ADR Flashcards
What’s the other name for TYPE A adverse drug reactions?
Type A = augumented
What’s the other name for Type B ADR?
Type B = bizzaire/ idiosyncratic
What’s type A reactions?
Type A (augmented)
- reactions that are predictable from the known pharmacology
- often represent an exaggeration of pharmacological effect of the drug
What are Type B reactions?
Types B (idiosyncratic/ bizarre)
- unpredictable from the knowledge of the basic pharmacology of the drug
- show no dose-response relationship
May be : chemical, biochemical, immunological -> these complex processes influence the reaction
Phases in drug development
Phase I - healthy volunteers ->to understand bioavailability of the drug
Phase II - inpatient -> to identify dose, kinetics and dynamics of the drug
Phase III - patients -> 1st efficacy and safety studies (how effective under ideal condition) with exclusion and inclusion criteria (comparison to placebo)
When the drug company can apply for the license for the drug?
Once the drug got through phase 1, 2 and 3
Where can this be usually detected in drug development process:
Type A reactions
Type B reactions
Types A -> usually during phases 1 - 3
Type B -> usually during phase 4 *
* only with large exposure, when drug is on the market
What’s ‘role of 3’ in pre-marketing detection of the ADR?
Role of 3 in ADR
- if 30 exposed persons -> 1 in 10 show ADR
- if 300 exposed -> 1 in 100 will show ADR
- 3000 espossed -> 1 in 1000 show ADR
- 30 000 -> 1 in 10 000 show ADR
* Not all ADR will show up in the early phases of clinical trials (some rare reactions detected only with large exposure - when clinically available)
Are the long term effects detected in phase III pre-marketing testing?
Not, as it is short-lasting
What phase III for?
Phase III is for efficacy
How to recognise ADR?
When a patient develops new symptoms
T -> temporal relationship -> does the effect occur after the drug has started? (most ADR occur in first 3 months after the drug started)
R - re-challenge -> if you give same drug, same dose again -> pt will develop symptom again (done in mild ADR only)
E - exclusion of other causes -> to check if the symptom is not due to other cause
N - novelty -> check if someone else had same drug reaction; but maybe you will be first to identify the ADR
D - de-challenge -> dose reduction/ withdrawal (would reduction of drug improve the effect?)
What’s the yellow card?
To report suspected ADR -> MHRA* collects the data and assess the safety of the drug
MHRA = Medicine and Healthcare products Regulatory Agency
What is ADR with Warfarin?
- MoA
- antidote
Warfarin -> May cause hematoma
*higher the dose = higher risk of bleeding
- MoA: warfarin prevents vit K -> vitamin K- dependant clotting factors (2, 7, 9 and 10) are decreased
- antidote: vitamin K
What factors will determine the dosage of Warfarin )?
Warfarin doses
- elderly -> lower doses -> this is because the liver get smaller with age
- weight increase -> higher doses
- gender
- age
- other meds
- nutritional status
- genetics
*to determine the dose -> we check INR
Direct Oral Anticoagulant
- elimination depends on what organ?
DOAC
- excreted by the kidney
Therefore in kidney impairment -> need to reduce the dose due to risk of bleeding
What is MoA of DOCS?
- DOACs (Apibaxan and ‘…baxans’) -> Xa inhibitor
- Dabigatran IIa (antithrombin)
What type of ADR Toxic Epidermal Necrolysis is?
TEN is type B ADR reaction
Toxic Epidermal Necrolysis
- what happens?
Toxic epidermal necrolysis (TEN)
- potentially life-threatening skin disorder
- most commonly seen secondary to a drug reaction
- the skin develops a scalded appearance over an extensive area
- TEN is severe end of a spectrum of skin disorders which includes erythema multiform and Stevens-Johnson syndrome
Clinical features (+ sign) of TEN
Features
- systemically unwell e.g. pyrexia, tachycardic
- positive Nikolsky’s sign: the epidermis separates with mild lateral pressure
Examples of drugs that are known to cause Toxic Epidermal Necrolysis
Drugs known to induce TEN
- phenytoin
- sulphonamides
- allopurinol
- penicillins
- carbamazepine
- NSAIDs
Management of TEN
Management of *TEN*
- stop precipitating factor (drug)
- supportive care, often in intensive care unit
- intravenous immunoglobulin has been shown to be effective and is now commonly used first-line
- other treatment options include: immunosuppressive agents (ciclosporin and cyclophosphamide), plasmapheresis
The difference between SJS and TEN
SJS - 10% of the body is blistered
TEN - 30% or more blistered
What is pathophysiology of TEN/SJS
Drug is recognised by the body as a foreign -> immune system response against them -> cytokines produced and skin attacked by T cells -> blisters
What are Immune Check Inhibitors?
Immune Check Inhibitors
- Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) -> T cells to kill tumor cells (
- Immunotherapy uses the body’s immune system to fight cancer
Summary: these drugs allow the body’s immune system to attack the cancer
What are examples of ADR associated with Immune Checkpoint Inhibitors?
- thyroiditis
- pituitary failure
- adrenal insufficiency
- lung inflammation
- skin inflammation
What are drug - drug interactions?
Drug-drug interactions
- the alteration of the effect of one drug by co-administration of another
*these are common but only some of clinical importance
What are Pharmaceutical interactions?
Pharmaceutical interactions
- outside of the body
- two different drugs are mixed together (e.g. IV bag) -> these drugs interact chemically -> crystalise each other out -> as a result patient does not get a drug
What are Pharmacokinetic dinteractionsions?
Pharmacokinetic = what a body does to a drug
ADME: administration, distribution, metabolism and excretion
What are types of pharmacodynamic drug interactions?
Pharmacodynamic drug interactions
What the drug does to the body
Types:
A. Synergistic -> positive effect (combining two drugs leads to larger effect than expected)
B. Antagonistic -> one drug inhibit action of the other
Example of pharmacokinetic interaction (absorption)
Absorption affected
- Microbiota in the gut is affected by antibiotic
- If microbiota is dysregulated -> drugs may be affected
eg. oral contraceptives may not be as effective while taking antibiotics -> as microbiota dysregulated -> absorption of drug affected -> less effective oral contraception
Example of pharmacokinetic reaction (metabolism)
Metabolism
Enzymes induction and inhibition
Drugs are metabolised by liver enzymes
- Enzyme induction interaction -> enzyme is increased -> more metabolite
Effect: reduced effect of other (metabolised drugs)
- Enzyme inhibition -> enzyme is decreased -> less metabolism -> accumulation of other drugs
Examples of enzyme INDUCERS
What ADR may St John’s Wort cause?
St John’s Wort -> it is an enzyme inducer -> more metabolism -> some drug effects is reduced (e,g, reduced immunosuppressants, steroids)
*ST John’s Wort -> herbal medication; anti-depressant and anti-viral properties
What effects can grapefruit juice have on the drugs?
Grapefruit juice* contains substances (furanocoumarins) -> act as ‘suicide ‘of enzymes in the gut wall
Less enzymes -> less metabolism -> potential for drug overdose
*generally adviced to avoid citrous fruits
Examples of drugs that may interact with grapefruit juice
- statin e.g. simvastatin and atorvastatin
- high blood pressure treatment -> nifedipine
- organ-transplant rejection drugs -> cyclosporines
- anti-anxiety drugs -> buspirone
- corticosteroids -> Crohn’s disease or ulcerative colitis -> budesonides
- Antiarrhythmics -> amiodarone
- antihistamines -> fexofenadine
Examples of ADR associated with excretion (3)
- digoxin
- lithium
- methotrexate
*narrow therapeutic index -> monitoring required
- If other drugs given may lead to reduction in excretion of the above drugs -> OD)
Drugs are given with the drugs above: amiodarone, verapamil, quinidine NSAIDs, diuretics
Interaction of Lithium and Bendrofluazide
Lithium is similar in terms of the structure to Na+
As diuretic will increase Na+ excretion -> Lithium will be retained instead
(as body tried to conserve Na+ -> conserve Lithium as similar structure)
What type of ADR is the interaction between Spironolactone and ACE inhibitor?
Spironolactone and ACE Inhibitor
- pahrmacodynamic/ synergistic type of reaction -> both lead to K+ retention -> hyperkalaemia
What type of reaction is co-prescription of: NSAIDs and anti-hypertensives
NSAIDs and anti-hypertensives
- antagonistic reaction -> reduced efficacy or toxicity
- NSAIDs affect intrarenal prostaglandin levels (less dilation) while anti-hypertensives will usually dilate renal arteries
