Anesthesia Pharmacology - Wu

Pharmacology
Module Title: Basics of Infection, Immunity, and

Neoplasia
Course: Pharmacology
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Course outline
General principles of chemotherapy
Drugs for UTIs
Drugs for malaria, leishmaniasis and schistosomiasis
Antiretroviral drugs and drugs for opportunistic infections
Anticancer chemotherapy
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Objective
By the end of this course the students will be able to
Explain the type of treatment available to control
infectious diseases like malaria, leishmaniasis,
schistosomiasis, HIV and microorganisms that infect the
urinary tract
Know the basics of cancer chemotherapy
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General Principles of Chemotherapy
Antibiotics: antimicrobials from organisms (natural
agents)
Antimicrobials: synthetic, semisynthetic, and natural
agents
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Selective Toxicity
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Mechanisms of microbial resistance
Resistance often correlates with
Frequency of antimicrobial use
Total quantity of drug dispensed
Location of the patient when receiving the medication
Immune status of the patient
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Mechanisms of microbial resistance
Processes that contribute to resistance
Drug resistance due to altered targets
Drug resistance due to decreased accumulation
• Decreased uptake
• Increased efflux
Drug resistance due to enzymatic inactivation
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To minimize the emergence of resistance
Only use chemotherapeutic agents when they are clearly
indicated
Use a narrow-spectrum drug known to be effective
against the pathogen
Use an effective dose of the chemotherapeutic agent
Ensure that the duration of chemotherapy is adequate
Use older chemotherapeutic drugs whenever possible
Use multiple drugs in combination chemotherapy when
the pathogen is noted to develop resistance to an
individual drug rapidly
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Selection of antimicrobial
1) The identity of the organism
• Microscopy, antigen detection, NAAT (nucleic acid
amplification test), culture, antibody detection
2) The susceptibility of the organism to a particular agent
• Bacteriostatic (arrest growth of bacteria), bactericidal (kill
bacteria)
• Minimum bactericidal concentration (MBC): lowest
concentration of antibiotic that kills 99.9% of bacteria
• Minimum inhibitory concentration (MIC): lowest
antimicrobial concentration that prevents visible growth of
an organism after 24 hrs. of incubation
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3) The site of the infection
• The prostate, testes, placenta, the vitreous body of the
eye, and the central nervous system (CNS)
• Blood–brain barrier (BBB): chloramphenicol and
metronidazole (lipid soluble), ionized at physiologic
pH (penicillin)
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4) Patient factors
• Pregnancy, age, hepatic function, renal function, risk-
factor for multidrug resistant organisms
5) The safety and efficacy of the agent, and
6) The cost of therapy
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Drugs for UTIs
Definition of urinary tract infections
UTI may be asymptomatic (subclinical infection) or
symptomatic (disease)
Urinary tract infection:
• Asymptomatic bacteriuria (ASB)
• Cystitis (bladder inflammation)
• Prostatitis (inflammation of prostate), and
• Pyelonephritis (inflammation of the tubules, interstitium,
and renal pelvis)
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Drugs for UTIs
Urinary tract infection:
• Symptoms
Lower UTIs (LUTI): dysuria, urgency, frequency,
nocturia, and suprapubic heaviness
Upper UTIs (UUTI): systemic symptoms such as
fever, nausea, vomiting, and flank pain
Uncomplicated UTI: infection confined to the bladder,
or acute cystitis
Complicated UTI: fever or signs of systemic illness
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Drugs for UTIs
Epidemiology: F>M (M=F, old age; M>F, infants)
Microbes that cause UTIs:
• E. coli (75–90%)
• Staphylococcus saprophyticus (5–15%), younger women
• Klebsiella, Proteus, Enterococcus, and Citrobacter
species, along with other organisms (5–10%)
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Drugs for UTIs
Drugs for UTI
Oral
• Trimethoprim/sulfamethoxazole
• Nitrofurantoin
• Fosfomycin
• Fluroquinolones: ciprofloxacin and levofloxacin
• Penicillins: amoxicillin/clavulanic acid
• Cephalosporins: cefdinir, cefpodoxime-proxetil
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Drugs for UTIs
Drugs for UTI
Parenteral
• Aminoglycosides: gentamicin, tobramycin and
amikacin
• Penicillins: ampicillin/sulbactam,
piperacillin/tazobactam
• Fluroquinolones: ciprofloxacin and levofloxacin
• Cephalosporins: ceftriaxone, ceftazidime, cefepime
• Carbapenems/ monobactams: Imipenem cilastatin,
meropenem, doripenem, ertapenem, azetronam
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Drugs for UTIs
Drugs for UTI: oral
Trimethoprim/sulfamethoxazole
• MOA: interfere with the metabolism of folic
acid/bacteriostatic
Indication
• Uncomplicated LUTI: 960 mg tab po daily for 3 days
• Complicated LUTI: 960 mg tab po daily for 7-10 days
• Recurrent UTIs: 240 mg tab po daily for 6 months
• Acute pyelonephritis: 960 mg tab po daily for 14 days
• Pregnant mothers: avoid in 1st and 3rd trimester
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Drugs for UTIs
Trimethoprim/sulfamethoxazole
• ADE:
Hypersensitivity reactions (rashes, fever,
eosinophilia) in 3% and rarely, Stevens-Johnson
syndrome most severe form
Hemolytic aplastic anemia in G6PD deficient patients
Kernicterus in neonates
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Drugs for UTIs
Nitrofurantoin (1950s):the 1st tolerable and effective agent
• MOA: complex yet not fully understood
Possible: Intracellular conversion of nitrofurantoin to
highly reactive intermediates by bacterial reductases that
react nonspecifically with many ribosomal proteins and
disrupt metabolic processes and the synthesis of proteins,
RNA, and DNA
• Indication:
uncomplicated LUTI: 100mg bid for 5days
Recurrent LUTI: 50 mg/d for 6 months
• ADE: Anorexia, nausea, and vomiting
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Drugs for UTIs
Fosfomycin
• MOA: inhibits a very early stage of bacterial cell wall
synthesis
• Indication: uncomplicated LUTI: 3g stat
• ADE: diarrhea, vaginitis, nausea, and headache
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Drugs for UTIs
Drugs for UTI: oral/parenteral
Penicillins: amoxicillin/clavulanic acid
;ampicillin/sulbactam, piperacillin/tazobactam
• MOA: inhibit bacterial cell wall synthesis
• Indication: amoxicillin/clavulanic acid
Uncomplicated LUTI: 500 mg tid for 7 days
Complicated LUTI: 500 mg tid for 7-10 days
Acute pyelonephritis: 500 mg tid for 14 days
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Drugs for UTIs
Penicillins: amoxicillin/clavulanic acid
;ampicillin/sulbactam, piperacillin/tazobactam
• Indication: ampicillin/sulbactam,
piperacillin/tazobactam
Hospitalized patients; ; IV aminoglycoside ± IV
ampicillin; extended-spectrum IV penicillin ±
aminoglycoside
• For pregnant mothers
• ADE: Hypersensitivity reactions, rash,
pseudomembranous colitis
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Drugs for UTIs
Cephalosporins: cefdinir, cefpodoxime-proxetil
• MOA: inhibit cell wall synthesis
• Indication: uncomplicated UTI: cefpodoxime-proxetil
100 mg every 12 hours; cefdinir 300 mg every 12 hours or
600 mg every 24 hours; ceftriaxone, ceftazidime,
cefepime used in hospitalized patients ± aminoglycosides
• For pregnant mothers
• ADE: Hypersensitivity reactions, autoimmune hemolytic
anemia, disulfiram-like reaction, vitamin K deficiency;
Low rate of cross reactivity even in penicillin-allergic
patients, increase nephrotoxicity of aminoglycosides.
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Drugs for UTIs
Fluroquinolones: ciprofloxacin and levofloxacin
• MOA: DNA gyrase inhibitors; bactericidal
• Indication:
Uncomplicated LUTI:
ciprofloxacin 250 mg bid/ levofloxacin 250 mg/d for 3 days
Complicated LUTI:
ciprofloxacin 500 mg bid for 7-10 days/ levofloxacin 250 mg/d
for 10 days of 750mg daily for 5days
Acute pyelonephritis:
ciprofloxacin 500 mg bid for 14 days/ same like uncomplicated
LUTI
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Drugs for UTIs
Fluroquinolones: ciprofloxacin and levofloxacin
• IV fluoroquinolone for hospitalized patients
• ADE: Nausea; avoid: calcium containing medications,
theophylline and caffeine; interference with collagen
synthesis; causes tendon rupture
• C/I: hypersensitivity, pregnancy and children
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Drugs for UTIs
Drugs for UTI: parenteral
Aminoglycosides: gentamicin, tobramycin and amikacin
• MOA: Bactericidal; irreversible inhibition of initiation
complex through binding of the 30S subunit; can cause
misreading of mRNA; also block translocation; require O2
for uptake; therefore ineffective against anaerobes
• Indication: IV aminoglycoside ± IV ampicillin;
extended-spectrum IV cephalosporin or extended-
spectrum IV penicillin ± aminoglycoside; for hospitalized
patients
• ADE: : nephrotoxicity, neuromuscular blockade (absolute
contraindication with myasthenia gravis), ototoxicity
(especially with loop diuretics), teratogenicity
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Drugs for UTIs
Drugs for UTI: parenteral
Carbapenems/ monobactams: Imipenem cilastatin,
meropenem, doripenem, ertapenem, azetronam
• MOA: cell wall synthesis inhibitors
• Indication: IV carbapenem, for hospitalized patients
• ADE: GI distress, rash, and CNS toxicity (seizures) at
high plasma levels
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Drugs for malaria, leishmaniasis and
schistosomiasis
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schistosomiasis
Drugs used against malaria
Based on chemical structures and modes of action
• Antifolate compounds: sulfadoxine (dihydropteroate
synthase inhibitor); pyrimethamine, trimethoprim,
proguanil and chlorproguanil (dihydrofolate reductase
inhibitor)
ADE: Pyrimethamine: megaloblastic anemia (also
proguanil in renal failure), pancytopenia, pulmonary
infiltration
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schistosomiasis
• Aryl amino alcohol compounds: quinine, quinidine,
chloroquine, amodiaquine, mefloquine, halofantrine,
piperaquine, and lumefantrine
• 8-Aminoquinoline: primaquine and tafenoquine
MOA: Hemoglobin (digested by asexual malaria)=
globin (used by the malaria)+ heme (toxic
(sequestered as hemozoin pigment by
malaria),quinolines inhibit this sequestration which
result in oxidative damage to membranes or other
critical biomolecules)+ free radicals
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schistosomiasis
• Aryl amino alcohol compounds
ADE: hemolytic anemia in G6PD deficiency
(primaquine); quinine, Cinchonism (tinnitus, high-
tone hearing loss, nausea, vomiting, dysphonia,
postural hypotension), hypoglycemia, prolonged QT
interval; chloroquine, neuropsychiatric reactions
acutely and retinopathy (>100g) chronically
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schistosomiasis
• Artemisinin compounds: artemisinin, artesunate,
artemether, β-arteether, and dihydroartemisinin (DHA)
MOA: malaria through its digestive product (heme-
iron) activate artemisinin and its derivatives that
subsequently generate free radicals which in turn
alkylate and oxidize macromolecules in the parasite
ADE: anaphylaxis, urticaria and fever
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schistosomiasis
• Others: atovaquone and antibacterial drugs
(tetracycline, doxycycline, and clindamycin)
MOA: atovaquone inhibits cytbc1, part of the
respiratory chain and transporter of H+ into the
intramembranous space of mitochondria of malaria
ADE: renal failure in patients with renal impairment
(tetracycline)
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schistosomiasis
Uncomplicated P. falciparum malaria
• 1st line artemisinin based combination therapy (ACT)
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schistosomiasis
Severe P. falciparum malaria
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schistosomiasis
Other malaria species
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schistosomiasis
Second line treatment for malaria
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schistosomiasis
Prophylactic drugs for malaria
• P. falciparum
Chloroquine or Hydroxychloroquine
(sensitive)/mefloquine 250mg (resistant): weekly, take
300 mg (C)/310 mg (HQ)1-2 weeks before travel, then
while in malarious area and up to 4 weeks after leaving
the malarial area.
Doxycycline or Atovaquone proguanil (mefloquine
resistant): daily, take 250 mg and100 mg/100mg 1-2
days before travel, then while in malarious area and up
to 7 days after leaving the malarial area.
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schistosomiasis
Prophylactic drugs for malaria
• P. vivax
Chloroquine or Hydroxychloroquine: see under P.
falciparum
Primaquine: daily, take 50mg 1-2 days before travel,
then while in malarious area and up to 7 days after
leaving the malarial area.
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schistosomiasis
Drugs used against leishmaniasis
Visceral leishmaniasis (VL): L. donovani in East Africa
and the Indian subcontinent, and L. infantum in North
Africa, Europe, and Latin America
Cutaneous leishmaniasis (CL): L. major, L. tropica, and
L. aethiopica cause CL in North and East Africa, Central
Asia, and the Middle East (Old World). While L.
Mexicana, L. Viannia braziliensis, and L. amazonensis
cause CL in parts of Central and South America, the USA,
and Mexico (New World).
Mucosal leishmaniasis (ML): L. Viannia braziliensis
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schistosomiasis
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schistosomiasis
Drug MOA Indication ADE
Antimonials: Unclear VL: 20 mg/kg by IV/IM for 28-30 Injection site pain,
Meglumine days pancreatitis, elevated
antimoniate SSG + paromomycin for 17 days. liver enzymes,
and sodium ML: SSG 20mg/kg for 30 days arthralgias, myalgias,
stibogluconat CL: 20 mg/kg for 20 days gastrointestinal upset,
e (SSG) and cardiac arrhythmias
Amphotericin Formation VL (deoxycholate): 0.75–1.0 mg/kg Deoxycholate: Nausea,
B of free on alternate days for a total of 15 vomiting, fever,
(deoxycholat radicals that infusions hypokalemia, renal
e and produce VL (LAmB): 3 mg/kg daily on days failure, anemia, and heart
liposomal oxidative 1–5, 14, and 21 (total dose, 21 problems; liposomal less
(LAmB)) damage to mg/kg). toxic; HIV patients
Leishmania ML: LAmB 2–3 mg/kg for 20 days (LAmB)
cells
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schistosomiasis
Drug MOA Indication ADE
Paromomycin Binds to 30S VL: 11 mg of base/kg IM daily Reversible ototoxicity,

ribosome, for 21 days reversible rise in hepatic
protein CL:(16 mg/kg daily (L. transaminases and local
synthesis aethiopica) pain at the injection site
inhibitor
Miltefosine Unclear VL: 50 mg PO for 28 days Teratogenic, nausea and
vomiting
Pentamidine Interference in CL: 4 mg of salt/kg separated Abscess formation at the
isethionate Leishmania by a 48-h interval (Leishmania injection site, myalgia,
DNA, RNA (Viannia) guyanensis) hypotension,
and protein hypoglycemia, and diabetes
synthesis mellitus
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schistosomiasis
Schistosoma infection is contracted through contact with
freshwater bodies harboring infected intermediate-host
snails
Epidemiology: Peak age: 10-15 years; sub-Saharan Africa
(70 % of infected)
Clinical features
Cercarial dermatitis (“Swimmer’s Itch”)
Acute schistosomiasis (Katayama Fever)
Intestinal schistosomiasis (S. mansoni, S. japonicum)
Hepatosplenic schistosomiasis
Urogenital schistosomiasis (S. haematobium)
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schistosomiasis
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schistosomiasis
Drug for schistosomiasis: Praziquantel
 MOA: increases calcium permeability results in
depolarization of cells; causes contraction and paralysis of
worm musculature
Indication: All patients with acute schistosomiasis
should be treated with praziquantel
• Schistosoma mansoni, S. haematobium: 40 mg/kg PO in
2 divided doses for 1 day
• S. japonicum: 60 mg/kg PO in 3 divided doses for 1 day
ADE: Headache, dizziness, drowsiness and GI
disturbances
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Antiretroviral drugs and drugs for
opportunistic infections
HIV-1 Replication and Drug Targets
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HIV drugs
Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
abacavir (ABC), didanosine (DDI), emtricitabine (FTC),
lamivudine (3TC), stavudine (D4T), zalcitabine (DDC)
and zidovudine (AZT)
Nucleotide Reverse Transcriptase Inhibitor (NTRTIs):
Tenofovir disproxil, alafenamide (TDF and TAF)
Nonnucleoside Reverse Transcriptase
Inhibitors(NNRTIs): Nevirapine (NVP), Efavirenz
(EFV), Delavirdine (DLV), Etravirine (ETV), Rilpivirine
(RPV, also have long acting injectable)
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HIV drugs
Protease Inhibitors (PIs): Saquinavir (SQV), Indinavir
(IDV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir
(no longer in market)(APV), Lopinavir (LPV/r),
Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir
(TPV) and Darunavir (DRV)
“Boosting” PIs With a CYP Inhibitor: The metabolic
clearance of HIV PIs is inhibited by cobicistat, a ritonavir
analogue that lacks antiretroviral activity and that was
developed for exclusive use as a pharmacokinetic
enhancer
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HIV drugs
Entry Inhibitor: Enfuvirtide (T-20), Maraviroc (MVC)
Integrase Inhibitor: Raltegravir (RAL), dolutegravir
(DTG), Elvitegravir (EVG), Bictegravir, Cabotegravir
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HIV drugs
Drug ADRs and other information
NRTIs Bone marrow suppression (can be reversed with
granulocyte colony-stimulating factor [G-CSF] and
erythropoietin), peripheral neuropathy, lactic acidosis
(nucleosides), anemia (ZDV), pancreatitis (didanosine).
zidovudine, didanosine, zalcitabine, and stavudine cause
lipodystrophy (hyperlipidemia, glucose
intolerance/insulin resistance, and fat redistribution). TDF
not used (CrCl) <70, and TAF (CrCl) <30
NNRIs Rash and hepatotoxicity are common to all NNRTIs.
Vivid dreams and CNS symptoms are common with
efavirenz
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HIV drugs
Drug ADRs other information
Protease Inhibitors Hyperglycemia, GI intolerance (nausea, diarrhea),
lipodystrophy (Cushing-like syndrome). Nephropathy,
hematuria, thrombocytopenia (indinavir). Rifampin
(potent CYP/UGT inducer) reduces protease inhibitor
concentrations; use rifabutin instead; rilpivirine
Contraindicated in not new patients, HIV RNA levels
>1000 copies/ml and using PPIs
Integrase inhibitors Increase creatinine kinase; Weight gain, Cabotegravir is
an integrase inhibitor that is given in combination with
rilpivirine as a monthly injection after oral test.
Entry Inhibitors Skin reaction at injection sites (Enfuvirtide)
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HIV drugs
HAART (Highly Active Antiretroviral Treatment): the
use of at least three anti-retroviral drugs with different
mechanism of actions for the treatment of HIV infection
to have effective viral suppression.
HIV infection be treated with ART and that therapy be
initiated a soon as possible after diagnosis.
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HIV principles of treatment
Preferred regimen for initial treatment
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HIV opportunistic infections
Pneumocystis jiroveci Pneumonia/ toxoplasma gondi/
• Trimethoprim/sulfamethoxazole 15–20 mg/kg TMP
(75–100 mg/kg SMX) daily administered IV or PO
every 6–8 hours or 960mg tablets TID
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Cryptococcosis
• 1st: amphotericin B, 0.7 mg/kg/day IV, plus flucytosine
(100 mg/kg/day) given PO in four divided doses as
induction therapy for 14 days.
• Then, once the patient is stable (e.g., afebrile, with the
resolution of symptoms), then consolidation therapy
with oral fluconazole 400 mg/day for 8 weeks or until
CSF cultures are sterile can be initiated
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Cryptococcosis
• Amphotericin B
• MOA: Binds ergosterol (unique to fungi); forms membrane
pores that allow leakage of electrolytes; amphotericin
“tears” holes in the fungal membrane by forming pores.
• ADE: Fever/chills (“shake and bake”), hypotension,
nephrotoxicity, arrhythmias, anemia, IV phlebitis;
hydration decrease nephrotoxicity; Liposomal amphotericin
B decrease toxicity
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Cryptococcosis
• Fluconazole
• MOA: Inhibit fungal sterol (ergosterol) synthesis by
inhibiting the cytochrome P-450 enzyme that converts
lanosterol to ergosterol
• ADE: liver dysfunction (inhibits cytochrome P-450)
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Cytomegalovirus
• CMV retinitis: oral valganciclovir, IV ganciclovir, IV
ganciclovir followed by oral valganciclovir, IV foscarnet,
and IV cidofovir
• MOA: they are prodrugs which are converted to
monophosphates by virus-specific thymidine kinase; then
converted to triphosphate by cellular enzymes;
triphosphates inhibits DNA synthesis and viral replication
• ADE: malaise, headache, GI distress and nephrotoxicity
(IV administration)
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Drugs used for Tuberculosis: 1st line
Drugs Clinical use ADEs
Rifamycins: Rifampin Mycobacterium tuberculosis; delay Minor hepatotoxicity and drug interactions
(R), rifabutin resistance to dapsone when used for (cytochrome P-450); orange body fluids
leprosy. Used for meningococcal (nonhazardous side effect). Rifabutin favored over
prophylaxis and chemoprophylaxis rifampin in patients with HIV infection due to less
in contacts of children with H cytochrome P-450 stimulation.
influenzae type b.
Isoniazid (H) Mycobacterium tuberculosis. The Hepatotoxicity, cytochrome P-450 inhibition, drug-
only agent used as solo prophylaxis induced SLE, anion gap metabolic acidosis, vitamin
against TB. Also used as B6 deficiency (peripheral neuropathy, sideroblastic
monotherapy for latent TB. anemia), seizures (in high doses, refractory to
benzodiazepines). Administer with pyridoxine (B6).
Pyrazinamide (Z) Mycobacterium tuberculosis Hyperuricemia, hepatotoxicity.
Ethambutol (E) Mycobacterium tuberculosis Optic neuropathy
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Drugs used for Tuberculosis
TB treatment is administered in two phases:
• Intensive (initial, bactericidal) phase: Tubercle bacilli
are killed, symptoms resolve, and usually the patient
becomes noninfectious
• Continuation (sterilization) phase: Eliminate
persisting mycobacteria and prevent relapse
• Dosing frequency: 2RHZE/ 6RH (standard regimen)
and DOT (Directly Observed Therapy)
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Anticancer drugs
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Anticancer drugs
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Anticancer drugs
 Alkylating agents
MOA: Exert their cytotoxic effects via transfer of their
alkyl groups majorly DNA and to various cellular
constituents reacting chemically with sulfhydryl, amino,
hydroxyl, carboxyl, and phosphate groups of other cellular
nucleophiles as well subsequently resulting in cell death
ADE:
• Myelosuppression(i.e.,melphalan, chlorambucil,
cyclophosphamide, and ifosfamide) with a nadir of the
peripheral blood granulocyte count at 6–10 days and
recovery in 14–21 day
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Anticancer drugs
ADE:
• Highly toxic to dividing mucosal cells and to hair follicles,
leading to oral mucosal ulceration, intestinal denudation,
and alopecia.
• Nausea and vomiting commonly follow administration of
nitrogen mustard
• Melphalan, the nitrosoureas, and the methylating agent
procarbazine have the greatest propensity to cause
leukemia (after 4 years of treatment in 5%), which is
less common after cyclophosphamide
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Anticancer drugs
Nitrogen mustards: Mechlorethamine, cyclophosphamide,
ifosfamide, melphalan, chlorambucil, bendamustine
Ethyleneimines and methylmelamines: Altretamine,
thiotepa
Alkyl sulfonates: Busulfan
Nitrosoureas: Carmustine, streptozocin
Triazenes: Dacarbazine, temozolomide
Methylhydrazines: Procarbazine
Platinum coordination complexes (similar
MOA):Cisplatin, carboplatin and oxaliplatin
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Anticancer drugs
 Alkylating agents: Nitrogen mustards
Cyclophosphamide:
• Indication: Cancer: Breast cancer, ovarian cancer, non-
Hodgkin’s lymphoma, Chronic lymphoid leukemia, soft
tissue sarcoma, neuroblastoma, Wilms’ tumor,
rhabdomyosarcoma; Autoimmune diseases like Wegener
granulomatosis, rheumatoid arthritis, and the nephrotic
syndrome
• ADE: ‘‘Signature” adverse effect of cyclophosphamide:
hemorrhagic cystitis (because of the acrolein moiety)
prevented and treated with mesna and diuresis (IV fluids)
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Anticancer drugs
 Alkylating agents: Nitrogen mustards
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Anticancer drugs
Platinum coordination complexes (similar MOA):
• Cisplatin:
MOA: Forms intrastrand and interstrand DNA cross-
links; binding to nuclear and cytoplasmic proteins
Indication: Non-small cell and small cell lung cancer,
breast cancer, bladder cancer, cholangio carcinoma,
gastroesophageal cancer, head and neck cancer, ovarian
cancer, germ cell cancer
ADE: Nephrotoxicity, peripheral sensory neuropathy,
ototoxicity, nerve dysfunction
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Anticancer drugs
 Antimetabolites
Folic acid analogues: Methotrexate, pemetrexed,
trimetrexate
Pyrimidine analogues: Fluorouracil, Floxuridine,
Capecitabine, Trifluridine
Cytidine analogues: cytarabine (cytosine arabinoside;
ara-c), azacitidine (5-azacytidine), decitabine, gemcitabine
Purine analogues: 6-thiopurine analogues, fludarabine
phosphate, cladribine, clofarabine (2-chloro-2′-fluoro-
arabinosyladenine), nelarabine (6-methoxy-arabinosyl-
guanine), pentostatin (2′-deoxycoformycin)
06/02/2024 71
Anticancer drugs
 Antimetabolites: Folic acid analogues:
Methotrexate
MOA: Inhibits DHFR (dihydrofolate reductase) (A);
inhibits TS (thymidylate synthase); inhibits de novo purine
nucleotide synthesis (B)
06/02/2024 72
Anticancer drugs
Methotrexate
• Indication:
Breast cancer, head and neck cancer, osteogenic
sarcoma, primary central nervous system lymphoma,
non-Hodgkin’s lymphoma, bladder cancer,
choriocarcinoma
Systemic lupus erythematosus, rheumatic arthritis,
crohn’s disease, psoriasis, with misoprostol to terminate
early pregnancies
06/02/2024 73
Anticancer drugs
Methotrexate
• ADE: Mucositis, diarrhea, myelosuppression with
neutropenia and thrombocytopenia
• Add leucovorin to reduce myelosuppression and mucositis
Pemetrexed: Mesothelioma, non-small cell lung cancer
• ADE: Myelosuppression, skin rash, mucositis, diarrhea,
fatigue, hand-foot syndrome
Trimetrexate: ovarian cancer, mesothelioma, and
adenocarcinomas of the lung
06/02/2024 74
Anticancer drugs
 Antimetabolites: Pyrimidine analogues:
Capecitabine (oral dosage form):
• (1) metastatic breast cancer who have not responded to a
regimen of paclitaxel and an anthracycline;
• (2) metastatic breast cancer when used in combination
with docetaxel in patients who have had a prior
anthracycline-containing regimen; and
• (3)metastatic colorectal cancer.
06/02/2024 75
Anticancer drugs
 Antimetabolites: Pyrimidine analogues:
Capecitabine
• ADE: Diarrhea, hand-foot syndrome (painful erythema
and swelling of the hands and feet, and treatment with the
steroid dexamethasone is effective in reducing the
incidence and severity of this skin toxicity),
myelosuppression, nausea and Vomiting
06/02/2024 76
Anticancer drugs
 Antimetabolites: Cytidine analogues
Gemcitabine
• MOA: Inhibits DNA synthesis and repair; inhibits
ribonucleotide reductase with reduced formation of
dNTPs (deoxyribonucleotide triphosphate);
incorporation of gemcitabine triphosphate into DNA
resulting in inhibition of DNA synthesis and function
• Indication: Pancreatic cancer, bladder cancer, breast
cancer, non-small cell lung cancer, ovarian cancer, non-
Hodgkin’s lymphoma, soft tissue sarcoma
• ADE: Nausea, vomiting, diarrhea, myelosuppression
06/02/2024 77
Anticancer drugs
 Natural products
Microtubule-damaging agents: Vinca alkaloids, eribulin,
taxanes, estramustine and epothilones
Camptothecin analogues:Topotecan and irinotecan
Antibiotics: Dactinomycin (actinomycin D), anthracyclines
and anthracenediones
Epipodophyllotoxins: Podophyllotoxin derivatives,
etoposide and teniposide
Drugs of diverse mechanisms of action: Bleomycin,
mitomycin, mitotane, trabectedin, L–asparaginase,
hydroxyurea, retinoids and arsenic trioxide
06/02/2024 78
Anticancer drugs
 Natural products: Microtubule-damaging agents
Vinca alkaloids: vincristine
• Vincrstine
Indication: ALL, Hodgkin’s and non-Hodgkin’s
lymphoma, rhabdomyosarcoma, neuroblastoma, Wilms’
tumor
ADE: Neurotoxicity with peripheral neuropathy,
paralytic ileus, myelosuppression, alopecia, SIADH
• Vinorelbine
Indication: Non-small cell lung cancer, breast cancer,
ovarian cancer
ADE: Myelosuppression, constipation, SIADH
06/02/2024 79
Anticancer drugs
 Natural products: Microtubule-damaging agents
Taxanes (Paclitaxel (bark of the Western yew tree):
• Paclitaxel
Indication: Breast cancer, non-small cell and small cell
lung cancer, ovarian cancer, gastroesophageal cancer,
prostate cancer, bladder cancer, head and neck cancer
ADE: Acute: Nausea, vomiting, hypotension,
arrhythmias, hypersensitivity; chronic:
Myelosuppression, peripheral sensory neuropathy
06/02/2024 80
Anticancer drugs
 Natural products: Antibiotics
Anthracyclines and Anthracenediones
• Doxorubicin
Indication: Breast cancer, Hodgkin’s and non-
Hodgkin’s lymphoma, soft tissue sarcoma, ovarian
cancer, non-small cell and small cell lung cancer,
thyroid cancer, Wilms’tumor, neuroblastoma
ADE: Nausea, red urine (not hematuria);
Cardiotoxicity (dilated cardiomyopathy), alopecia,
myelosuppression, stomatitis
06/02/2024 81
Anticancer drugs
Natural products: Drugs of diverse mechanisms of action
Hydroxyurea
• MOA: Hydroxyurea inhibits the enzyme ribonuleotide
reductase (RNR), which catalyzes the reductive
conversion of ribonucleotides to deoxyribonucleotides, a
rate-limiting step in the biosynthesis of DNA
• Indication: myeloproliferative syndromes, particularly
CML, polycythemia vera, myeloid metaplasia, and
essential thrombocytosis, for controlling high platelet or
white cell counts
• ADE: Leukopenia, anemia, and occasionally
thrombocytopenia
06/02/2024 82
Anticancer drugs
 Hormones and Related Agents in the Therapy of Cancer
Drugs that target the glucocorticoid receptor:
prednisolone and dexamethasone
• MOA: antiproliferative and apoptotic responses in
sensitive cells
• Indication: ALL(with vincristine), CLL, Multiple
myeloma (with melphalan), Hodgkin’s and NHLs
• ADE: glucose intolerance, immunosuppression,
osteoporosis, and psychosis
06/02/2024 83
Anticancer drugs
Estrogens and androgens in cancer: Breast cancer
• Antiestrogen approaches for the therapy of HR+ (ER and
PR) breast cancer include the use of SERMs, SERDs
(selective estrogen receptor down regulators), and
aromatase inhibitors (exemestane, anastrozole and
letrozole)
• SERMS; Tamoxifen analogues (e.g., toremifene,
droloxifene, idoxifene); “fixed-ring” compounds (e.g.,
raloxifene, bazedoxifene, lasofoxifene, arzoxifene,
miproxifene, levormeloxifene);
• SERDs (e.g., fulvestrant), “pure antiestrogens”
06/02/2024 84
Anticancer drugs
 Hormones and
Related Agents
in the Therapy of
Cancer
Estrogens and
androgens in
cancer
Breast cancer
06/02/2024 85
Anticancer drugs
06/02/2024 86
Anticancer drugs
• SERMs:Tamoxifen
The SERMs bind to the ER and exert either estrogenic or
antiestrogenic effects, depending on the specific organ
Uterine endometrium (endometrial hypertrophy, vaginal bleeding,
and endometrial cancer);
The coagulation system (thromboembolism)
Bone metabolism (increase in bone mineral density, which can
slow development of osteoporosis) and
Liver (tamoxifen lowers total serum cholesterol, low-density
lipoprotein cholesterol, and lipoproteins and raises apolipoprotein
A-I levels)
06/02/2024 87
Anticancer drugs
• Drugs That Target the Progesterone Receptor
Medroxyprogesterone acetate is available for oral
administration; an alternative oral progestational agent is
megestrol acetate
Indication: metastatic hormone-dependent breast cancer and
are also used in the management of endometrial carcinoma
previously treated by surgery and radiotherapy
06/02/2024 88
Anticancer drugs
Androgen Deprivation Therapy
• GnRH agonists and antagonists: GnRH agonist (goserelin
and leuprolide); GnRH antagonists (Degarelix), treatment of
advanced prostate cancer
• Drugs that target the androgen receptor: Steroidal,
including cyproterone or nonsteroidal, including enzalutamide,
flutamide, bicalutamide, and nilutamide
• Drugs that inhibit androgen synthesis: Ketoconazole and
abiraterone used in astration-resistant prostate cancer
06/02/2024 89
Anticancer drugs
Androgen Deprivation Therapy
• GnRH Agonists and Antagonists
Prostate Cancer
GnRH agonists: Leuprolide, goserelin, histrelin,
triptolerin, nafarelin
GnRH antagonists:Degarelix (Cetrorelix)
Breast Cancer
GnRH agonist: Goserelin and leuprolide
06/02/2024 90
References
Barrett, K. E., Barman, S. M., Boitano, S. & Brooks, H. L.,
2012. Ganong’s Review of Medical Physiology. 24th ed. New
York : The McGraw-Hill Companies, Inc.
Brunton, L. L., Hilal-Dandan, R. & Knollmann, B. C., 2018.
Goodman & Gillman's The Pharmacotherapeutic Basis of
Therapeutics. 13th ed. New York: McGraw-Hill Education.
Katzung, B. G., 2018. Basic & Clinical Pharmacology. 14th
ed. New York: McGraw-Hill Education.
Whalen, K., Sharma, S. & Velpandian, T., 2019. Lippincott®
Illustrated Reviews: Pharmacology. South Asian ed. India:
Wolters Kluwer Health .
06/02/2024 91
Many Thanks!
06/02/2024 92
Questions?
06/02/2024 93

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