Teratogenic drugs - PowerPoint PPT Presentation

1 / 40
About This Presentation
Title:

Teratogenic drugs

Description:

Teratogenic drugs 1. In 60 s, teratogenic effects were recognized: Thalidomide: defects of limb and other organs Valproic acid: Neural tube defects – PowerPoint PPT presentation

Number of Views:2812
Avg rating:3.0/5.0
Slides: 41
Provided by: RayuduGopa
Learn more at: https://medweb.usc.edu
Category:

less

Transcript and Presenter's Notes

Title: Teratogenic drugs


1
Teratogenic drugs
  • 1. In 60s, teratogenic effects were recognized
  • Thalidomide defects of limb and other
    organs
  • Valproic acid Neural tube defects
  • (spina
    bifida, anencephaly)
  • Craniofacial
    (cleft palate lips)
  • 2. Word Teratogen is coined (teratos
    monster)
  • 3. Pregnant women (balance therapy and safety)
  • Inadequate treatment affects mother
    fetus
  • Treating with teratogens fetal
    abnormalities

2

Critical periods of embryonic development
Embryonic period
Term
Fetal period
Implant- ation
Physiological defects Minor morphological
Prenatal death
Major morphological Abnormalities
3
Mechanistic basis for teratogenicity
  • 1. Drugs affect growth
  • (e.g., anticancer drugs)
  • 2. Drugs affect differentiation
  • (e.g., retinoic acid)
  • 3. Drugs affect folic acid metabolism
  • (e.g., TMP-SMX)
  • Neural tube defects

4
  • FDA categories - Teratogenic risks of drugs

A
B
C
D
X
5

Preferred versus teratogenic drugs
Very safe
A
Safer drugs
Preferred
B
Safe
Low risk
C
Used risk-versus benefits
High risk
D
Teratogenic
Highly teratogenic
X
Not used
6
Category A - examples Very safe
  • Folic acid
  • Protects from neural tube defects
  • Levothyroxine
  • Does not cross placenta

7
Category B - examples Safe
  • 1. Bacterial cell wall synthesis inhibitors
  • Penicillins, cephalosporins, vancomycin
  • Adults Hypersensitivity reactions,
    diarrhea
  • Fetus not these side effects
  • 2. Bacterial protein synthesis inhibitors
  • Erythromycin
  • Adults epigastric distress,
  • cholestatic jaundice
  • Clindamycin diarrhea

8
Category C - examplesLow risk (used,
risk-versus-benefits)
  • Gentamicin
  • Selective for aerobic (-) bacteria
  • Adults renal toxicity and ototoxicity
  • Fetus No renal toxicity
  • Limited ototoxicity
  • TMP-SMX
  • Trimethoprim causes folate deficiency

9
Category D - examplesHigh risk (used,
risk-versus-benefits)
  • Tetracyclines
  • Deposit in calcifying bone and teeth
  • Anticancer drugs
  • Inhibit cell growth or cause cell death
  • TMP-SMX
  • Sulfamethoxazole causes kernicterus

10
Pneumocystis carinii Infection in HIV-infected
mothers Neonate may be infected If mother is not
treated.
  • Urinary tract infections
  • TMP-SMX (not used)
  • Cephalexin (cephalosporin)

11
  • Risks involved treating with TMP-SMX at the term

Sulfa drug-induced displacement of bilirubin can
cause kernicterus in the neonate
Benefit of preventing P. carinii pneumonia
(fatal) in the mother and neonate
Phototherapy
12
Category X - examples
Contraindicated
  • Retinoic acid
  • Ribavirin

13
Treatment of women who may become pregnant
  • 1. Nearly 50 of pregnancies in USA are
    unplanned.
  • 2. If drugs that cause teratogenic action
    (category D or X) in the first trimester are
    prescribed to a woman who may become pregnant,
    there is a chance for exposure of the embryo to
    these drugs.
  • 3. By that time woman realizes that she is
    pregnant, the fetal development is in a critical
    period for teratogenic susceptibility.

14
Teratology
Menstrual cycle
Embryo age (d)
Ovulation, fertilization
1
Predifferentiation period (usually not
susceptible teratogenesis)
10
Expected start of menses
Period of early Differentiation
organogenesis (Highly susceptible
to teratogenesis
Positive pregnancy tests
20
30
60
Period of advanced organogenesis (relatively
resistant to teratogenesis) (In utero death)
15
Treatment of women who may become pregnant
  • Examples from Acne treatment
  • Retinoic acid (category X)
  • causes teratogenic effects in all
    stages
  • Enquire patient is pregnant or not
  • Need pregnancy test
  • Need one form of contraceptive
  • Tetracycline (category D)
  • Effects are seen after first trimester
  • Enquire patient is pregnant or not
  • No need for pregnancy test or

  • contraceptive

16

Treatment of women who may become pregnant
May become pregnant
Pregnancy
Retinoic acid
Teratogenic effects
Need for both pregnancy test and continuous
use of contraceptive
1st trimester
2nd trimester
3rd trimester
Tetracycline
Safe
Teratogenic effects
No need for pregnancy test or contraceptive
2nd trimester
3rd trimester
1st trimester
Deposits in bone and teeth
17
Antimycobacterial drugs
for tuberculosis
Special requirements
1. Mycobaterial cell can be dormant.
2. The lipid-rich mycobacterial cell wall is
impermeable to many drugs.
3. Often they are intracellular, residing
within macrophages.
4. Resistance is developed to single drug.
Combination chemotherapy is required
18

Lipid-rich cell wall of Mycobacterium
Pore
Extractable phospholipids

Mycolic acids
Arabinogalactan
Proteoglycan
Cytoplasmic membrane
19

Mycobacteria residing in macrophages
Infiltrating macrophages
Early tubercle
20

Combination chemotherapy for tuberculosis
First-line of drugs
Isoniazid
9 -12 months
Rifampin
6 months
First 2 months
Oral drugs Enter macrophage Kill intracellular
bacilli Enter CSF
Pyrazinamide
Kills isolates resistant to Isoniazid rifampin
Ethambutol or Streptomycin
I.V. Cannot enter macrophages Kills extracellular
bacilli
21
Isoniazid
Isonicotinic acid hydrazide, INH
  1. Bactericidal for growing M. tuberculosis
  • It is highly effective and specific against
  • M. tuberculosis and other members
    of
  • M. tuberculosis complex (e.g., M.
    bovis)

22
Isoniazid inhibits mycolic acid
synthesis in M. tuberculosis
katG gene
Catalase- peroxidase
Free radical
Isoniazid
Radicals are not removed
AhpC (hydroperoxide reductase)
OxyR gene
Synthesis of mycolic acid
Inactive
Not detectable
23
Isoniazid inhibits mycolic acid synthesis
Acetyl CoA
Fatty acid synthase 1
Fatty acids
Isoniazid free radical
Fatty acid synthase 2 (InhA)
(cross links)
Mycolic acids
Cell wall
24
Isoniazid does not inhibit
mycolic acid synthesis in M. leprae
katG gene
Catalase- peroxidase
Free radical
Isoniazid
Radicals are removed
AhpC (hydroperoxide reductase)
OxyR gene
Synthesis of mycolic acid is not affected.
Active
high
25
Isoniazid - pharmacokinetics
  • Orally given drug, well absorbed.
  • Enter CSF even in the absence of inflammation.
  • Drug is inactivated in the liver by
  • N-acetylation (N-acetyltransferase)
  • Dose is reduced In chronoic liver disease.

26
Isoniazid - adverse effect
Hepatitis
  • Reactive intermediate generated in the liver
    covalently reacts with proteins and causes
  • liver necrosis

High risk Alcoholics and pregnant women
Age group Hepatitis
Under age 20 rare
Age 21-35 0.3
Age 36-50 1.2
Above 50 2.3
27

Isoniazid causes liver necrosis

Isoniazid
N-Acetyltransferase-2
Phase II
Excreted by kidney
Phase I
Cyt P-450
Alcohol
(CYP2E1)
Acetylhydrazine
Isonicotinic acid
Liver necrosis
Risk factors
Acetylation of proteins
Activation of innate immune system
28
Prophylactic therapy
with isoniazid
  • To prevent clinical tuberculosis in persons who
    tested positive for skin test (PPD).
  • 2. Usually given to patients with age lt35
    years.
  • Not given to patients gt50 years.
  • 4. High risk patients Given irrespective of
    age.
  • (Immune compromised persons,
  • HIV-positive patients,
  • close contacts, including children)

29
Rifampin
  • Mechanism
  • 1. Inhibits transcription
  • 2. Binds to the b-subunit of RNA polymerase.
  • 3. This prevents binding of the enzyme to DNA.

30

Rifampin - pharmacokinetics
  • 1. Rapidly absorbed after oral administration.
  • 2. Biliary secreted and reabsorbed
  • 3. Deacetylated in the liver. (metabolite
    active)
  • Deacetylated metabolite biliary
    excreted,
  • but poorly reabsorbed
  • (facilitates fecal excretion)
  • 4. Rifampin very well penetrates into the CSF.
  • Useful in the treatment of tubercular
    meningitis

31
Rifampin - adverse effects
  • Hepatitis Requires liver function tests
  • Alcohol increases the risk.
  • Hypersensitive reaction, flu-like illness with
    chills, fever, and fatigue.
  • 3. Causes reddish-orange discoloration of
    saliva, tears, and urine.

32
Rifampin - drug interaction
Induces
Rifampin
Cyt P-450
Increases metabolism
Deacetylation
Rifampin
Warfarin Cyclosporin A Antifungal
azoles Sulfonylureas Theophylline
Increase dose of these drugs
Decreases plasma concentration
33

Rifampin - clinical applications
  • 1. Broad-spectrum antibiotic
  • Gram-positive and gram-negative
  • Acid-fast bacilli (M. Tuberculosis,
    M. kansasii,

  • M. avium- intracellulare, and M. laprae)
  • For prophylactic therapy
  • 1. Alternative to isoniazid
  • (when resistance to
    isoniazid is known)
  • 2. Prevent meningococcal disease
  • Asymptomatic carriers or
  • Close contacts of a person exposed to

  • Neisseria meningitidis
  • 3. Persons expsoed to H. influenzae type b and
    are at risk of transmitting infection to children

34
Pyrazinamide
pncA gene
Mycobacterial enzyme
Enters Into bacteria
Pyrazinamidase
Pyrazinoic acid
Pyrazinamide
Lowers pH
Fatty acid Synthase 1
Inhibits growth of bacteria
35
Pyrazinamide indirectly inhibits mycolic acid
synthesis
Acetyl CoA
Pyrazinamide (pyrazinoic acid)
Fatty acid synthase 1 (FAS1)
Fatty acids
Isoniazid free radical
FAS2
Fatty acid synthase 2
Phospholipids
Mycolic acids
36
Renal excretion of uric acid - gout
Uric acid not protein bound
Glomerulus 100 filtered
Uric acid retained
Acute attacks of gout
90 reabsorbed
lt5 secreted
Pyrazinamide Ethambutol
Net excretion 6-12
37
Ethambutol
  • Absorbed after oral administration.
  • Enters CSF.
  • Blocks arabinosyl transferase
  • (involved in arabinogalactan synthesis)
  • 4. Suppresses growth of isoniazid- or
    rifampin-resistant tubercle bacilli.

38
Ethambutol - causes optic neuritis
  • Patient loses the ability to discriminate between
    red and green.
  • Difficulty with traffic signals.

39

Antimycobacterial drugs - mechanisms
1. Mycobacterial cell wall synthesis inhibitors
Isoniazid free radicals inhibit mycolic acid
synthesis.
Pyrazinamide pyrazinoic acid inhibits cell
growth. Inhibits FAS1 decrease
phospholipids needed for cytoplasmic
membrane.
Ethambutol Inhibits arabinosyl transferase
involved in cell wall synthesis.
2. Transcriptional inhibitor
Rifampin binds to b-subunit of RNA
polymerase and prevents its binding to
DNA.
40

Antimycobacterial drugs - side effects
1. Isoniazid Hepatitis, peripheral neuropathy
2. Rifampin Hepatitis, discoloration of body
fluids
3. Pyrazinamide Gout
4. Ethambutol Gout optic neuritis
Write a Comment
User Comments (0)
About PowerShow.com