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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
Q

Absolute CI to Azathioprine

A

Hypersensitivity to Azathioprine
Active or ongoing infection

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24
Q

Pregnancy Cat of Azathioprine?

A

Category D

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25
Q

complications of Azathioprine?

A

Myelosuppression (all cell lines)

GI effects (MC leading to discontinuations

↑ Lymphoproliferative
disease or skin CA

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26
Q

moa of THIOGUANINE?

A

Natural AZA metabolite

Inhibits purine synthesis via purine analogs that inhibit DNA/RNA synthesis

Preferential against T lymphocytes

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27
Q

Off label use for THIOGUANINE

A

Severe psoriasis

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28
Q

Dosing regimen of THIOGUANINE

A

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

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29
Q

MC SE of Thioguanine

A

Myelosuppression

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30
Q

MOA of Cyclosporine?

A

Inhibits intracellular calcineurin → ↓ IL-2 & IFNγ, T lymphocytes
Psoriasis

31
Q

MOA of Mycophenolic Acid & Mycophenolate Mofetil?

A

MPA:
Lipid soluble, weak organic acid Antifungal, antibacterial, antiviral, immunosuppressive
Oral for moderate to severe psoriasis

MMF:
MPA derivative
↑ Bioavailability, tolerance, immunosuppression

32
Q

MoA and Indication for Tacrolimus?

A

Macrolide that inhibits calcineurin by binding FK506 binding protein

Oral: prevents transplant rejection Topical: Atopic Dermatitis

33
Q

MoA for Thalidomide?

A

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
Q

Cyclophosphamide MOA?

A

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
Q

Indications for CYCLOPHOSPHAMIDE

A

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
Q

Chlorambucil moa

A

From nitrogen mustard

Alkylating agent crosslinking DNA

37
Q

PK of Chlorambucil?

A

Oral bioavailability is 87%

99% protein bound

Slower onset than cyclophosphamide

38
Q

Indications for Chlorambucil

A

Should not be used in non malignant cases

no US FDA approved indications

Off label:
Pemphigus vulgaris
Bullous pemphigoid
Pyoderma gangrenosum

39
Q

Pregnancy Cat for Chlorambucil

A

Category D

40
Q

MOA for Doxorubicin?

A

DNA intercalation → synthesis termination

Specific to S phase of cell division

41
Q

Agents that cause Alopecia

A

Agents: Doxorubicin, cyclophosphamide, vincristine

41
Q

agents that cause Acneiform Eruption

A

Associated Agents: Actinomycin D, MTX, cisplatin.

41
Q

Agents that cause Malformed nail plates/Dystrophy

A

Anthracyclines (Doxorubicin), taxanes (Paclitaxel, docetaxel)

41
Q

Presentation of Acneiform eruptions?

A

Folliculitis with erythematous macules, papules, and pustules.

41
Q

Agents that cause nail pigmentation?

A

Doxorubicin, vincristine, cyclophosphamide, MTX, 5-fluorouracil.

41
Q

PK of Doxorubicin

A

Pegylated liposomal doxorubicin (PLD) has better tolerance than standard doxorubicin

Prevents phagocytosis by RES

41
Q

Indications for Doxorubicin

A

AIDS-related Kaposi sarcoma

CTCL, MF, Sezary syndrome

42
Q

Risks for Doxorubicin

A

Cardiotoxicity
Infusion site reactions

43
Q

MC complication of Doxorubicin

A

MC PLD SE: Myelosuppression

Less cardiotoxicity with non
liposomal doxorubicin

+ antiretrovirals = Hepatotoxicity

Drug interactions: digoxin, cyclosporine, CCBs, ciprofloxacin

44
Q

Indications for Doxorubicin?

A

AIDS-related Kaposi sarcoma

CTCL, MF, Sezary syndrome

45
Q

PK for Doxorubicin

A

Pegylated liposomal doxorubicin (PLD) has better tolerance than standard doxorubicin

Prevents phagocytosis by RES

46
Q

Risks for Doxorubicin

A

Cardiotoxicity
Infusion site reactions

46
Q

Complications for Doxorubicin

A

MC PLD SE: Myelosuppression

Less cardiotoxicity with non
liposomal doxorubicin

+ antiretrovirals = Hepatotoxicity

Drug interactions: digoxin, cyclosporine, CCBs, ciprofloxacin

46
Q

agent in Neutrophilic Eccrine Hidradenitis (NEH) and Syringosquamous Metaplasia

A

Cytarabine

47
Q

Implicated agents in Acral Erythema

A

Cytarabine Doxorubicin Fluorouracil , MTX.

48
Q

Implicated agents in Inflammation of Actinic Keratoses Cutaneous Hyperpigmentation

A

Systemic fluorouracil

49
Q

Implicated agents in Cutaneous Hyperpigmentation

A

Bleomycin

50
Q

Implicated agents in Radiation Recall Reaction

A

MTX

51
Q

agents that cause Radiation Enhancement Reactions

A

Doxorubicin Dactinomycin

52
Q

agents that cause Sclerotic Dermal Reactions

A

Bleomycin, Docetaxel

53
Q

Agents that cause Raynaud Phenomenon

A

Bleomycin, vincristine, cisplatin

54
Q

MoA of Acyclovir

A

Active form: acyclovir triphosphate → causes premature termination of

55
Q

Indications for acyclovir

A

● 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
Q

SE of acyclovir

A

● 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
Q

Indications for Valacyclovir

A

● 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
Q

AE for Valacyclovir

A

● 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
Q

MoA of Famciclovir and Penciclovir

A

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
Q

Indications for Famciclovir and Penciclovir

A

● 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
Q

MOA of Trifluridine

A

MOA
- Irreversible competitive inhibitor of thymidylate synthetase
- HSV DNA polymerase

62
Q

Indications of Trifluridine

A

Primary and recurrent HSV keratoconjunctivitis, keratitis
- Acyclovir-resistant mucocutaneous HSV infections in patients with AIDS (off-label)

62
Q

MoA, indications, AE for Ganciclovir, Vanciclovir

A

competitively inhibits the binding of deoxyguanosine triphosphate to DNA polymerase → inhibits viral DNA synthesis

63
Q

MoA, indications, AE for Foscarnet

A

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
Q

MoA, indications, AE for Cidofovir

A

competitively inhibits of viral DNA polymerases

➔ CMV retinitis
➔ Acyclovir-resistant
HSV infections

➔ Renal impairment
➔ Nausea
➔ Alopecia

65
Q

MoA, indications, AE for Interferon

A

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
Q

Treatments for HIV?

A

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
Q
A

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