onset Bell palsy (off-label)
56
SE of acyclovir
● Generally well-tolerated. ● Uncommon reactions include renal impairment (5% incidence). ● Major risk for impairment is renal tubular crystallization with rapid IV administration. ● Crosses the human placenta and is excreted in breast milk. ● Determined safe for use during pregnancy (pregnancy category B). ● Recommended for herpes treatment during pregnancy. ● Safe for administration during active breastfeeding, as long as the nursing mother does not have active lesions near or on the breast.
57
Indications for Valacyclovir
● Initial and recurrent HSV genital infections ● Suppression and reduction of transmission of genital HSV infections ● Herpes zoster (shingles) ● Herpes labialis (cold sores) ● Varicella (chickenpox)
58
AE for Valacyclovir
● Adverse effects similar to acyclovir, including potential for acute renal failure and CNS effects. ● Immediate hypersensitivity and symmetrical drug-related intertriginous and flexural exanthem reported. ● Severe effects of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) in high dosages. ● Pregnancy category B risk. ● Precipitates in renal tubules; caution in renal impairment.
59
MoA of Famciclovir and Penciclovir
Famciclovir, biotransformed to active compound penciclovir, inhibits HSV-2 polymerase. ● Phosphorylation to penciclovir monophosphate by HSV- or VZV-induced thymidine kinases. ● Penciclovir triphosphate competitively inhibits viral DNA polymerases, similar to acyclovir.
60
Indications for Famciclovir and Penciclovir
● Initial and recurrent HSV genital infections. ● Suppression of recurring genital HSV infections. ● Initial and recurrent HSV labialis (cold sores). ● Herpes zoster (shingles). ● Varicella infection (chickenpox) in HIV patients (off-label).
61
MOA of Trifluridine
MOA - Irreversible competitive inhibitor of thymidylate synthetase - HSV DNA polymerase
62
Indications of Trifluridine
Primary and recurrent HSV keratoconjunctivitis, keratitis - Acyclovir-resistant mucocutaneous HSV infections in patients with AIDS (off-label)
62
MoA, indications, AE for Ganciclovir, Vanciclovir
competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase → inhibits viral DNA synthesis
63
MoA, indications, AE for Foscarnet
Noncompetitively inhibits viral DNA polymerases at pyrophosphate binding site ➔ CMV retinitis ➔ Acyclovir-resistant HSV infections ➔ CMV esophagitis or colitis (off-label) ➔ Ganciclovir-resistant CMV infections (off-label) ➔ Renal toxicity → renal impairment ➔ Electrolyte + metabolic abnormalities → seizures
64
MoA, indications, AE for Cidofovir
competitively inhibits of viral DNA polymerases ➔ CMV retinitis ➔ Acyclovir-resistant HSV infections ➔ Renal impairment ➔ Nausea ➔ Alopecia
65
MoA, indications, AE for Interferon
Immunomodulation ○ Induction of gene transcription ○ Inhibition of cellular growth ○ Interference with oncogene expression ○ Alteration of cell surface antigen expression ○ Increased phagocytic activity of macrophages and cytotoxicity of lymphocytes ● Viral infections (IFN-alpha) ○ Condylomata acuminata ○ Chronic hepatitis C infection ○ Chronic hepatitis B infection ○ AIDS-related Kaposi sarcoma ● Multiple sclerosis (IFN-beta) ● Chronic granulomatous disease (IFN- gamma) ● Neoplastic diseases - melanoma (IFN-alpha) ● Flu-like symptoms ● Injection site reactions ● Alopecia ● Psoriasis ● Fixed drug eruptions ● Eczematous drug reactions ● Sarcoidosis ● Lupus ● Pigmentary changes ● Lichenoid eruptions ● Bone marrow suppression
66
Treatments for HIV?
Treated with antiretroviral therapy (ART) - Use of multidrug regimens - Eradication of HIV infection cannot be achieved with available ARV regimens - Pool of latently infected CD4 T cells is established during the early stages of acute HIV - MOA: - Block the virus at various points in its 7-stage life cycle - Pharmacokinetic boosters/ enhancers → Improve the pharmacokinetic profiles of some ARV → Ritonavir, Cobicistat
67

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