Pharmacodynamics 2 (DONE) Flashcards
Methods of classifying a response to a drug
Clinical- subjective vs objective
Surrogate endpoint
Biomarker
Types of response to a drug
Stimulation e.g. adrenaline stimulates heart
Depression e.g. quinidine depresses heart
Irritant e.g. counterirritants increase blood flow to site of injury
Replacement e.g. insulin in diabetes
Cytotoxicity e.g. antibiotics, chemotherapeutics
Why monitor concentration not dose?
Concentration (exposure) in body gives rise to effect
Concentration drives effect
Generally proportionality between dose and concentration
Why aren’t plasma concentrations routinely monitored?
Limited PK variability Wide safety margin of a drug Cost Tolerance Multiple active species Time delays Single dose therapy Duration vs intensity
What are multiple active species? Give example
Conversion of parent to active metabolite
Alprenolol is more active when given orally cf. IV
How does single dose therapy work? Give examples
Drug returns out of balance physiologic system to normal
Feedback control systems then maintain homeostasis
Correlation between effect and peak exposure may exist
e.g. asthma- salbutamol, headache- paracetamol, fungal infections- fluconazole
Duration vs Intensity
Methotrexate- odd relationship between response and dose/concentration
Inhibits dihydrofolate reductase, OK to shut down short term, weekly dosing vs daily
Corticosteroids- acute vs chronic dosing, cushingoid state
What is tolerance?
Effectiveness of a drug diminishes with continual use- reduced pharmacological response, the degree of tolerance varies
Morphine- days of repeated dosing
Ethanol- develops slowly
Acute tolerance- tachyphylaxis
A rapid decrease in the response to a drug due to previous exposure to that drug
Rate of change of drug is as important as absolute concentration e.g. nifedipine
Therapeutic implications of tolerance
Development of tolerance to desired therapeutic response- adjust dosage regimen e.g. nitroglycerin
Tolerance to harmful effects of drug e.g. protriptyline has long half life but do not use loading dose due to harmful CNS effects
Time-effects on PD relationship example
Digoxin- distribution between blood and cardiac tissue is slow, amount of digoxin is still rising in the heart while it is being eliminated from the blood
Describe rate of distribution into tissue
Tissue distribution takes time
Occurs at various rates and to various extents
Several factors determine distribution pattern- delivery of drug to tissue by blood, ability to cross tissue membranes, binding within blood and tissues, partitioning into fat
Hard to control anaesthesia for obese patients as fat tissue absorbs drug very slowly, will need higher dose and will stay asleep for longer
Blood flow (perfusion) vs permeability
Perfusion-rate limitation: membranes offer no resistance, drug in equilibrium with interstitial fluid and tissue, blood and tissue viewed as one compartment
Permeability-rate limitation: tissue cell membranes offer resistance, movement into tissue slow and insensitive to perfusion, blood and tissue viewed as separate compartments
At both capillary and cell membranes: special case e.g. BBB, tissue cell membranes and capillary membrane offer resistance
Time effects on PD relationship- oral
In contrast to IV bolus dose plasma drug concentration first rises then falls after single oral dose
May lead to hysteresis in the concentration-response relationship
Looking for hysteresis is a technique PK use to assess if there is discordance between concentration-time and effect-time
Alternative reasons for delayed measured response
Response primarily dependent on active metabolite
Response controlled by events occurring subsequent to drug reaching site of action
