Adverse drug effects Flashcards
Adverse drug reaction
Response to a drug that is noxious and unintended and that occurs at doses normally used. Includes abuse, medication error, during therapeutic use and overdose. Causes 6.5% of all hospital admissions
Most common ADR 1
- Beta blockers: Bradycardia, heart block, hypotension, wheezing if asthma
- Opiates: Constipation, vomiting, confusion, urinary retention
- Digoxin: toxicity (N+V, arrhythmias)
- Prednisolone: GI complications (worsening of diabetes and ulcers), hyperglycaemia, osteoporotic fracture, bruising
Most common ADR 2
- Clopidogrel: GI bleeding
- NSAIDs: GI complications (pain, ulcers), Cerebral haemorrhage, renal impairment, wheezing, rash
- Diuretics: Renal impairment (AKI), hypotension, electrolyte disturbances (hypokalaemia), gout
- Warfarin: bleeding
- ACE /AII inhibitors: Renal impairment, hypotension, electrolyte disturbances (hyperkalaemia)
Classification of ADR’s A-C
- Augmented: dose related, predictable and avoidable i.e. insulin causing hypoglycaemia
- Bizarre: not dose related and not predictable, tend to be rare but serious i.e. anaphylaxis
- Chronic treatment effects: variable occur with prolonged but not short duration treatment i.e. osteoporosis with steroids
Most common ADR D-E
- Delayed effects: variable, occur some time after discontinuation of treatment. Different to chronic as don’t need to be taken for a long time i.e. drug induced fetal abnormalities
- End of treatment: variable effects occurring on withdrawal of a drug i.e. Addisonian crisis after steroid treatment
Drugs causing gynaecomastia and galactorrhoea
Gynaecomastia: Spironolactone, oestrogens, Methyldopa, Digoxin
Galactorrhoea: Antipsychotics, Tricyclics, Metoclopramide, Oestrogens, Methyldopa. Dopamine antagonists increase prolactin causing galactorrhoea
Common side effects: skin and general appearance
Angioedema: aspirin, ACEI
Skin rashes: antibiotics (Penicillin used in glandular fever)
Steven-John: anticonvulsants
Short stature in puberty: steroid use in childhood
Yellow teeth: tetracyclines in childhood
Squamous cell carcinoma: Immunosuppressants for organ transplant
ADR- criteria for diagnosis
- Timing with drug treatment: not or delayed
- Improvement after drug discontinued (dechallenge) or dose reduced. Ans worsening with increased dose (Type A dose related ADRs)
- Associated with high plasma drug concentrations (Type A dose related ADRs)
- Reaction previously recognised as caused by a drug that the patient is exposed to
- Illness that is commonly the result of an adverse drug reaction (e.g. postural hypotension, confusion)
- Exclusion of other causes
ADR- avoiding anaphylaxis
- Take a careful drug history
- Inform other health professionals
- Record allergies: Hospital and GP notes, Drug charts
- Check with patient before administering drugs
- Inject first dose slowly
- Particular care in atopic subjects
Avoiding ADR
- Only prescribe when there is a clear indication
- Use drug with most favourable risk-benefit
- Check with patient for previous ADRs / Allergy
- Careful patient education
- Monitor therapy: therapeutic range and side effects
- Particular care in susceptible patients
Why can new drugs be unsafe
- Lack of experience in special patient groups: Elderly, children, lactating women, pregnancy, multiple disease, polypharmacy
- Unlikely to detect ADR especially rare ones: only exposed to 1500 people
- Exposed for short duration only: cant detect delayed reactions
Objectives of pharmacovigilance
- Identify previously unrecognised hazards
- Evaluate changes in risks and benefits
- Take action to promote safer use
- Provide optimal information to users
Yellow card scheme
- Used to collate information on suspected ADR important for early detection
- Voluntary- done by healthcare professionals, patients can only report side effects
- Particularly focus’s on: serious ADR’s, ADR’s in children, ADR’s in new drugs (black triangle)
- Can be done electronically, on the app and on paper
Actions from the yellow card scheme
- Withdrawal drug if risks exceed benefits (rare)
- Make changes to promote safer use: remove indication, add contraindication, add warning, add drug interaction, add ADR
- Inform users: drug safety update, send letter
Drug interactions
A clinically meaningful alteration in the effect of one drug (object) due to the co-administration of another drug, food or chemical
Results of drug interactions
- No clinically significant effect
- Clinical harm or benefit
- Increased effect: Summative or synergistic
- Decrease effect: Antagonistic
- Tends to only happen where there is a narrow therapeutic index
- Consequences: increased hospital admission and length of stay, reduction in confidence, lasting morbidity and reduction in functional ability
The two mechanisms of drug interactions
- Pharmacodynamics: drugs act on the same target site of clinical effect (receptor or body site). Example: opiates and benzos causing respiratory depression
- Pharmacokinetics: altered drug concentration at target site of clinical effect. Changes in the processes of absorption, distribution, metabolism and excretion. OCP failure with antibiotics
Pharmacodynamic interactions
- Synergism/summative: additive effects.
- Antagonism: opposing effects
Pharmacodynamic example of additive effect
- Beneficial: rifampicin + isoniazid at Mycobacterium TB (antimicrobial)
- Harmful: alcohol + benzodiazepine at GABAa (sedative- CNS depression)
- Harmful: Sildenafil and Isosorbide Mononitrate: markedly increases hypotensive effect of Isosorbide Mononitrate
Pharmacodynamic examples of antagonism effects
- Harmful: salbutamol + atenolol at ß-adrenoceptors (bronchodilation and bronchoconstriction- reduced effect of salbutamol)
- Beneficial: naloxone + morphine at opioid receptor (reverses sedative effects of morphine and may precipitate opiate withdrawal)
Pharmacokinetic interactions
How drug metabolism is effected by: Absorption, Distribution, Metabolism and Excretion
Pharmacokinetics: absorption
- May be affected by causing changes in pH, gastric emptying and direct chemical interactions
- Can effect rate (faster or slower) or extent (less or more complete) of drug absorption
How can changes to the pH of the stomach affect absorption of a drug
- Decreased acidity causes slower absorption as there is more drug ionisation
- Increased acidity causes faster absorption as there is less drug ionisation
- Antacids cause decreased stomach acidity and alcohol increases it
How can changes to gastric emptying affect drug absorption with examples
- Slowed gastric emptying means it takes longer to reach the small intestine, therefore it takes longer to reach peak plasma concentration and this will be lower
- Drugs which slow gastric emptying: opiates, antimuscarinics (atropine), TCA’s (Imipramine)
- Drugs which increase gastric emptying: Metoclopramide, muscarinic agents (bethanechol)
- Delayed gastric emptying: lower peak concentration and a prolonged duration
Drugs: physicochemical interactions
- If there is direct chemical interactions between drugs then you get reduced absorption
- Antacids form insoluble complexes with tetracyclines, quinolones, iron, bisphosphonates: can cause treatment failure
- Cholestyramine binds non-selectively to acidic drugs e.g digoxin & warfarin - can be used to overdose
How does activated charcoal work
- Reduces absorption of toxins in the gut by up to 60%
- Adsorbs toxins to surface of charcoal
- Charcoal binds toxins in bowel so is excreted in faeces
Distribution interactions: plasma proteins
- Drugs that are highly protein bound may be displaced from their plasma protein by another drug, increasing free drug concentration (therefore increasing clinical effects)
- Drugs might be displaced from their receptor site
- Drugs which are highly protein bound: warfarin, phenytoin, tolbutamoid, sulphonamides
- Usually minor and transient due to increase in metabolism and excretion
Significance of valproate and phenytoin
- valproate displaces phenytoin from its plasma protein increasing free Phenytoin
- Valproate also inhibits metabolism of phenytoin causing toxicity
Another example of a drug that displaces another drug from its receptor site
Quinidine displaces digoxin from cardiac receptors, increasing plasma concentration of digoxin which can lead to toxicity. Digoxin toxicity can range from nausea and vomiting to cardiac arrhythmias and death. Quinidine also causes decreased renal excretion of digoxin. Dont use both together
Metabolism interactions
- Mainly due to shared hepatic metabolism through the cytochrome oxidase (CYP450 system)
- CYP 450 Enzyme inducers accelerate metabolism → reduced effect
- CYP 450 Enzyme inhibitors slow metabolism → enhanced effect
CYP 450: induction and inhibition
- CYP450 induction: additional enzymes are synthesised in the liver, which accelerates metabolism causing a reduced clinical effect. Takes a few days to weeks
- CYP-450 inhibition: slow metabolism causes enhanced clinical effect immediately. Existing CYP-450 made less effective
Drugs which are CYP-450 inducers
- phenytoin
- carbamazepine
- chronic alcoholism
- St Johns Wort
- rifampicin
- barbiturates
Drugs which are CYP-450 inhibitors
- Cimetidine
- Erythromycin / Clarithromycin
- Ciprofloxacin
- Sulphonamides
- Isoniazid
- Verapamil
- Metronidazole
- Omeprazole
- Grapefruit juice
- Alcohol (acute)
- Amiodarone
- Antifungals
Examples of induction interactions
- barbiturates (inducer) enhance metabolism of warfarin, causing reduced anticoagulant effect
- phenytoin (inducer) enhances metabolism of COCP, making it less effective
- rifampicin (inducer) enhances metabolism of theophylline, reducing bronchodilation
Give an example of how withdrawing a CYP 450 induce can have clinical effects
- carbamazepine (inducer) enhances warfarin metabolism, reducing the anticoagulant effect
- the warfarin dose is therefore titrated above normal by the clinician to account for this
- if carbamazepine is withdrawn acutely and replaced by another antiepileptic, warfarin clearance will fall and the anticoagulant effect will increase
- this could result in haemorrhage
What drug can St Johns Wort interact with
- warfarin
- COCP
- digoxin
- SSRI (serotonin syndrome)
- carbamazepine
- phenytoin
- theophylline
- ciclosporin (causing transplant failure)
- it is a CYP450 inducer so increases metabolism, therefore reducing the effects of these drugs
What drugs can grapefruit and cranberry juice interact with
- CCBs
- benzodiazpeines
- simvastatin (myopathy)
- they inhibit CYP3A4 so would increase the effects of these drugs
Oral contraception and antibiotics
Oestrogens are conjugated in the liver and excreted in bile into the gut. Bacteria will deconjugate these complexes and release free oestrogens which is recycled back into the liver. Enterohepatic recycling causes increased effect of the OCP. Been concerns that antibiotics which effect liver enzymes (Ampicillin, Doxycycline) could reduce effectiveness of COCP. If taken long term the gut is recolonised by resistant antibacterial.
How can excretion be affected by drug interactions
- Inhibition of active tubular secretion, resulting in increased plasma concentration
- Probenecid inhibits tubular secretion of acidic drugs like penicillin and methotrexate (can cause increased concentration). In methotrexate can be toxic, in Penicillin may prolong effect
- Quinidine and verapamil inhibit tubular secretion of digoxin which increase digoxin levels and toxicity
How do lithium and thiazides interact in the kidneys
- Thiazides cause sodium loss so there is compensatory sodium retention in the proximal tubules
- Proximal tubules cannot distinguish sodium and lithium, so lithium is also retained and accumulates (may cause toxicity)
Co-administration of potassium chloride and spironolactone
- severe hyperkalaemia- can cause cardiac failure and death
- Especially prone in renal impairement
- DCT- excretion of Na+2 and reabsorption of K+
- Spironolactone- monitoring of serum K+
Co-administration of theophylline and ciprofloxacin
- theophylline toxicity: headache, dizziness, hypotension, hallucinations, tachycardia, seizures
- hepatic metabolism of theophylline is inhibited by Ciprofloxacin via CYP450
- Other inhibitors of CYP450: Clarithromycin, erythromycin, fluvoxamine and cimetidine
Co-administration of Methotrexate and Trimethoprim
Folate deficiency as both are dihydrofolate reductase inhibitors. Can cause bone marrow suppression- toxic drug interaction
What can be done to reduce drug interactions
Avoid combination, adjust dose, monitor therapy. Big risk with drugs with narrow therapeutic index
What can Warfarin prescribed with Erythromycin/Metronidazole cause
- Increased warfarin effect
- You should select alternative antibiotics
What can Warfarin prescribed with Aspirin/NSAID do
- Increased bleeding risk
- Action: avoid concomitant use/ PPI cover
What can Carbamazepine prescribed with Erythromycin/Clarithromycine/Fluconazole
- Increased effect of Carbamazepine
- Action: Monitor CBZ levels
What can Lithium prescribed with NSAID/diuretics do
- Increased Lithium levels
- Action: decrease lithium dose by 50%
What can the OCP and Rifampicin/Carbamazepine do
- Effect: pregnancy
- Action: avoid or use higher E2 containing pill >35 ug
What can SSRI’s and st Johns wort, Triptans, MAOI’s do
- Effect: Serotonin syndrome, hypertensive crisis
- Action: avoid and monitor for signs of serotonin syndrome
