Intro Flashcards
Drug Development
Takes 10-15 years, 3 clinical development stages
Pre Clinical Development
Establish Pharmacological action, Safety in animals
Required before first time in man studies Drug Development
Pharmaceutical and analytical studies
Safety Pharmacology, Toxicology and toxicokinetic studies at least 2 preclinical species
Drug metabolism and distribution
Phase 1 studies Drug Development
Usually healthy volunteers
Confirm pharmacology established from animal studies
n = 20-50 over ~ 1 year
Phase 2 studies Drug Development
Wider use in patient groups Establish potential therapeutic value Determine effective dose range Explore common adverse effects n = 50-300 over ~ 2-5 years
Phase 3 studies Drug Development
Large scale trials in patient groups, Comparisons with placebo Establish clinical benefit Establish common adverse effects n = 500-2000 over 2-4 years
Basis of licensing decisions
Quality
Efficacy
Safety
Drugs with narrow Therapeutic index (often have interaction issues)
Carbamazepine Corticosteroids* Ciclosporin Digoxin Lithium Methotrexate Oral contraceptives* Phenytoin Sulphonylureas Theophylline Warfarin * reduced levels a problem, high levels less likely to be
Digoxin Monitoring
Therapeutic range 1.0-3.8 nmol/l (0.8-2.0 ng/ml)
Steady state after 7 days (t1/2 ~ 36 hours)
Time of sampling at least 6h after previous dose
Immunoassay can cross-react with other drugs e.g spironolactone
Unreliable for 10 days after use of digoxin antibodies (Digibind)
Gentamicin Monitoring
Bactericidal efficacy directly related to peak concentration. Unlikely below 5 mg/l (peak)
Ototoxicity and nephrotoxicity related to total drug exposure.
Concentration above which toxicity more likely: 12 mg/l (peak) & 2mg/L (trough)
Peak level: 1hr after I.M dose or ½ hr after I.V dose
Trough level: just before the next dose
Phenytoin
Plasma concentration closely related to acute rather than long-term adverse effects
Therapeutic range 40-80 mol/l (10-20mg/l)
Steady state in 2 weeks, longer the higher the dose
Little fluctuation in plasma concentration; therefore timing of sampling of little significance
Free phenytoin level sometimes useful e.g. liver/renal disease, drug interactions
Why?
Highly protein bound to albumin may be displaced by other drugs
Total level may be therapeutic, free level toxic
Adverse drug reactions
response to a drug that is noxious and unintended and that occurs at doses normally used for prophylaxis, diagnosis, or treatment of disease or for modification of physiological function
Most common drug and ADRs causing hospital admission
NSAIDs
Diuretics
Warfarin
ACE /AII inhibitors
Beta blockers
Opiates
Digoxin
Prednisolone
Clopidogrel
ADR NSAIDS
(GI complications, Cerebral haemorrhage, renal impairment, wheezing, rash)
ADR Diuretics
Renal impairment, hypotension, electrolyte disturbances, gout
ADR Warfarin
bleeding
ADR ACE Inhibitors
Renal impairment, hypotension, electrolyte disturbances
ADR Beta Blockers
Bradycardia, heart block, hypotension, wheezing
ADR Opiates
Constipation, vomiting, confusion, urinary retention
ADR Digoxin
toxicity
ADR Prednisolone
GI complications, hyperglycaemia, osteoporotic fracture
ADR Clopidogrel
GI bleeding
ADR Clasifications
Augmented Bizarre (Idiosyncratic) Chronic treatment effects Delayed effects End-of-treatment
ADR Augmented
Dose-related and predictable Avoidable
insulin causing hypoglycaemia
warfarin causing bleeding
nitrates causing headaches
