Intentional and Unintentional Presentations Flashcards
What are the most common drugs & ADRS causing hospital admission?
- NSAIDs - GI complications, cerebral haemorrhage, renal impairment, wheezing, rash
- Diuretics - renal impairment, hypotension, electrolyte disturbances, gout
- Warfarin - bleed
- ACE/AII inhibitors - renal impairment, hypotension, electrolyte disturbance (hyperkalaemia)
- beta blockers - bradycardia, heart block, hypotension, wheezing
- opiates - constipation, vomiting, confusing, urinary retention
- digoxin - toxicity
- prednisolone - GI complications, hyperglycaemia, osteoporotic fracture, worsening diabetes
- clopidogrel - GI bleeding
What is an ‘augmented’ ADR?
- dose-related and predictable
- avoidable
- example
- insulin causing hypoglycaemia
- warfarin causing bleeding
- nitrates causing headache
What is a ‘bizarre/idiosyncratic’ ADR?
- not dose-related
- not predictable
- examples
- penicillin: anapylaxis
- halothane: hepatitis
- chloramphenicol: agranulocytosis
- phenytoin: toxic epidermal necrolysis
What is a ‘chronic treatment effect’ ADR?
- variable
- occur with prolonged but short duration treatment
- Examples
- osteoporosis with steroids
- steroid induced Cushing’s syndrome
- phenothiazine-induced tardive dyskinesia
- fenfluramine-induced pulmonary hypertension
What is a ‘delayed effect’ ADR?
- variable
- occurs sometime after discontinuation of treatment
- example
- drug-induced foetal abnormalities
- drug-induced cancers (recipients or offspring)
What is an ‘end-of-treatment’ ADR?
- variable
- effects occur on withdrawal of a drug
- examples
- adrenocortical insufficiency after steroid treatment
- drug withdrawal seizures
- withdrawal reactions following paroxetine
What drugs cause gynaecomastia?
- Spironolactone
- Oestrogens
- Methyldopa
- Digoxin
What drugs cause galactorrhoea?
- Antipsychotics
- Tricyclics
- Metoclopramide
- Oestrogens
- Methyldopa
How do you avoid anaphylaxis in patients?
- 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
How do you avoid adverse drug reactions?
- 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
- Appropriate use of drug
- Common and/or important adverse effects (look up in BNF or Summary of Product Characteristics (SPC)
- Monitor therapy
- Particular care in susceptible patients
What are the objectives of pharmacovigilance?
- Identify previously unrecognised hazards
- Evaluate changes in risks and benefits
- Take action to promote safer use
- Provide optimal information to users
What is the yellow card scheme?
- Means by which suspicions that an ADR has occurred may be collated
- Voluntary - relies on co-operation of healthcare professionals.
- Patients can only report side-effects
- Purpose is early identification of previously unrecognised safety hazards
-
All drugs included - focus on:
- Serious ADRs
- Reactions in children
- New drugs (black triangle)
- Around 18,000 reports per year
- Data from the scheme made available publicity on Yellow Card website as drug analysis prints.
- There is an app available
What are the potential regulatory actions once ADRs have been reported?
- Withdraw drug if risks exceed benefits (rare)
- Make changes to promote safer use
- Remove indication
- Add contraindication
- Add warning or precaution (e.g. monitoring)
- Add drug interaction
- Add ADR
- Inform users
- Drug Safety Update
- Dear Dr/Pharmacist letter
What is meant by an ADR that has been caused by pharmacodynamic mechanism?
- Drugs act on the same target site of clinical effect (receptor or body system)
- Opiates and benzodiazepines causing respiratory depression
What is meant by an ADR that has been caused by a pharmacokinetic mechanism?
- Altered drug concentration at target site of clinical effect
- ADME
- OCP failure with antibiotics
What are the two types of pharmacodynamic interactions?
- synergism/summative - additive effects
- rifamicin + isoniazid at Mycobacterium TB (antimicrobial)
- this example is actually beneficial
- alcohol + benzodiazepines at GABAa causing sedation - harmful
- sildenafil and isosorbide mononitrate - increases hypotensive effects
- rifamicin + isoniazid at Mycobacterium TB (antimicrobial)
- antagonism - opposing effects
- salbutamol +atenolol on b-adrenoceptors (bronchodilation and bronchoconstriction)
- naloxone + morphine on opioid receptor (reverses sedative effects of morphine and may precipitate opiate withdrawal
What are the four types of pharmacokinetic drug interactions?
- Absorption
- Distribution
- Metabolism
- Excretion
What is the effect of absorption interactions?
- Rate
- Faster or slower
- Extent
- Less or more complete
- Mechanisms
- pH
- Gastric emptying and intestinal motility
- Physico-chemical interaction
Describe how pH can effect absorption of a drug:
Antacid –> less acidic stomach contents –> more drug ionisation –> slower absorption
Alcohol –> more acidic stomach contents –> less ionisation –> faster absorption
What are some examples of drugs that decrease rate of gastric emptying?
- Opiate analgesics (e.g. morphine, pethidine) – much slower
- Antimuscarinic drugs (e.g. atropine, propantheline) – slower
- Tricyclic anti-depressants – antimuscarinic side-effects (e.g. imipramine) – slower
What are some examples of drugs that increase gastric emptying?
- Metoclopramide
- Muscarinic agents (e.g. bethanechol)
What is the clinical significance of altered gastric emptying?
For a single dose
- Lower peak concentration
- Prolonged duration
However effect on rate and extent of absorption depends on whether drug absorbed in stomach or small bowel.
How does a physiochemical interaction affect pharmacokinetics?
- Direct chemical interaction reduced absorption
- Antacids form insoluble complexes with tetracyclines, quinolones, iron, bisphosphonates
- Will reduce reduction in antibiotic absorption by as much as 60-70% leading to treatment failure
- Cholestyramine binds non-selectively to acidic drugs e.g digoxin & warfarin
- Activated charcoal binds certain drugs
- Reduces absorption of toxins in the gut by up to 60%
- Adsorbs toxins to surface of charcoal
- Charcoal binds toxins in bowel
- Not absorbed by digestive system so toxins excreted in faeces
- Antacids form insoluble complexes with tetracyclines, quinolones, iron, bisphosphonates
How do distribution interactions cause ADRs?
- Displacement from plasma protein binding increase in free drug concentration
- Involves drugs with high protein-binding
- warfarin, tolbutamide, phenytoin, sulphonamides, statins, amiodarone, NSAIDs, heparin, furosemide
- Usually minor and transient due to compensatory increase in metabolism and excretion
- May become even more significant if 2nd mechanism
- valproate displaces phenytoin + inhibits its metabolism
Example of distribtuion interactions: digoxin + quinidine
- Quinidine displaces digoxin from cardiac receptors (reducing their volume of distribution)
- Leads to a marked increase in plasma concentration of digoxin in more than 90% of patients within 24 hours.
- The effects from this interaction range from nausea and vomiting to death – digoxin toxicity.
- Quinidine also decreases renal and non-renal excretion rates of digoxin, which leads to increased steady-state concentrations of the cardiac glycoside
- Patients taking digoxin should avoid the use of quinidine
How can metabolism interactions cause ADRs?
Mainly due to shared hepatic metabolism pathway through the cytochrome oxidase (CYP 450) system
- CYP 450 Enzyme inducers accelerate metabolism reduced effect
- CYP 450 Enzyme inhibitors slow metabolism enhanced effect
What is the effect on P450 when something is said to ‘induce it’?
- Additional P450 in the liver
- General increase in hepatic function
- Liver grows larger and blood flow increases
- Drug metabolising enzymes (increased Cytochrome P450) increased
- Increased clearance of a wide range of drugs, environmental chemicals and endogenous substances
- Takes days or weeks
What is the effect on P450 when something ‘inhibits’ it?
- No reduction in quantity of P450
- Existing P450 made less effective
- Onset immediate
What are common inducers?
- Phenytoin
- Carbamazepine
- Barbiturates
- Rifampicin
- Alcohol (chronic)
- St John’s Wort
What are common inhibitors?
- Cimetidine
- Erythromycin / Clarithromycin
- Ciprofloxacin
- Sulphonamides
- Isoniazid
- Verapamil
- Metronidazole
- Omeprazole
- Grapefruit juice
- Alcohol (acute)
- Amiodarone
- Antifungals
Explain what happens when a patient is taking both carbamazepine and warfarin, and carbamazepine is withdrawn:
- Carbamazepine causes induction of warfarin metabolism - warfarin clearance increased
- Warfarin dose titrated above normal dose by clinician (Blood levels normal)
- Carbamazepine withdrawn acutely and replaced by valproate
- Warfarin clearance falls (blood levels rise above normal)
- Patient may have serious complications
- Haemorrhage
How can excretion interactions cause ADRs?
- inhibition of active tubular secretion
- cause increased drug levels for prolonged time
What is the interaction between lithium and thiazide?
Probable mechanism:
- Thiazides cause diuresis and initial sodium loss
- Compensatory sodium retention in proximal tubules
- Proximal tubules do not distinguish sodium from lithium
- Lithium also retained and accumulates
What is the interaction between KCL + spironolactone?
- combination may result in hyperkalaemia
- serious - can lead to cardiac failure and death
- especially important to remember in renal failure
- mechanism occurs in the kidney at the distal portion of the nephron and leads to excretion of sodium ions while saving the potassium ions
- patients prescribed spironolactone must undergo evaluation of serum potassium
What is the interaction between theophylline and ciprofloxacin?
- Concurrent administration may lead to toxic increases in theophylline.
- (side note - levels of theophylline can be increased in heart failure, hepatic failure and viral infection)
- Hepatic metabolism of theophylline is inhibited by ciprofloxacin via the cytochrome P-450 enzyme system. Theophylline is metabolized by CYP1A2 and to a lesser extent by CYP3A4.
- Ciprofloxacin and other drugs, including clarithromycin, erythromycin, fluvoxamine, and cimetidine, are all potent inhibitors of CYP1A2. Because they have little effect on CYP1A2, levofloxacin or ofloxacin should be considered as an alternative to ciprofloxacin.
- Theophylline toxicity is a serious condition; Signs of theophylline toxicity include headache, dizziness, hypotension, hallucinations, tachycardia, and seizures.
What is the interaction between methotrexate and trimethoprim?
- Methotrexate now widely used for conditions such as rheumatoid arthritis.
- Trimethoprim commonly used for simple UTIs.
- Both drugs are dihydrofolate reductase enzyme inhibitors.
- Danger of folate deficiency, bone marrow suppression-toxic drug interaction.
- Importance of folic acid replacement.
Recite the essential drug interactions to remember:
