adverse effects of drugs Flashcards
main causes of adverse effects:
1.Incidence of 4 per 1000
2.Antibiotics (16%)
-1 in 1000 risk of an ADE (allergy most common)
-1 in 4000 chance of preventing a serious complication of upper respiratory tract infection
3.Anticoagulants (32% of patients >65 years of age)
4.Warfarin, rivaroxaban, and dabigatran are in top 10 causes of ADEs
4.Opioid analgesia
Greater than the death rate from heroin
5.Insulin
unwanted vs desirable effects of opiates and anti histamines ( H1 antagonist )
Opiates
-When treating pain, constipation is an unwanted effect
-When treating diarrhea, constipation is a desirable effect
Anti-histamine (H1 antagonists)
-When treating allergy drowsiness is unwanted
-When used to prevent travel sickness drowsiness may be desirable
types of toxicity:
1.predictable aka pharmalogical toxicity which deals w :
2. unpredictable aka non pharmacological toxicity
3. — toxicity ( pretty much predictable )
4. —–
5. toxixty can be defined based on target organs as:
- predictable includes :
- excess pharmacological action
- class of drugs
- alternative pharmacological action includes:
- aspirin –> bleedings vs anti inflammatory action
- anti histamines for multiple receptors - non predictable:
- seen only a specific member of a class
- due to action of drug as ACE inhibitor ( cough) - overdose toxixty
- idiosyncratic
- hepatic , renal , neuro
history of ADE:
- Thalidomide:
Marketed by Chemie Grünenthal, Germany
Introduced as a sedative and anti-emetic (1957)
Withdrawn in 1961 due to teratogenic effects
Identified by William McBride an Australian gynaecologist & Widukind Lenz a German pediatrician - Diethylstilbestrol:
Non-steroidal estrogen
Approved by FDA in 1941
To prevent miscarriage
For estrogen deficient states
Post-coital contraceptive
Shown to be a teratogen in 1971
DES Daughters
increased risk of the development of clear cell adenocarcinoma (CCA) of the vagina and cervix
Pregnancy-related problems
sources of adverse drug effect (ADE) :
1.Active Pharmaceutical Ingredient (API)
2.API is usually well tested in vitro and in vivo before approval
3.API-mediated toxicity is due to
-A species-specific effect
-A metabolite, possibly species-specific
4.Contaminants
-Due to synthesis
-Due to degradation of API
5.Toxicity may only occur in a small number of patients
-Only detected after a large number of patients are treated
5.Excipients
-Most excipients are well characterised and are considered to be safe
- most drugs are tested for — prior to approval , most — is due to — which is often not known or characterised prior to use
- metabolism is often referred to as detoxification however its toxification
- toxicity
- toxixty
- toxification
paracetamol requires replenishing — which is not — active while N-acetylcysteine is —- active and converted to —
- glutathione GSH
- orally
- orally
-GSH
poly-pharmacy:
- many diseases require the use of — classes of pharmaceutical agents
- often there’s a choice of — of drug use
- for simplicity phase — studies usually use – specific class of drug
- approval is granted for use w this class only
- phase – studies can be used to expand the classes of drugs that can be co admisntred
- —- may be important w different drugs
- additional
- class
- phase iii
- one
- iv
- dosage changes
drugs interactions:
Too many possibilities to consider
Rational approach is necessary
What other drugs is the patient likely to be on for their disease?
What is the metabolic pathway and what other drugs use this pathway?
Most interactions will be identified from adverse reaction reporting
( check slide 17)
contaminants:
- while a very pure form of the API os used there may still be by-products from— as:
- API degrades over time infected by —- conditions as:
- sytheies as:
-May be batch specific
-May be due to some conditions changing during manufacture
-These may cause ADE especially cancer - storage as: heat light humidity
degradation studies :
1.API degradation has two major effects
-Reduced dose of API
-Presence of potentially toxic by-products
2.Accelerated stress test
-High temperature (40ºC±2ºC)
-Humidity (75%± 5% relative humidity)
-Light
-Determine shelf-life
-Determine storage conditions
3.Forced degradation studies
-Extreme conditions
-Identify degradation by-products and test them for toxicity
generic:
- the patent life of drug is — after that period other companies may make generic versions of the drug
- generic drugs are — than the branded products but not the same:
- 20
- much cheaper
-Synthetic method is likely different
-Salt form may be different
-Formulation/excipients are different
-contaminants are different
-Not made to the same standard as branded product
read:
Degradation products of API and contaminants from synthesis can be toxic
Zantac (ranitidine) and Angiotensin II Receptor Blockers recalled due to presence of N-Nitrosodimethylamine (NDMA)
Nitroso-STG-19 (NTTP) has been identified in batches of sitagliptin
NDMA and NTTP are nitrosamines and probable carcinogens
Maiden Pharmaceuticals (India) withdraw cough syrups after 60 deaths of children in Gambia (Oct 2022)
Cough syrup from Digital Vision (India) caused 11 deaths in India (2019)
Indonesia bans all cough syrups after 99 deaths (Nov 2022)
Suspected diethylene glycol and ethylene glycol contaminants in cough syrups
The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the — of drug action when administered at the — molar dose under similar conditions in an appropriately designed study” (FDA) , this is the definition of :
- site
- same
- bioequivelence
bioequivalence is usually measured by comparing —- between the products
Cmax ( concentration) and AUC
