Adverse drug reactions Flashcards by Emilia McColm

Define adverse drug reactions (ADRs).

Any undesirable effect of a drug beyond its anticipated
therapeutic effects occurring during clinical use.
– Including physical and mental harm, as well as loss of
function

… response to a medicinal product which is
noxious and unintended.
… may be new and previously unrecognised.

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How many of all adult admissions to hospital are due to ADRs?
How many of these are avoidable?

1-in-16

3-in-4 of these ADRs were avoidable

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Why are ADRs so important?

1 in 16 of all adult hospital admissions, median bed stay is 8 days so 4% of NHS bed capacity and a cost of >£500 million per year.

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How many of all adult admissions to hospital experience an ADR whilst in hospital?
How many of these are avoidable?
Why is this important?

1-in-7
1 in 2
It increases mean bed stay by 0.25 days

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How many of all paediatric admissions to hospital are due to ADRs?
How many of these are avoidable?
Why is this so important?

1-in-30
1-in-4
Projected cost of >£100 million annually

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How many of all paediatric admissions to hospital experience an ADR whilst in hospital?
How many of these caused serious harm?

1-in-6

1-in-100

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Why may ADRs in children be different? (3)

Altered FREQUENCY
– INCREASED frequency of hepatotoxicity to valproate

Altered SEVERITY
– REDUCED susceptibility to hepatotoxicity from paracetamol in infants

UNIQUE to childhood population
– GROWTH SUPPRESSION from corticosteroids

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Give 4 examples of ADRs in children.

Aspirin –> Reye’s syndrome
Systemic chloramphenicol (abx) –> Gray baby syndrome
High dose pancreatic enzyme replacement –> bowel stenosis
SSRIs –> increased suicidal ideation in teenagers

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Explain WHY ADRs may be different in children.

This is to do with changes in metabolic capacity. Using the following enzymes as examples:
CYP3A4 - the % of adult activity increases gradually, and doesn’t reach 100% until 1-10 years.
CYP1A2 - even at 1-10 years, this is only at 40%.
CYP2D6 - 25% at 8-28 days.
UGT2B7 - almost 170% at 1-10 years.

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Describe the A-E classification of ADRs.

Type A (augmented)
Type B (bizarre)
Type C (continuing)
Type D (delayed)
Type E (end-of-use)
(Type F (failure), G (genetic) and I (idiosyncratic))

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Describe the DoTS classification of ADRs.

Dose
Timing
Susceptibility

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What is a type A (augmented) reaction?

Exaggeration of a drugs normal pharmacological
actions when given at usual therapeutic doses.
It is normally dose-dependent and usually identified in clinical trials.

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Most common drugs to cause type A ADRs. (4)

– Anti-platelets
– Diuretics
– NSAIDs
– Anticoagulants

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Explain primary and secondary pharmacology in relation to type A reactions, using the examples of aspirin, bisoprolol and salbutamol.

Primary pharmacology = augmentation of desired actions
Secondary = often different organ systems

Aspirin - bleeding vs gastric irritation
Bisoprolol - bradycardia vs bronchospasm
Salbutamol - bronchodilation vs lactic acidosis

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Pharmacologically Predictable ADRs - what are the 4 types (and give examples)?

Pharmaceutical e.g. phenytoin
Pharmacokinetic e.g. digoxin
Pharmacogenomic e.g. warfarin
Pharmacodynamic e.g. unfractionated heparin

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Phenytoin - describe the toxicity and the mechanism.

Ataxia, nystagmus, etc

Increased bioavailability due to change in formulation

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Digoxin - describe the toxicity and the mechanism.

Visual aura, nausea, arrhythmias, etc

Decreased elimination in renal failure

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Warfarin - describe the toxicity and the mechanism.

Bleeding

CYP2C9 polymorphism

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Unfractionated heparin - describe the toxicity and the mechanism.

Bleeding

Potentiates action of antithrombin III

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64 year old man
PC: Increased DIB over 1 week with ankle swelling
PMH: Stable CAD, CKD stage III and T2DM
DH: Furosemide 20mg, bisopolol 10mg, ramipril
5mg, simvastatin 20mg, clopidogrel 75mg
Recently started new medication for back pain.

Which of the following medications is the likely cause?
Paracetamol, tramadol, codeine, diclofenac or fentanyl

Diclofenac –> heart failure

How do NSAIDs work?

COX inhibitors - prevent prostaglandin production from arachidonic acid

Function of prostaglandins - GI.

Gastric mucosal synthesis

Increase gastric pH

Function of prostaglandins - renal.

Regulate tubular physiology

Increase renal blood flow

Function of prostaglandins - pain.

Mediate inflammation
Peripheral pain receptors
Spinal cord neurones

Function of prostaglandins - CVS.

Platelet aggregation | Vascular homeostasis

78 year old woman with TDS care package PC: Increased confusion over past 4 weeks following a fall PMH: AF, controlled hypertension DH: Lisinopril 10mg, indapamide 1.5mg, warfarin, simvastatin 20mg, bisoprolol 5mg Which of the prescribed medications is the likely cause of the confusion?

Warfarin --> subdural haematoma

33 year old woman PC: Life threatening GI bleed PMH: APS, multiple PE/DVTs DH: Prednisolone 5mg, warfarin Started antimicrobial for cutaneous infection Which of the following medications has precipitated the bleed? Amoxicillin, cefuroxime, flucloxacillin, co-amoxiclav, fluconazole

Fluconazole --> reduced metabolism of warfarin

Describe the pharmacology of warfarin.

Warfarin consists of a racemic mixture of R- and S- form. Both the enantiomers of warfarin undergo CYP-mediated metabolism - CYP1A1, CYP1A2, CYP3A4 for R. CYP2C9 for S. NB. warfarin inhibits the synthesis of vitamin K-dependent clotting factors (2,7,9,10).

CYP2C9 inhibitors, i.e. reduce metabolism of warfarin and so potentiate its effects --> bleeding. Give some examples.

* Amiodarone * Efavirenz * Fluconazole * Fluvastatin * Ketonazole

What is the dosing range of warfarin?

0.5-20mg/day

CYP2C9 inducers, i.e. increase metabolism of warfarin and so reduce its effects. Give some examples.

* Carbemazepine * Phenobarbitol * Phenytoin * Rifampicin

What are type B (bizarre) reactions?

Novel responses that are not expected from known pharmacological response. – Difficult to predict – Often immune-mediated

What are type C (continuing) reactions?

Reactions persist for a relatively long time after discontinuation of the medication. – Dose- and time-dependent – Reaction independent of medication half-life

Give two examples of type C reactions.

Bisphosphonates -> jaw osteonecrosis | Corticosteroids -> osteoporosis

What are type D (delayed) reactions?

Reactions that become apparent some time | after use of a medication.

Give four examples of type D reactions.

Carbimazole -> agranulocytosis Typical antipsychotics -> tarditive dyskinesia Chemotherapy -> infertility Many drugs -> teratogenicity Stilbestrol -> clear cell adenocarcinoma of the genital tract Thalidomide --> phocomelia

What are type E (end-of-use) reactions?

Reactions associated with withdrawal of | medications.

Give three examples of type E reactions.

Benzodiazepines -> agitation/insomnia Corticosteroids -> adrenal insufficiency Opiates -> ‘flu like withdrawal

Why should you inform patients about side effects/discuss medication choices with patients? (3)

Medical law/ethics -> consent Early identification of ADRs Increase tolerance of ADRs

What does the black upside down triangle mean?

This medicinal product is subject to additional monitoring

What should you monitor with gentamycin?

Pharmacokinetics - trough plasma levels

What should you monitor with warfarin?

Pharmacodynamics - INR

What should you monitor with ACE-I?

Objective side effects - renal function

What should you monitor with aspirin?

Subjective side effects - gastritis

How can we prevent ADRs?

``` ASK INFORM MONITOR DIAGNOSE AND TREAT REPORT ```

How do you treat ADRs?

``` Treat Stop drug Supportive care Specific antidotes Document ADR ```

How do you report?

Local reporting – Speak with pharmacists and clinical pharmacologists – Complete an incident form ``` Yellow card scheme to report: – ADRs – Medical device adverse incidents – Defective medicines – Counterfeit medicines or devices ```

What do you report to the yellow card scheme? (4)

– All suspected ADRs for new medicines (▼ symbol) – All suspected ADRs occurring in children, even if a medicine has been used off-label – All serious suspected ADRs for established vaccines and medicines, including unlicensed medicines, herbal remedies, and medicines used off-label - If you are unsure, please report

What is the phase III trials rule of 3?

If an adverse effect in a clinical trial is not seen in n subjects then you can be 95% confident it will occur in <1/(n/3) i.e. if a trial had 1500 patients and rash was not seen, then we are 95% confident that the true ADR rate is <1/500. Conversely, if a true ADR rate is 1/1000, you would need a trial of 3000 subjects to reliably pick it up.