S2: clinical PK and PD Flashcards
What is bioavailability?
Measure of drug absorption where it can be used
Drug administered by IV bolus is said to have 100% bioavailability
Affected by:
-absorption: age, food, vomiting/malabsorption
-first pass metabolism: gut lumen, gut wall, liver
Describe modified release preparation
If elimination is rapid, large fluctuations in [plasma] will be seen
Modified release preparations can help – [plasma] becomes more dependent on rate of absorption vs rate of elimination
Can help with adherence
Outline factors which affect therapeutic agent distribution
Blood flow, capillary structure
Lipophilicity and hydrophilicity
Protein binding
Explain drug-protein binding and distribution
Typically, only free drug will be able to afford response at target receptor site and/or be eliminated
Second drug can displace first drug from binding proteins
More free first drug to elicit a response, can potentially cause harm
What is the equation to calculate Vd?
Vd = dose/[plasma drug]
Compare a smaller and larger Vd
Smaller apparent Vd – suggests drug confined to plasma and ECF
Larger apparent Vd – suggests drug is distributed throughout tissues
Describe cytochrome P450 enzymes
Majority of phase 1 catalysed reactions utilise the P450 system
Oxidation reactions the most important
Found abundantly in the smooth ER in hepatocytes and other tissues
Outline important CYPs
CYP1A – induced by smoking CYP2C – many inhibitors CYP2D – metabolises many drugs CYP2E – alcohol metabolism CYP3A – 50% therapeutics
Describe the importance of CYP450 enzymes in metabolism
Active -> inactive
Inactive -> active
Active -> active
CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase 1 metabolism eg. age, chronic alcohol, smoking
Define drug elimination
Removal of drugs activity from the body metabolism and/or excretion
Fluids – primarily by the kidney, sweat, tears, breast milk
Solids – faeces, hair
Gases – volatile compounds
Define clearance
Volume of blood cleared per unit time
State the equation for half life
Half life = 0.693 * Vd/clearance
Describe the clinical importance of zero order kinetics
Dose change can produce unpredictable change in [plasma]
Half life is not calculable
(most drugs exhibit first order kinetics at therapeutic doses)
Describe the steady state
Steady state [plasma] effectively reached in 4-5 half lives
Therapeutic benefit optimal at steady state
(after termination of drug administration, 4-5 half lives for negligible drug to remain)
Infusion = elimination at steady state
State the equation for maintenance dose
Maintenance dose = (CL * Css)/F * t Cl = clearance Css = [plasma] we want t = dose interval F = bioavailability
Describe loading doses
Rapid onset required or drug with a long half-life
Therapeutic response needed sooner rather than later
Single dose to achieve desired concentration taking into account apparent Vd
State the equation for loading dose
Loading dose = Css * Vd
Describe the importance of dosing schedules
Maintain a dose within the therapeutic range
To be safe
Achieve adherence
Initiating and terminating treatment – titrating up and down (increasing or decreasing dose)
What is the therapeutic index?
A dose that produces toxicity in 50% of the population
AND the dose produces a clinically desired effect
Define potency
A drug that causes the same affect at lower doses is more potent
Describe phase I and phase II metabolism
Phase I - CYP450s
-increase ionic charge
-eliminate directly or go on to phase II
-oxidation & reduction occur during phase I metabolism
Phase II - hepatic enzymes: cytosolic
-further increase ionic charge
-enhances renal elimination
-involves conjugation reactions: sulfation & glucuronidation are the most common
Can a partial agonist have a higher affinity for the same receptor as a full agonist?
YES
Partial agonists can have greater, the same or lower affinity for the same receptor as a full agonist
BUT
Partial agonists will have lower efficacy than a full agonist
