This word document, deals with Amphotericin-B(antifungal), its drug profile, and important pharmacological headings, with reference to updated textbooks and research articles.

1. 1. AMPHOTERICIN-B:
A. DRUG CLASS: Polyene
B. SOURCE: (Ref: Katzung, 14th ed., Page: 853)
- Although AMB & AMA are produced by Steptomyces nodosus  AMA is not in
clinical use.
C. MECHANISM OF ACTION:(Ref: Goodman & Gilman, 13th edition, Chapter 61, Pg.:
1087)
- AMB(Amphotericin-B)  mainly shows propensity to bind to ergosterol in
membrane of sensitive fungi
- Earlier  AMB was though to form pores/ channels, which increased fungal
membrane permeability, allowing the leakage of cytosolic molecules & ions,
culminating in fungal cell death.
- According to recent evidence  AMB forms aggregates, which separates ergosterol
from lipid bilayers of fungal cell membrane (Sponge activity), resulting in disruption
of membrane structure, leading to subsequent fungal cell death (Anderson et al,
2014).
D. PHARMACOKINETIC PROFILE: (Ref: Goodman & Gilman, 13th edition, Chapter 61,
Pg.: 1088; Katzung, 14th edition, Chapter: 48, Pg.:853-54).
- Negligible GI absorption  warrants systemic use of AMB via intravenous (i.v)
route.
- 90% of plasma-protein binding capacity
- Pharmacokinetic properties & dosing  vary, based on formulation nature
- Azotemia, liver failure & dialysis  do not show significant impact on plasma drug
concentration (C)  therefore no dosage adjustments are required.
- AMB  nearly insoluble in water  thus, prepared as colloidal suspension of AMB
& sodium deoxycholate for i.v injection.
- Half-life is approximately 15 days.

2. - Although AMB is widely distributed in most tissues, only 2-3% of “C” is attained in
CSF  necessitates use of ‘intrathecal therapy’ for certain types of fungal
meningitis.
E. ADVERSEEFFECTS & TOXICITIES: (Ref: Goodman & Gilman, 13th edition, Pg.: 1090;
Katzung, 14th ed., Pg.:856; Antibiotics Simplified, 4th edition, Pg.:154; Antibiotics manual:
A guide to commonly used antimicrobials, 2nd ed., Pg.: 1-2)
Include:
I. INFUSION-SITE REACTIONS:
- Include fever, chills, rigor, muscle spasms, vomiting, headache, hypotension &
phlebitis (at site of injection)
- Usually tend to cease on their own within 35-40 minutes
- In order to prevent infusion-site reactions  focus on the following:
a. Oral acetaminophen
b. i.v hydrocortisone sodiumsuccinate (0.7 mg/kg)
c. Slowing infusion rate
d. Reduce daily dose
e. Test dose of 1 mg of AMB (i.v) helps to assess severity of reaction
- With rapid i.v infusion  hypotension, hypokalemia, shock & arrhythmias can occur,
thus avoid rapid infusions!
- Of the various AMB formulations available:
a. Liposomal form  causes lowest reactions
b. ABCD (Amphotericin B Colloidal Dispersion)  causes greatest reactions!
- Patients with pre-existing cardiac / pulmonary disease  have high risk of
developing hypoxia/ hypotension due to AMB.

3. II. EFFECTS ON KIDNEY & ASSOCIATED TOXICITIES:
- AMB  shows nephrotoxicity in various ways:
a. Directly affecting distal tubule
b. Indirect affects, via vasoconstriction of afferent arteriole
c. Reduced renal perfusion  leads to reversible pre-renal failure
d. With prolonged dosage  renal tubular injury can lead to irreversible renal
damage
e. With damaged renal tubular cells  reduced erythropoietin production leads to
varying degree of anemia (mainly hypochromic, normocytic anemia; treated
with recombinant form of erythropoietin)
- With AMB-induced nephrotoxicity  wasting of magnesium & potassium occurs 
thus, patients on AMB therapy may require frequent supplementation of Mg++ & K+.
- Lipid formulations (particularly Liposomal AMB)  causes less nephrotoxicity,
compared to that of conventional form of AMB
- Azotemia  occurs in 80% of patients who receive C-AMB for deep mycoses
- Azotemia  can either be of minute severity, or be severe enough to necessitate
dialysis
- Renal tubular acidosis may also occur
III. MISCELLANEOUS EFFECTS:
- Elevated transaminases
- Rashes
- Intrathecal use of AMB  can result in seizures, arachnoiditis, etc.
- Leukoencephalopathy.
F. DRUG INTERACTIONS: (Ref: Antibiotics manual: A guide to commonly used
antimicrobials, 2nd ed., Pg.: 1-2)
1. AMB + Antineoplastics  high risk of nephrotoxicity, bronchospasm & hypotension
 exercise great caution!
2. AMB + Corticosteroids & ACTH  monitor for serum electrolytes & cardiac
function
3. AMB + Digitalis glycosides  AMB-induced hypokalemia can precipitate digitalis
toxicity

4. 4. AMB + Flucytosine  increased toxicity of latter
5. AMB + Imidazoles(fluconazole)  high risk of fungal resistance to AMB  exercise
great caution!
6. AMB + Nephrotoxic drugs  pharmacodynamic synergism  high risk for additive
nephrotoxicity  exercise great caution!
7. AMB + Skeletal muscle relaxants  AMB-induced hypokalemia can enhance the
curariform effects of skeletal muscle relaxants
8. AMB + Leukocyte transfusions (Given immediately after or with leukocyte
transfusions) Acute pulmonary toxicity may occur  thus, temporarily separate
these infusions as far as possible; monitor pulmonary function.
G. AVAILABLEFORMULATIONS: (Ref: Goodman & Gilman, 13th ed., Pg.:1087-88)
Include:
1. Conventional AMB(C-AMB):
- AMB  insoluble in water  thus bile salt deoxycholate is added to be made
suitable for i.v infusion
- Marketed as lyophilized powder for injection
- Never add electrolytes to infusion solutions  can complicate drug administration!
- Dose: 0.6 mg/kg.
2. Amphotericin-B Colloidal Dispersion (ABCD):
- Contains equimolar amounts of AMB & cholesteryl sulfate
- Provides much lower “C” than C-AMB
- Chills & hypoxia are more common, compared to that of C-AMB (White et al, 1998)
- Although this formulation is less nephrotoxic  it causes more fever & chills
compared to that of C-AMB (Bowden et al, 2002)
- Dose: 5 mg/kg.
3. Liposomal AMB(L-AMB):
- In this formulation  AMB is incorporated into a small, liposomal vesicle
formulation
- Can be given at higher doses (Boswell et al, 1998)
- Dose: 5 mg/kg

5. 4. Amphotericin-B Lipid Complex (ABLC):
- Consists of a complex of AMB with 2 phospholipids (Slain, 1999)
- Approved for salvage therapy of deep mycoses
- Dose: 5 mg/kg in 5% dextrose in water, infused i.v., once daily, over 2 hours.
H. ANTIFUNGAL SPECTRUM: (Ref: Antibiotics Simplified, 4th ed., Pg.; 153)
1. Good: Most species of Candida & Aspergillus, C. neoformans, dimorphic fungi & many
molds
2. Moderate: Mucorales
3. Poor: C. lusitaniae, A. terreus.
I. MECHANISM OF RESISTANCE: (Ref: Katzung, 14th ed., Pg.: 855)
- Mainly attributed to impairment of ergosterol bindings, owing to:
a. Reduced membrane concentration of ergosterol
b. Modification of sterol target molecules  thereby reducing drug affinity.
J. DOSAGEADJUSTMENTS FOR SPECIAL POPULATIONS: (Ref: Antibiotics manual:
A guide to commonly used antimicrobials, 2nd ed., Pg.: 1-2)
- For renal impairment  monitor RFT closely, no dosage adjustments required
- For hepatic impairment  monitor LFTs routinely
- For pediatrics  same as for adults.
K. INDICATIONS/USES:(Ref.: Goodman & Gilman, 13th ed., Pg.: 1089-90)
- Invasive mucormycosis
- Cryptococcal meningitis (with flucytosine)
- Severe histoplasmosis, blastomycosis, coccidioidomycosis, penicilliosis
- Salvage therapy for invasive aspergillosis, extracutaneous sporotrichosis, fusariosis,
etc.
- Profound neutropenia with fever (Refractory to broad-spectrum antibiotics, over 5-7
days)

6. L. IMPORTANTCATCHPOINTS FOR HEALTH-CAREPROFESSIONALS: (Ref.:
Antibiotics manual: A guide to commonly used antimicrobials, 2nd ed., Pg.: 1-2;
Antibiotics simplified, 4th edition, Pg.: 155)
1. Pre-medication with acetaminophen, diphenhydramine, meperidine & hydrocortisone
 reduces infusion toxicity
2. For C. lusitaniae, P. boydii & Fusarium spp.  AMB is ineffective  focus on using
voriconazole!
3. Monitoring parameters include:
a. LFTs
b. Electrolytes (Mg, K)
c. Blood counts
d. Hemoglobin.
4. If rigors develop during AMB treatment:
- Use meperidine
- Meperidine  has a neurotoxic metabolite  excreted renally  thus use with
caution in patients with renal impairment!
5. To prevent AMB-induced nephrotoxicity:
- Focus on proper hydration & sodium loading
- Provide boluses of NS infusion before & after AMB infusion
- Sodium loading  inexpensive, and an easy way of protecting kidneys!
- On the day of C-AMB administration  use 1 liter of NS (normal saline i.v).
VISHNU.R. NAIR,
PHARM.D INTERN,
NATIONAL COLLEGE OF PHARMACY, KOZHIKODE, KERALA (AMRI HOSPITAL ACADEMIC
TRAINEE).