teratogenicity dr.elza

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