teratogenicity dr.elza
TRANSCRIPT
DRUG INTERACTION
By Dr . Elza Emmanuel
DEFINITION
MODIFICATION OF RESPONSE TO ONE DRUG BY
ANOTHER WHEN THEY ARE ADMINISTERED
SIMULTANIOUSLY OR IN QUICK SUCCESSION ie,
THE EFFECTS OF ONE DRUG ARE AFFECTED BY
THE EFFECT OF ANOTHER DRUG.
Severity of drug interacton in most cases is highly unpredictable
The doctor must know which drugs are not to be prescribed concurrently
PRECIPITANT DRUG-THE DRUG
THAT PRECIPITATE AN INTERACTION
OBJECT DRUG-THE DRUG WHOSE
ACTION IS AFFECETED
MECHANIISM OF DRUG INTERACTION
1. Pharmacokinetic
2. Pharmacodynamic
PHARMACOKINETIC INTERACTIONS
These interactions alter the concentration of the object drug at its site of action by affecting its absorption,distribution,metabolism or excretion
ABSORPTION
Due to formation of insoluble &poorly absorbed complexes in the gut lumen
Eg:Btw Tetracyclines & calcium/iron salts
Can be minimized by administering two drugs with a gap of 2-3 hours
DISTRIBUTION
Due to displacement of one drug from its binding sites on plasma proteins by another drug
Eg:Quinidine & Digoxin
METABOLISM
Certain drugs reduce or enhance the rate of metabolism of other drugs
Eg:Microsomal enzyme inducers like barbiturates, rifampicin can cause contraceptive failure
EXCRETION
Important in case of drugs actively secreted by tubular transport mechanisms
Eg:Probenacid inhibits tubular secretion of penicillins &cephalosporins and prolongs their plasma t1/2
PHARMACODYNAMIC INTERACTIONS
These interactions are due to modification of action of one drug at the target site by another drug independent of change in its concentration
This results in Enhanced response-SYNERGISM Attenuated response-
ANTAGONISM Abnormal response
EXAMPLES
Fall in BP & MI due to use of sildinafil by patients receiving organic nitrates
Severe hyperkalaemia by concurrent use of ACE inhbitors & K+ sparing diuretics
Additive ototoxicity due to use of aminoglycoside in patient receiving furosemide
DRUG INTERACTIONS BEFORE ADMINISTRATION
Certain drugs react with each other and get inactivated if their solutions are mixed before administration
Eg:Penicilln G/Ampicillin +Gentamicin Thiopentone
sodium+Succinylcholine
ADVERSE DRUG REACTION
EXPECTED UNDESIRABLE EFFECTSTYPE A ADRS
SIDE EFFECTS
These are undesirable effects which are observed even with the therapeutic doses of the drug
They are usually mild and manageable Eg:Promethazine has antiallergic action
-Desirable effect,but it also produces sedation in therapeutic doses-Side effect
SECONDARY EFFECTS
These are indirect consequences of the main pharmacodynamic action of the drug
Eg:Development of superinfection after suppression of bacterial flora by antibiotics
TOXICITY
These are exaggerated form of side effects which occur due to overdoses or after prolonged use of the drug
Eg:Bleeding due to high doses of heparin
UNEXPECTED UNDESIRABLE EFFECTS/TYPE B ADRS/BIZZARRE EFFECTS
DRUG ALLERGY[HYPERSENSITIVITY REACTIONS]
Allergic responses to drug occur when there has been previous exposure to drug & when this sensitised individual is re-exposed to the same drug again
Drugs may elicit Type I,II,III & IV Hypersensitivity reactions.
TYPE I HSR
Allergy develops with in minutes & lasts for 2-3 hour Drug causes formation of tissue sensitizing IgE
antibodies that are fixed to mast cells or leucocytes. The subsequent exposure to drug degranulates
mast cells or activates leucocytes with release of chemical mediators [histamine,serotonin] of allergy
The patient if untreated suddenly passes into anaphylactic shock.
Eg:Anaphylaxis after parenteral administration of penicillin or radiocontrast media
TYPE II HSR
It results when a drug binds to RBC & is recognised by IgG Ab.
The Ag-Ab reaction triggers the lysis of RBC by complement activation /action of cytotoxic T cell/phagocytosis by macrophages.
Results within 72 hr of drug administration
Eg:Drug induced Thrombocytopenia,SLE after quinidine use
TYPE III HSR
Ag-Ab form complexes which are deposited on vascular endothelium & activate complement
Eg:Glomerularnephritis after giving NSAID
TYPE IV HSR
These reactions are mediated by sensitised T cells following contact with an antigen
Sensitised T cells results in release of cytokines which activate macrophages,granulocytes & natural killer cells
Eg:Contact dermatitis ,Photosensitivity.
GENETICALLY DETERMINED ADVERSE EFFECTS
Drug reactions in some individuals may be qualitatively different from effects usually observed from majority of subjects
The mechanism is of genetic origin Eg:The genotype with atypical
pseudocholine esterases cannot hydrolyse succinylcholine,in that case even the therapeutic dose of sccinylcholine leads to prolonged respiratory failure
IDIOSYNCRATIC DRUG RESPONSES
These are harmful & sometimes fatal reactions that occur in a small minority of individuals,for which the cause is yet poorly understood.
Eg:Malignant Hyperthermia on using halothane ,succinylcholine
TYPE –C [CHRONIC EFFECTS]
Adverse effects that are associated with prolonged use of drug.
Eg:Cushing syndrome after chronic use of prednisolone
TYPE-D[DELAYED EFFECTS]
Adverse effects that occur in patients years after treatment or effects appearing in their children who did not receive the treatment
Eg:Clear cell carcinoma of vagina in the daughters of women who took diethylstilbesterol during pregnancy
TERATOGENICITY
By Dr . Elza Emmanuel
DEFINITION
Capacity of a drug to cause fetal abnormalities when administered to pregnant mother.
The placenta does not strictly constitute a barrier and any drug can cross it to a greater or lesser extent.
FACTORS THAT DETERMINE THE EFFECTS OF TERATOGENS1. Point in development
when drug exposure occurs
2. Duration of exposure3. Susceptibility of fetus4. Dose reaching fetus
Drugs can affect fetus at 3 stages
1. Fertilization & implantation -conception to 17 days- failure of pregnancy
2. Organogenesis-18 to 55 days- deformities -MOST VULNERABLE PERIOD
3. Growth & development- 56 days onwards-developmental & functional abnormalities.
MECHANISM OF TERATOGENICITY Poorly understood Multifactorial 1.Drugs directly affect the process
of differentiation 2.Drugs may interfere with the
passage of oxygen & nutrients through placenta
3.Deficiency of a critical substance
FDA USE-IN-PREGNANCY RATINGS
CATEGORY -A
Controlled studies show no risk
Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy.
CATEGORY -B
No evidence of risk in humansAdequate, well-controlled studies in
pregnant women have not shown an increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote, but remains a possibility.
CATEGORY-C
Risk cannot be ruled out. Adequate, well- controlled human
studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is administered during pregnancy, but the potential benefits may outweigh the potential risk.
CATEGORY - D
Positive evidence of riskStudies in humans, or investigational or post-
marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective
CATEGORY - X
Contraindicated in pregnancy
Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk that clearly outweighs any possible benefit to the patient.
CLASSIFICATION BASED ON TERATOGENIC POTENTIAL
Category Characteristics Examples
A Controlled human studies show no risk
Folic AcidThyroxine
B Animal studies OK no human data
Paracetamol, Erythromycin
C Animal studies not OK no human Data
RifampicinMorphine
D Evidence for risk +++Benefits outweigh risk
Antiepileptics
X Evidence for risk +++Risks outweigh benefits
Thalidomide Retinoids
COMMON TERATOGENIC DRUGS
Alchohol Androgens Anticonvulsants Antineoplastics Iodides
IsotretinoinLithium Methimazole Tetracyclines Warfarin
THALIDOMIDE -A LESSON IN MEDICINE PHOCOMELIA : THIS ABNORMALITY ('SEAL LIMBS') CONSISTS OF AN ABSENCE OF DEVELOPMENT OF THE LONG BONES OF THE ARMS AND LEGS
THALIDOMIDE
Developed in Germany in 1954 Promoted as a tranquiliser and anti emetic Taken by thousands of pregnant women Resulted in >10,000 children with birth
deformities Withdrawn in 1961 Has found new uses as an immune
modulator & for multiple myeloma
LESSONS FROM THALIDOMIDE
The placental barrier is not effective against most orally administered drugs
Animal teratogenic testing can be misleading
PHENYTOIN
Cleft lip/palate, microcephaly, mental retardation
VALPROATE
NEURAL TUBE DEFECT
ISOTRETINOIN
Mental retardation and learning disabilities
Eye & ear deformities
Cleft lip, cleft palate & other facial abnormalities
Heart defects
Microcephaly & Hydrocephaly
FETAL ALCOHOL SYNDROME
FETAL WARFARIN SYNDROME
Saddle nose;
retarded growth;
defects of limbs, eyes, central nervous system
YELLOW STAINING OF THE TEETH IN A CHILD EXPOSED TO MATERNAL TETRACYCLINE IN UTERO
DIETHYLSTILBESTROL
In 1971, DES was shown to cause clear cell carcinoma, a rare vaginal tumor in girls and women who had been exposed to this drug in utero.
ANTIBIOTICS• Category A: None available• Category B: PenicillinsCephalosporinsclindamycinerythromycinmetronidazole- 2nd & 3rd trimesters, contraindicated 1st trimesterazithromycinacyclovir
GASTROINTESTINAL TRACT• Category A: Doxylamine• Category B: rabeprazoledicyclominesucralfatebisacodylloperamidelactulosepantoprazole metoclopramideranitidine ondansetron
ALLERGIC DISORDERS• Category A: Doxylamine• Category B: chlorpheniramineCyproheptadinemontelukastlevocetirizinecetirizine
Category Xtestosterone estradiol(dipyridamole/aspirin) 3rd trimester simvastatinlovastatinMisoprostolThalidomideIsotretinoin
TAKEHOME MESSAGES Avoid all drugs during pregnancy unless compelling reasons exist.
Folate therapy during pregnancy can reduce spontaneous as well as drug induced malformations.
THANKYOU