Lecture 16: Adverse Drug Reactions

Question 1

WHO definition of ADR adverse drug reactions

Answer 1

a response to a drug which is noxious and unintended, wand which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for the modifications of physiological function

Question 2

ADR from anti-hypertensive medications

Answer 2

antihypertensive B blocker, prescribed at normal dose, causing hypotension = adverse reaction.

• noxious and unintended
• now requires fluids or medicines to elevate BP

Question 3

American Society of health-system pharmacists definition

Answer 3

Any unexpected, unintended, undesired or excessive response to a medicine that:
(change way now use the medicine)
- requires discontinuing the medicine
- requires changing the medication therapy
- requires modifying the dose, except for minor dosage adjustments
(extra treatment)
- necessitates admission to hospital
- prolongs stay in healthcare facility
- necessitates supportive treatment
(negative outcome)
- significantly complicates diagnosis
- negatively affects prognosis
- results in temporary or permanent harm, disability or death

Question 4

How do “medication errors” relate to ADRS

Answer 4

** diagram
Medication errors: mishaps due to prescribing, transcribing, dispensing, administering, adherence or monitoring of a drug.
- more common than adverse drug events
- harm less than 1%

Question 5

Adverse drug event

Answer 5

an injury resulting from the use of a drug, includes:
- harm caused by the drug (ADR + overdoses)
- harm from use of the drug (dose reductions and discontinuation of drug therapy)
ADR can occur from medication errors (25%), but the remaining 75% occurs due to reasons other than medication mistakes. (e.g. due to having a hypotensive response to a medication due to individuality)

Question 6

Allergy

Answer 6

ADR mediated by an immune response

e. g. rash , hives
- penicillin

Question 7

Side effect

Answer 7

an expected and known effect of a drug, that isnt intended in the therapeutic outcome

i. e. ADR
e. g. due to having too of a medicine

Question 8

ADR range of severities

Answer 8

Most ADRs are Mild (no treatment change required)
- e.g. ACE inhibitor accumulation of bradykinans causing a cough. Just reassure patient, may have to reduce dose
Some are moderate (requires a change in treatment or additional treatment)
Rare to have Severe ADRs (hospital admission required for disabling, life threatening ADRs. congenital abnormality)

Question 9

Classification of ADRS

Answer 9

Type A - augmented pharmacological effect
Type B - bizarre
Type C - chronic effects
Type D - delayed effect
Type E - end of treatment
Type F - failure of treatment

Question 10

Type A ADR classification

Answer 10

extension of pharmacological effect
often predictable and dose dependant
responsible for at least 2/3 of ADRs
e.g. anticholinergic effects with tricyclic antidepressants
Note: not always predictable. e.g. spirolactone induce gynocomastia (breast enlargement) = different from therapeutic effect
vs. Beta blocker whose adverse reaction is same as therapeutic effect

Question 11

Type B ADR classification

Answer 11

Idiosyncratic or immunologic (drug allergy)
Rare and unpredictable
Dose dependant
e.g. penicillin rash
e.g. malignant hyperpyrexia in anaethesia
Note: often learn about due to knowing someone else experienced this

Question 12

Type C ADR classification

Answer 12

Chronic effects
associated with longterm use
accumulation of dose/damage
e.g. analgesic neuropathy: long term NSAIDs causing damage to kidneys after years of use –> predictable

Question 13

Type D ADR classification

Answer 13

Delayed effects
carcinogenicity
teratogenity

Question 14

Type E ADR classification

Answer 14

End of treatment

e. g. Seizures after stopping phenytoin (abruptly stopping anti-seizure/epilepsy medication)
- analgesic (rebound pain)
- addiction to opioids
- abruptly stopping SSRIs antidepressants

Question 15

Type F ADR classification

Answer 15

Failure of treatment

e.g. inadequate dosage of oral contraceptive (esp. when used with a specific enzyme inducer)

Question 16

Intermediate Drug allergies

Answer 16

Intermediate drug allergies occurs within 1 hour

Type 1: anaphylaxis: mediated by IgE and mast cells and/or basophils

Question 17

Delayed Drug allergies

Answer 17

Delayed drug allergies occur after 1 hour (most after 6 hours, and typically after days)

a) Type II (cytotoxic): Days. IgG and IgM antibody and complement mediated cell destruction (immune ssytem attacks RBC causing anaemia (low Hb))
b) Type III (immune complex): 3-4 wks. IgG:drug immune complexes and complement activation
c) Type IV (cell mediated): Week. T-cell mediated e.g. contact dermatitis

Question 18

Why are there multiple types of delayed drug allergies?

Answer 18

body contains different mediators and antibodies in its immune system
delayed allergies occur after the medicine has primed the immune system
Note: present in ways that arent always immediately obvious that the cause was due to medication
e.g. Type IV contact dermatitis, and Type II anaemia due to autoimmune RBC destruction

Question 19

Why do ADRs matter

Answer 19

1. Death and serious harm (common in US)
2. Hospital admission/prolonged stay (new people to hospital + due to medications being prescribed to people already in hospital and hence are more susceptible)
3. Cost (extra time and extra treatment)
   NOTE: 35-46% of ADRS are preventable (1/3-1/2)

Question 20

Which drugs are common causes of ADRs

Answer 20

anticoagulants
opioids
insulin (e.g. severe adverse reaction in elderly)

Question 21

Which patients are at higher risk of ADRs

Answer 21

1. Younger children + older adults (need to tailor children’s doses to their age, weight or BMI)
   - Older patients tend to have more comorbidiites, diminished physiological reserve, and more frequent use of multiple drugs
2. Individuals with multiple co-morbidities (particularly renal or hepatic impairment if drugs are metabolised and eliminated by these organs)
   - how well you clear these medicines
   - severity of adverse reaction
   (e. g. dizzy grandma vs child, is more likely to fall and hit head)
3. Polypharmacy (on multiple medications)
4. Women (lower BMI, smaller organ size, increase body fat, different gastric motility, lower GFR)
5. Race and Genetic polymorphisms (inherited factors that affect the pharmacokinetics of drugs –> predispose an individuals risk of ADRs. Ionised in poor metabolisers. e.g. cytochrome enzymes)

Question 22

What are 2x strategies to prevent ADRs

Answer 22

1. doctor based strategies

2. systems based strategies

Question 23

Doctor based strategies to prevent ADRs

Answer 23

Avoid and be vigilant of High risk drugs (use careful on at-risk patient)
Discontinue unnecessary drugs
Consider drugs as a cause of any new symptom
Avoid treating side effects with another drug
Avoid drug-drug interactions e.g. 2x antihypertensive medications causing hypotension (consider amount of medications in body and their likelihood of adverse reactions)
Adjust dosing based on age and creatinine clearance

Question 24

System based strategies to prevent ADRs

Answer 24

1. Computerise order entry
2. Electronic medication administration record
3. Bar coding
4. Smart pumps
5. Pharmacist intervention
6. Medication reconciliation (improves accuracy of list and inform clinician of patient’s allergies)
   Additionally:
7. Education programs (modest effects)
8. Accurate allergy list (stored in one place)

Question 25

Facilitation due to Computerised physician order entry

Answer 25

- provides a means of standardisation of practice - improving the completeness and legibility of orders - alert clinicians to drug-drug interactions and cumulative dose limits - updating clinicians with the most current medication information - providing dosage adjustment calculations based on patient characteristics - timely communications of critical changes in a patient's condition, in turn facilitating appropriate adjustments

Question 26

Medication reconciliation

Answer 26

Used as a system based strategy to reduce ADRs Medication reconciliation is a process that identifies medication discrepancies, informs prescribing decitions,a nd prevents .... of patients Step 1: Verification (review patients medication history. develop accurate medication list) Step 2: Clarification (ensure appropriate medications and doses. Use current list when writing medication orders) Step 3: Reconciliation (identify discrepancies b/w orders meds and listed medications. Make appropriate changes, document, and communicate update list, to provider within/outside the hospital)

Question 27

How do you find out about ADRs?

Answer 27

1. Medsafe 2. NZ formulary - gives common important side effects - helpful to show and talk to patient

Question 28

Where does knowledge for ADRs come from?

Answer 28

1. Drug development and clinical studies - phase 1-4 (small studies therefore didn't discover all ADRs) - case reports, series and case-control studies 2. Surveillance - post marketing surveillance (pharmacovigilance) + phase 4 studies - prescription event monitoring

Question 29

Post marketing surveillance as a source of ADRs

Answer 29

Pharmacovigilance is a process of identifying, reporting and responding to risk-benefit issues arising with marketed medicines

Question 30

ADR in relation to drug development

Answer 30

Phase 1 Tolerability: note dose at which ADR occurs Phase 3 Safety: learn adverse effects in target population (common ADRs in therapeutic dose range) Phase 4 Post marketing: confirm common adverse effects + learn uncommon adverse effects (v. rare. includes elderly and woman and reproduction people)

Question 31

Providing patient written information re ADRs

Answer 31

patient information section of medsafe | - lists important side effects and when to talk to doctors

Question 32

Critic re Medsafe and NZ formulary

Answer 32

``` too many ADRs were listed (median 50 per drug) number of ADRs vary b/w sources Substantial overlap b/w commonly experiences symptoms and frequently listed ADRs Recommendations: - emphasis of data from RCTs - provision of Absolute Risk estimates - discussion of the Nocebo phenomenon - positive framing of information ```

Question 33

Consequences of having a substantial overlap b/w commonly experienced symptoms and frequently listed ADRs

Answer 33

patient has a sense of likelihood that these side effects are due to their medicine and not due to common life = NOSEBO (expectation of having adverse reaction to medicine causes an adverse reaction to the medicine which isnt actually due to the medicine)

Question 34

How can you identify an ADR?

Answer 34

Always consider that the drug may be associated with a worsening patient condition or new medical problem - investigate whether the drug is the known cause of the reaction - rule out alternative explanations - establish a temporal link b/w onset of reaction and drug administration - if unsure: use a probability assessment tool e.g Naranjo probability scale

Question 35

What do you do if you identify an ADR?

Answer 35

1. withdraw the trigger medicine 2. record the suspected ADR in the chart 3. inform the patient, caregiver and family doctor 4. complete a CARM adverse drug reactions form

Question 36

Strategies for avoiding ADRs

Answer 36

Dont give drugs unless absolutely indicated Use familiar drugs (look out for adverse reactions in new medications) Prescribe as few drugs as possible, and give clear instructions - try give one new med at a time, therefore know cause if have a ADR See if patient is taking other medication (herbal, OTC and supplements) Before prescribing, ask if patient has had previous reactions to medication) Know that age, renal and hepatic diseases can alter drug metabolism, therefore give smaller doses Warn patient of common side effect and potential ADRs