Pharmacology Flashcards
Factors affecting the pharmacokinetics of a drug
Absorption
Distribution
Metabolism
Elimination
AUC - what does this represent in pharmacokinetics
Area under the curve (drug concentration y axis vs time x axis) - represents extent of absorption and bioavailability of a drug
pharmacokinetics vs pharmacodynamics
vs pharmacogenetics
Kinetics - study of the absorption, distribution, and elimination (by metabolism and excretion) of drugs.
Dynamics- study of the effect a drug has on a human body (ie the pain effect of a particular analgesic medication in children)
Genetics - genetic factors and their influence on drug metabolism and development of drug receptors (ie CYP450)
Factors affecting drug absorption
pH
gastric emptying
Both influenced by level of maturation of organ systems (absorption of diff drugs will be different in neonates vs children vs teens)
List factors in neonates that affect the absorption of medications compared with older children
Delayed gastric emptying and intestinal motility
Higher stomach pH
Reduced bile acid synthesis
Neonatal skin absorption
Thinner stratum corneum -> incr absorption of topical preparations
Increased skin perfusion -> incr absorption
Define bioavailability
How to calculate the bioavailability of a drug?
IV vs oral bioavailability
How much of the drug is absorbed and reaches the systemic circulation (ie 100mg is taken orally but only 60mg is absorbed and reaches systemic circulation so bioavailability is 0.6)
- Dependent on absorption and first pass metabolism
Calculates fraction (F) of administered drug dose that reaches systemic circulation in unchanged form
F = AUC (oral) / AUC (IV)
Bioavailability of IV drugs should be 100% vs oral drugs lower (incomplete absorption, undergoes first pass metabolism in gut, liver or excreted in bile)
Volume of distribution - definition
Volume that would accomodate all the drugs in the body if the concentration was the same as in plasma
Alterations can change half life of drugs because larger volumes require longer to be eliminated
Distribution - factors affecting this in neonates/younger children
- Pre-school children have LARGER volume of distribution (incr total body water content) for water soluble drugs compared with adults (sometimes require HIGHER dose of drug/loading dose). Lipophilic drugs have larger volume of distribution in infants (~12mo) due to increased fat
- Younger children have reduced protein binding c/w adults -> excess free unbound [drug] -> A/E/toxicity at lower [drug] and also results in higher Vd c/w adults
- Immature BBB so greater distribution of drugs to CNS
Metabolism - describe the phases
Mostly occurs in Liver
Also occurs to much lesser degree in lungs, kidneys and walls of GIT
- Phase I - oxidative mainly (also reduction or hydrolysis), driven by CYP450. enzymes low at birth but levels increase w age.
- Phase II - conjugation (glucuronidation, sulphation, methylation, acetylation, glutathionylation) -> excretion by kidneys
NOTE - some drugs undergo phase II then I, or just phase II OR phase I
Metabolism in neonates vs odler children
Liver enzymes generally low at birth, increase w age
Lower body temp can impair enzyme activity
What is first pass metabolism?
A phenomenon in which a drug gets metabolized at a specific location (usually LIVER) in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation. This effect can become augmented by various factors such as plasma protein concentrations, enzymatic activity, and gastrointestinal motility.
Note that IV medications are injected directly into systemic circulation so are not subject to the ‘first pass’ effect - 100% reaches systemic circulation. This will be reduced when the drug is administered orally, resulting in higher oral dose requirements.
What enzyme is responsible for caffeine metabolism?
CYP1A2
Note- reduced levels of this enzyme in neonates so limited metabolism, requires only once daily dosing in this age group
Erythromycin - effect on cyp450
CYP450 inhibitor
thus affects clearance of other drugs also metabolised by CYP450 but doesn’t affect their bioavailability
Factors affecting renal elimination
GFR
Tubular secretion
Tubular reabsorption
Also
- GA
- Postnatal age
- Weight
Note- kidney function is immature at birth -> eGFR increases with age
-> require dose reduction in younger children
Clearance and Rate of elimination formulas
First vs zero order kinetics
Clearance of drug = Cl renal + Cl hepatic + CL lung + CL other
= Rate of elimination / [medication in the plasma] = mg/L
FIRST ORDER KINETICS (majority of drugs)
So rate of elimination is directly proportional to the amt of drug in the body. Thus there is an exponential DECREASE in the amt of drug in the body over time.
ZERO ORDER KINETICS
- Rate of elimination is CONSTANT regardless of [drug]
ex: phenytoin, warfarin, aspirin - Straight diagonal line decrease on graph (y axis [drug] vs x axis time)
Features of short vs long half life
Short
Quick acting but wear off fast
Need to give more frequently
Long
- longer onset of action
- but effects persist for longer
- dosed less frequently
How many half lives to achieve steady state concentration?
5x
what parameter is most important in determining steady-state?
Half-life of a drug (5x half lifes to reach steady state)
Steady state concentration
Drug in = drug out (rate of absorption = rate of clearance)
Relative GC activity/potency of the following steroids:
Pred Methylpred Cortisol Dexamethasone Fludrocortisone
What is the physiological steroid dose?
D-MP(F)H (potent -> weak)
1,5,6,10,25
Dexametasone = 1mg Methylpred = 5mg Pred = 6mg (Fludrocortisone = 10) Hydrocortisone = 25mg
Physiological steroid = hydrocortisone 10mg/kg/m^2/day
Factors affecting distribution of a drug
- Blood flow to an area
- Capillary permeability
- Degree of plasma protein binding (only unbound molecules are free to diffuse to tissues whereas bound drug has to stay in plasma)
- Apparent Volume of distribution = dose administered/plasma concentration
What is phase II metabolism?
Conjugation mostly by liver
(glucuronidation, sulphation, methylation, acetylation, glutathionylation) -> excretion by kidneys
Apparent Volume of distribution = formula?
What does a high vs low Vd indicate?
Vd = dose administered/plasma concentration
(high Vd >16 = distributed amongst ECF
vs low Vd <3 = distributed only in plasma)