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  • 1 in 15 deaths in Australia are due to medications ARx because people are getting older, more medicines
  • If you're 80 years old you're on 5 medications, 5 diseases, 5 years to live
  • It's because about 50% of people have high BP and cholesterol - everyone's medicated
  • Main culprits:
    • Anti-rheumatics (mainly NSAIDs), anticoagulants, cytotoxics, opioids, corticosteroids, anti-hypertensives


Contents

Case 1 - presentation

  • A 65 yo man weighing 160 kg
    • Long standing complaint of painful knees (arthritis)
    • Is prescribed diclofenac (an NSAID)
    • Presents with (6 main drug interactions)
      • swollen ankles
      • wheezing
      • epigastric pain relieved by food – jaundice
        • COX-2 is a gastric protector
      • microcytic anaemia
      • rash
  • NSAIDs bind to COX
    • Can also bind to MHC protein also

Australian medicines handbook - NSAIDs: adverse effects

  • Gastrointestinal
    • Dyspepsia, gastritis & peptic ulceration
  • Platelet function
    • Reduced platelet aggregation
  • Renal impairment
    • decrease Na+ / water excretion (c.f heart failure)
  • Respiratory
    • aggravate asthma in aspirin sensitive asthmatics (5% of asthmatics)
  • Other:
    • skin rashes, hepatotoxicity

Case 1 – clinical questions?

Do I reduce the dose or stop it?

  • Which of them are likely to resolve if the dose is reduced?
  • Which of them would be likely to resolve if he was changed to ibuprofen (another NSAID)?
  • Which of them would be likely to resolve if he was changed to celecoxib (a COX-2 inhibitor)?
    • swollen ankles
    • wheezing
    • epigastric pain relieved by food
      • same on NSAIDs (COX effect)
      • COX2 is not in the stomach
    • jaundice
    • microcytic anaemia
    • rash

Case 1 - questions

  • Which of these are predictable (based on pharmacology)?
  • What is the pathophysiology of these adverse drug effects?
    • swollen ankles
    • wheezing
    • epigastric pain relieved by food
    • jaundice
    • microcytic anaemia
    • rash

Mechanisms of action

  • Arachidonic acid --COX-->Prostanoids
  • Prostanoids: support renal and platelet function, protect gastroduodenal mucosa, mediate inflammation, pain and fever

Two cyclooxygenase enzymes

  • COX1 is a housekeeping protein
  • COX2 is involved in inflammation
  • COX2 inhibitors turn out to kill people

Gastric protection mechanisms

  • Intravenous NSAIDs will cause problems for gastric mucosa (e.g. NSAIDs inhibit mucosal bloodflow): NOT due to local irritant effects of drug, but it's effects downstream
  • Enteric coating does not prevent ulcer formation

Cyclooxygenase in platelets

  • Causes bleeding
  • So far we're up to wheezing, jaundice and rash.

Mechanism of aspirin induced asthma

  • If you block cyclooxygenase, then AA can only go to LTs, not Prostanoids
    • Therefore you produce more LTs
    • Wheezing with NSAID --> wheezing with any NSAID

Rashes

  • Rashes are: foreign protein that triggers an immune response
  • Drug-induced immune response is not special compared to other rashes
    • Note Steven Johnson rash

Liver toxicity

  • Drugs are mostly too small to trigger immune system
    • Must bind to protein, and be presented as "altered self" as MHC, to trigger your immune system
    • This can occur with almost any drug
    • Rule: ARx: abnormal liver function tests, rashes, nausea and vomiting
      • PAP rule: phenytononin, amiodarone, penicillin; these cause all the side effects

Body getting rid of drugs

  • Designed to prevent you being poisoned by food
  • Body likes to undergo phase 2 conjugation (glucuronide or sulphonate) and urinate out
  • Or they'll activate them so they bind to something
    • If they don't bind to something you want, they may damage some useful part of your cell
    • These are toxic metabolites
  • Any protein can cause hypersensitivity

Diclofenac

  • Quinoneamine is often involved in a lot of drug reactions
    • Binds to useful parts of cells --> cytotoxicity or immune response

Paracetamol toxicity

  • Glucaronidated, and excreted in urine
  • Small amount hits CYP450
  • Normally binds to glutathione; but if you don't, then you have too much reactive metabolite for the glutathione to mop up; treat it with N-acetylcysteine.

Risk factors for drug induced hepatotoxicity

There is a wide genetic diversity amongst people

  • PK polymorphism (azathioprine)
  • PD polymorphism (valproate)
  • Drug interactions (isoniazid)
  • Alcohol - increase CYP2E1, make a toxic byproduct
  • Gender (diclofenac)
  • Age (flucloxacillin)
  • Disease (methotrexate in rheumatoid arthritis)

Adverse drug reaction classification

  • Idiosyncratic or dose-related?
    • A - Augmented (dose-related): occurs in everyone if you give enough
      • Extension of known predictable pharmacological effects
    • B - bizarre (idiosyncratic) - individual dependent

Golden rule

  • All substances are poisons; there is none that is not a poison.
  • The right dose distinguishes a poison and a remedy.”
  • Warfarin is also a rat poison

Dose-response - what is the optimal dose of warfarin to prevent ADRs?

  • We want INR of 2-3. Push to 4 if they have mechanical valve etc.
  • If it's >5 we give vitamin K to reverse it.

S-warfarin clearance

  • Variance in phenotype can mean you need a lot or a little warfarin for the same effect
    • Bizarre reactions WITHIN an augmented reaction

A bizarre ADR due to pharmacogenomic variation

  • Protein C or S deficiency -- warfarin induced skin necrosis
    • A very bizarre reaction. (Rare)

Comparison between Type A & Type B ADRs

  • A = predictable, dose dependent, common, low mortality, adjust dose to treat.
  • B = unpredictable, not dose dependent, uncommon, high mortality, stop the drug (swap to a new agent).

Therapeutic window

  • Warfarin has long half-life, INR doesn't vary much from day to day
  • Other drugs, need to keep concentration between therapeutic and toxic doses
    • E.g. painkillers: don't want to kill the person.

Predicting Drug toxicity: “The Therapeutic index”

  • Relative measure of the safety of a drug
  • Expressed as a ratio of the lethal dose (LD50) or toxic dose (TD50) to the therapeutic or effective dose (ED50)
  • The larger the ratio, the greater the relative safety of the drug

Predicting Drug toxicity: Therapeutic index

  • Anaesthetics have a low therapeutic index

Type A ADRs (Humans are an outbred species)

  • Theophylline clearance varies widely within the population
  • People are not the inbred lab rats the T. index is based on
  • So in humans, the therapeutic window is a dose range in which we have a small proportion of toxicity and a high proportion of therapeutic

Type B reaction mechanisms

  • Allergy
  • Individual variation in pharmacokinetics
    • enzyme polymorphism (perhexilene)
    • renal or hepatic failure (sotalol, chlormethiazole)
    • age (flucloxacillin)
  • Individual variation in pharmacodynamics – receptor polymorphism (TCAs)
    • organ failure (hypothyroidism & digoxin)
  • Drug interactions

Rule of “3’s”

  • If an adverse event occurs on average 1 in x subjects exposed, need to observe 3x subjects to have a >95% chance of observing one such adverse event.
  • Thus- if observe 300 patients in a clinical trial, very good chance of observing adverse event occurring on average in 1% (1 in 100) patients.
  • For 3000 patients, the figure is 1 in 1000.
  • But serious adverse events may occur only 1 in 10,000 exposed (turn up after marketing). Many drugs are withdrawn on the basis of very serious events that occur very rarely.
    • Absence of evidence is not evidence of absence. --> inevitably people prescribe new drugs
  • Sometimes type B reactions are picked up in overdose (find out later on)

Case 1 – clinical questions?

  • Which of them are likely to resolve if the dose is reduced?
  • Which of them would be likely to resolve if he was changed to ibuprofen (another NSAID)?
  • Which of them would be likely to resolve if he was changed to celecoxib (a COX-2 inhibitor)?
  • swollen ankles
    • Probably not - COX2 also renal
  • wheezing
    • Probably
  • epigastric pain relieved by food
    • Probably
  • jaundice
    • Probably
  • microcytic anaemia
    • Probably
  • rash
    • Probably

COX 2 inhibitors (COX 1 sparing)

  • Similar efficacy to NSAIDs
  • Less gastro-intestinal effects
  • Less effect on platelets
    • Increase risk of thrombotic events
  • Less effect on leukotrienes
  • Similar renal effects
    • ?COX 2 in kidney or still some effects on COX 1
  • Other problems
    • drug interactions

Adverse Drug Reaction classification - extended

Things that take a long time to get picked up.

  • Idiosyncratic or dose-related? (or other?)
    • A - Augmented (dose-related)
    • B - Bizarre (idiosyncratic)
    • C – Chronic/statistical
    • D – Delayed/teratogenic
    • E – End of use (withdrawal);
    • F - therapeutic Failure
    • G- Genetic

Chronic (Statistical) ADRs

  • Association is not obvious due to delayed onset &/or high background prevalence
    • Increased risk of myocardial infarction in COX-2 inhibitors
  • Other famous examples (long term associations take a long time to figure out; RCTs needed to show one way or the other; chicken and egg - hard to tell)
    • flecainide and other class I antiarrhythmic drugs & death after MI
    • HRT & breast cancer
    • SSRIs and suicidal behaviour

Cyclooxygenase in Platelets

Coxibs cause infarcts due to clotting

  • Platelets contain COX-1 but not COX-2
  • Thromboxane A2 is predominant COX product
  • Thromboxane A2 promotes platelet aggregation
  • Typical NSAIDs reduce platelet aggregation, resulting in a mild bleeding diathesis

Case 2

  • A 20 year old woman has an uncomplicated appendectomy
    • given IV morphine for post operative pain relief
  • She develops a rash at the infusion site.
  • She also becomes very sleepy and is breathing less frequently
  • She vomits a number of times
  • The vomiting is treated with metoclopramide.
  • She then develops a dystonic reaction (opisthotonus)
  • Which of these adverse effects are less likely to occur if the dose is reduced?
    • Sedation; no, type A
    • Infusion rash; yes, type B (but dose related, not all opiates)
    • Vomiting; no, type A
    • Dystonia; this is an extrapyramidal syndrome (D2 receptor blockade) - this drug can cause Parkinson's; this is type A with the antiemetic
  • Which of them would be likely to resolve if she was changed to pethidine/fentanyl (another opioid drug)?
  • Would the dystonic reaction recur if she was changed to ondansetron or trifluperazine?
    • Trifluperazine is a serotonin antagonist not a dopamine antagonist
    • So the dystonia resolves

Analgesics are dangerous

  • Cause some of the most deaths

Case 3

  • A 45 year old man with heart failure presents with bradycardia, mild confusion and nausea
    • His medications include
    • ACE inhibitor (enalapril)
    • Diuretic (frusemide)
    • Digoxin (increases force of contraction by blocking the ______)
  • His ECG

Are these adverse effects due to digoxin?

  • Nausea
  • Confusion
  • Bradycardia
    • What factors would you use to decide?
      • Timing (before and after)
      • Offset (if we give digoxin binding antibodies)
      • Dose
      • Level

Causality & adverse drug reactions – epidemiologist viewpoint

Hill criteria

  • Consistency
  • Strength
  • Specificity
  • Temporal relationship
  • Biological plausibility



C.f. Clinical Determination: I'm not an epidem person; so this is what I use

  • Previous experience with drug
    • Literature
    • Company data
  • Presence or absence of other factors which might also cause the event
  • Timing of the event
  • Drug levels, evidence of overdosage
  • Result of withdrawal of drug (consistent timing)
  • Result of rechallenge (if really confusing; usually happens by accident)

Adverse drug reactions - conclusions

  • Most ADRs are predictable
    • Due to mechanism of action
    • About half are also preventable (in hindsight!) - read the product information
  • Some are unusual &/or serious
    • require reporting
    • consideration of other drugs that are contraindicated
  • understanding of mechanisms crucial

Questions to ask for suspected ADRs

  • Is this an adverse drug reaction? (can it be confirmed?)
  • Is this an idiosyncratic or dose related side effect? Are other drugs also likely to produce this reaction?
  • Reduce dose or stop drug?
  • Should I report to ADRAC?
    • Actually report to the TGA

What to report to TGA?

  • Surprising
  • Preventable
  • Allergic
  • New drugs w/ problem
  • Interaction
  • Severe
  • Harm



Prevention of ADRs

  • Use fewer drugs
  • Use safer drugs
    • (but absence of evidence  evidence of absence)
  • Use lowest effective dose - titrate (digoxin)
  • Use for shortest effective time
  • Check for vulnerable individuals
  • Note contraindications/precautions
  • Follow prescribing guidelines
  • Take a thorough drug history

A Good Medication History: AVOID Mistakes

  • Allergies?
  • Vitamins and herbs?
  • Old drugs and OTC? ....as well as current
  • Interactions?
  • Dependence? Do you need a contract?
  • Mendel: family History of benefits or problems with any drugs?

Case 4

  • A 35 yo man with mental retardation said to be on no regular medication
  • He has a resting pulse of 100/min,
  • BP is 130/80 L & 100/60 St.
  • He has poor coordination and cog-wheeling rigidity
  • His ECG shows a long QT interval

He's not meant to be on drugs. Someone was giving him antipsychotic drugs.

Questions

  • Could these be adverse drug reactions?
  • Idiosyncratic or dose related?
  • What should be done?
  • Are other drugs also likely to produce these reactions?  Which of these should be notified to ADRAC?

(You cannot exclude the explanation you haven’t considered)

All pathology is due to drugs until proven otherwise