adverse effects of drugs

Question 1

main causes of adverse effects:

Answer 1

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

Question 2

unwanted vs desirable effects of opiates and anti histamines ( H1 antagonist )

Answer 2

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

Question 3

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:

Answer 3

1. predictable includes :
   - excess pharmacological action
   - class of drugs
   - alternative pharmacological action includes:
   - aspirin –> bleedings vs anti inflammatory action
   - anti histamines for multiple receptors
2. non predictable:
   - seen only a specific member of a class
   - due to action of drug as ACE inhibitor ( cough)
3. overdose toxixty
4. idiosyncratic
5. hepatic , renal , neuro

Question 4

history of ADE:

Answer 4

1. 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   Withdrawn in 1961 due to teratogenic effects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
2. 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

Question 5

sources of adverse drug effect (ADE) :

Answer 5

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

Question 6

• 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

Answer 6

• toxicity
• toxixty
• toxification

Question 7

paracetamol requires replenishing — which is not — active while N-acetylcysteine is —- active and converted to —

Answer 7

• glutathione GSH
• orally
• orally
  -GSH

Question 8

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

Answer 8

• additional
• class
• phase iii
• one
• iv
• dosage changes

Question 9

drugs interactions:

Answer 9

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)

Question 10

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:

Answer 10

1. sytheies as:
   -May be batch specific
   -May be due to some conditions changing during manufacture
   -These may cause ADE especially cancer
2. storage as: heat light humidity

Question 11

degradation studies :

Answer 11

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

Question 12

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:

Answer 12

• 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

Question 13

read:

Answer 13

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

Question 14

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 :

Answer 14

• site
• same
• bioequivelence

Question 15

bioequivalence is usually measured by comparing —- between the products

Answer 15

Cmax ( concentration) and AUC

Question 16

bioequivelence is defined as – of test within — and — reference

Answer 16

• CI
• 0.8
  -1.25

Question 17

true or false:
generic drugs only need to show bioequeivelence with approved product in a small number od healthy volunteers

Answer 17

true

Question 18

problems w bioequievelence:

Answer 18

-Drug A: Brand product (AUC: 1)
-Drug B: Generic product (AUC: 0.8) bioequivalent
-Drug C: Generic product (AUC: 1.25) bioequivalent
-Thus 10 mg tablet
A=10 mg API
C=12.5 mg API
B= 8 mg API
-Patient optimised on Drug C and switched to B
37% reduction in dose of API
-Is that acceptable for this drug?

Question 19

Indian generic pharmaceutical company
Major supplier of generic medicines
Multiple violations of regulations with product recalls
In 2013 pleaded guilty to felony charges for selling adulterated drugs and fined $500 million
In 2014 banned by FDA from selling APIs to US
is —–

Answer 19

ranbaxy

Question 20

who is recruited into PII studies :

Answer 20

1.Drug companies design PIII studies to be successful
2.Choose patients most likely to respond
Clearly defined diagnosis
Often early stage of disease
No other diseases
No other medications
Over 18 years of age (under 70 sometimes)
3.Often does not reflect the real-world patient
4. following groups may require specific investigation:
Children
Women
Pregnant women
Elderly
Ethnic groups
Patients with other diseases
Patients on other medications

Question 21

co- morbidity:
1. — is the primary source of drug metabolism
2. patients w liver disease have — metabolic capacity
3. may —- clearance requiring dose adjustment
4. —- is the primary organ for excretion
5. kidney disease reduces — on drugs and metabolites
6. may require —-

Answer 21

liver
- reduce
- reduce
- kidney
- excretion
- dose adjustment

Question 22

the response to drug ( therapeutic and toxic ) shows —- which can be based on —-

Answer 22

• genetic variability
• race based

Question 23

as a result of the genetic variability racial groups may require — of dose or may be at greater risk of an —-

Answer 23

• adjusetment
• adverse effect

Question 24

genetic polymorphism play an important tole in —-

Answer 24

• pharmadynamic
• pharmakinetics
• toxicity

Question 25

-often polymorphism is — or — to determine
- genetic polymorphism is often associated with —
- — can be surrogate biomarker for genetic polymorphism
- there’s often a huge amount of — within the race as race is a self declared no diagnostic criteria and is multi ethnic
- the use of race indicates increased —- and is not —-
- —- is optimum but race can be a surrogate w some drugs

Answer 25

• unknown or impractical
• ethenicity
• race
• variability
• probability and not absolute
• genetic screen

Question 26

true or false:
- most drugs are used on a ‘’ one-dose-fits-all’’ basis
- the use of medicine and dosage is tailored for a specific patient rather than the population as whole which is known as —-

Answer 26

• true
• known as: personalised medicine

Question 27

is precision medicine the future ??

Answer 27

-It decreases the market size so price must increase. Who will pay?
-Allows drugs that failed at a population level to be revived for use in sensitive population
-Often responders/non-responders are identified from sub-group analysis of PIII data
-Is it scientifically valid?
-Is it an a priori analysis?
-Be careful!!

Question 28

a large phase iii study may involve up to — patient on drug
identifies adverse effect w incidence of —
adverse effect w <0,1 incidence are – to confirm
phase iii studies may suggest existence of – frequency events but — to confirm their incident

Answer 28

• 10,000
  -0.1%
• too rare
• low frequency
• impossible

Question 29

phase iv studies allow more – to be collected on a drug
1. increases —-
2. better — of low incidence adverse effects
3. generates — with using drugs especially 1st generation
- however , its still very hard to get an —– of incidence of rare adverse effects

Answer 29

• data
• patient population
• estimate
• comfort
• accurate indication

Question 30

pharmacoviligance:
- patient undergoing treatment provide a large — on adverse effects
- patient report adverse effect to doctor
- doctor report either to company or national authority
- company/national authority report to European authority

Answer 30

• large source

Question 31

ADE reporting:
1. spontaneous reporting:
2- prescription event monitoring:

Answer 31

1-
-Doctors who suspect an adverse reaction file a report
-Yellow card was first system introduced in UK (1964)
-IN US FDA have MedWatch system
-They are voluntary systems
-Work for the life of a drug
2-
-This can be utilised where there is a central agency for medicines
-In UK most drugs are on the NHS
NHS collects data on all presriptions issued
-A questionnaire is sent to doctors on adverse effects
-Provides data on true incidence of adverse events

Question 32

doctor related factors errors

Answer 32

-Lack of therapeutic training
-Inadequate drug knowledge and experience
-Inadequate knowledge of the patient
-Inadequate perception of risk
-Overworked or fatigued health care professionals
-Physical and emotional health issues
-Poor communication between health care professional and with patients

Question 33

SUMMARY OF PRODUCT CHARACTERISTICS (SmPC)

Answer 33

SmPC is the source of all information regarding use of drug and adverse effects
Use this to identify dosing, adverse effects and other warnings
SmPC structure
Section 1: Product details
Section 2: Therapeutic Indication(s)
Section 3: Benefits
Section 4: Risks
Section 5: Administration and dosage
Section 6: Other important information
Special Populations

Question 34

RMP vs REMS

Answer 34

Similar but different strategies
EMA Risk management plan (RMP) uses summary of product characteristics (SmPC) to communicate precautions with drugs
FDA risk evaluation and mitigation strategy (REMS) uses specific company communication plans
Black box warning