ADR

Question 1

What’s the other name for TYPE A adverse drug reactions?

Answer 1

Type A = augumented

Question 2

What’s the other name for Type B ADR?

Answer 2

Type B = bizzaire/ idiosyncratic

Question 3

What’s type A reactions?

Answer 3

Type A (augmented)

• reactions that are predictable from the known pharmacology
• often represent an exaggeration of pharmacological effect of the drug

Question 4

What are Type B reactions?

Answer 4

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

Question 5

Phases in drug development

Answer 5

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)

Question 6

When the drug company can apply for the license for the drug?

Answer 6

Once the drug got through phase 1, 2 and 3

Question 7

Where can this be usually detected in drug development process:

Type A reactions

Type B reactions

Answer 7

Types A -> usually during phases 1 - 3

Type B -> usually during phase 4 *

* only with large exposure, when drug is on the market

Question 8

What’s ‘role of 3’ in pre-marketing detection of the ADR?

Answer 8

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)

Question 9

Are the long term effects detected in phase III pre-marketing testing?

Answer 9

Not, as it is short-lasting

Question 10

What phase III for?

Answer 10

Phase III is for efficacy

Question 11

How to recognise ADR?

Answer 11

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?)

Question 12

What’s the yellow card?

Answer 12

To report suspected ADR -> MHRA* collects the data and assess the safety of the drug

MHRA = Medicine and Healthcare products Regulatory Agency

Question 13

What is ADR with Warfarin?

• MoA
• antidote

Answer 13

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

Question 14

What factors will determine the dosage of Warfarin )?

Answer 14

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

Question 15

Direct Oral Anticoagulant

• elimination depends on what organ?

Answer 15

DOAC

• excreted by the kidney

Therefore in kidney impairment -> need to reduce the dose due to risk of bleeding

Question 16

What is MoA of DOCS?

Answer 16

• DOACs (Apibaxan and ‘…baxans’) -> Xa inhibitor
• Dabigatran IIa (antithrombin)

Question 17

What type of ADR Toxic Epidermal Necrolysis is?

Answer 17

TEN is type B ADR reaction

Question 18

Toxic Epidermal Necrolysis

• what happens?

Answer 18

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

Question 19

Clinical features (+ sign) of TEN

Answer 19

Features

• systemically unwell e.g. pyrexia, tachycardic
• positive Nikolsky’s sign: the epidermis separates with mild lateral pressure

Question 20

Examples of drugs that are known to cause Toxic Epidermal Necrolysis

Answer 20

Drugs known to induce TEN

• phenytoin
• sulphonamides
• allopurinol
• penicillins
• carbamazepine
• NSAIDs

Question 21

Management of TEN

Answer 21

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

Question 22

The difference between SJS and TEN

Answer 22

SJS - 10% of the body is blistered

TEN - 30% or more blistered

Question 23

What is pathophysiology of TEN/SJS

Answer 23

Drug is recognised by the body as a foreign -> immune system response against them -> cytokines produced and skin attacked by T cells -> blisters

Question 24

What are Immune Check Inhibitors?

Answer 24

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

Question 25

What are examples of ADR associated with ***Immune Checkpoint Inhibitors***?

Answer 25

* thyroiditis * pituitary failure * adrenal insufficiency * lung inflammation * skin inflammation

Question 26

What are **drug - drug** interactions?

Answer 26

***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

Question 27

What are Pharmaceutical interactions?

Answer 27

***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

Question 28

What are Pharmacokinetic dinteractionsions?

Answer 28

***Pharmacokinetic*** = what a body does to a drug ADME: administration, distribution, metabolism and excretion

Question 29

What are types of pharmacodynamic drug interactions?

Answer 29

**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

Question 30

Example of pharmacokinetic interaction (absorption)

Answer 30

_**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

Question 31

Example of pharmacokinetic reaction (**metabolism**)

Answer 31

***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

Question 32

Examples of enzyme **INDUCERS**

Answer 32

Question 33

What ADR may ***St John's Wort*** cause?

Answer 33

***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

Question 34

What effects can **_grapefruit juice_** have on the drugs?

Answer 34

**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

Question 35

Examples of drugs that may interact with **grapefruit juice**

Answer 35

* 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***

Question 36

Examples of ADR associated with excretion (3)

Answer 36

**- 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

Question 37

Interaction of ***Lithium*** and ***Bendrofluazide***

Answer 37

***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)

Question 38

What type of ADR is the interaction between ***Spironolactone*** and ***ACE inhibitor***?

Answer 38

***Spironolactone*** and ***ACE Inhibitor*** * **pahrmacodynamic/ synergistic** type of reaction -\> both lead to K+ retention -\> **hyperkalaemia**

Question 39

What type of reaction is co-prescription of: **NSAIDs** and **anti-hypertensives**

Answer 39

***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