L1 Pharmacokinetics And Pharmacodynamics Flashcards
Pharmacokinetic factors
Bioavailability Half - life Drug elimination Inter subject variability Drug - drug interactions
Human factors affecting pharmacokinetics
Renal function - clearance Stress Pyrex is Alcohol - CYPs Smoking - CYPs Age Sex Exercise Diet Pregnancy and lactation - tetrogenic Liver function - Albumin
Bioavailability (F)
Measure of drug absorption where it can be used i.e. concentration of drug after it has been metabolised
IV bioavailability
100% i.e. 1
Bypasses the liver and transferred directly to the plasma concentration
Other routes bioavailability
Fraction of IV bioavailability
Factors affect bioavailability
Age - luminal changes Sex Food - chelation and gastric emptying Vomiting and malabsorption e.g. Crohn’s Absorption Formulation Liver function - first pass metabolism
Modified release preparations
Drugs can be modified to be absorbed slower
Therefore take less pills per day
Increases adherence
Factors affecting volume of distribution
Blood flow
Capillary structure i.e vasoconstriction
Lipophilicity - higher Vd
Protein binding - difficult to distribute to other compartments therefore decrease Vd
Protein binding
Albumin - acidic drugs
Globulins - hormones
Lipoproteins - basic drugs
Glycoproteins - basic drugs
Free drug
Only free drug that isn’t bound to proteins can elicit a response and be eliminated
Class II precipitate drugs
Displace class I object drug from protein binding sites as the class II drug has a higher affinity Therefore more Class I drug is free to elicit an effect
Factors that cause more free drug
Pregnancy - increased blood volume
Renal failure - less clearance
Hypoalbuminaemia - less protein to bind to drug therefore more is free
Volume of distribution
= dose (mg)/ plasma drug concentration at t=0 (mg/L)
Vd and plasma concentration
Vd is inversely proportional to plasma drug concentration
When there is a high plasma drug concentration the Vd is lower as less has been distributed
Phase 1 metabolism - first pass
- oxidation
- dealkylation
- reduction
- hydrolysis
- converts drug into lipophilic metabolites
- by cytochrome P450 - liver enzymes
Phase II metabolisation
- add covalent bonds to change size by conjugating enzymes
- glucuronide
- sulphate
- glutathione
- N-acetyl
- can be excreted by the kidney via urine or by the liver in bile
CYP3A4 inhibition
Grapefruit and citrus juice
- less metabolism of lovastatin so increased concentration in blood plasma
CYP 2D6 epigentics, metabolism and inhibition
Absent in 7% of Caucasians
Hyperactive in 30% of East Asians
Metabolises:
- Beta blockers
- SSRI
- opioids
Inhibited by:
- some SSRIs
- other anti arrhythmic drugs
- other antidepressants
St Johns Wort and carbamazapine
Induces CYPs
- increased oestrogen and progesterone break down so COCP less effective
- carbamazepine induces CYPs for increased carbamazepine metabolism
Renal clearance factors
- GFR and protein binding
- competition for transporters
- lipid solubility
- pH
- flow rate
- other drug interactions e.g. gentamicin is nephrotoxic
What is regally cleared
Low molecular weight polar molecules
What is cleared hepatically
High molecular weight metabolites conjugated with glucuronic acid
Zero order clearance
Rate of elimination is constant regardless of concentration
- dangerous as overdose can reach max tolerated dose quicker
First order clearance
Rate of elimination increases proportionally to the concentration given
Half life
Time taken to reduce the concentration by half
- Independent of concentration
Clearance ml/min
Volume of blood cleared per unit time
Elimination rate (UV)/ plasma drug concentration
Clearance, half life and Vd
High Vd - more distributed means it takes longer for the drug to be cleared
Therefore longer half life
Half life calculation
(0.693 (constant) x Vd )/ CL
Which drugs exhibit zero order kinetics
High dose
Alcohol
Salicylic acid
Phenytoin
Drug monitoring
Zero order kinetics
Long half life
Narrow therapeutic window
Drug - drug interactions
Steady state concentration
Reached in 5 half life’s
Where the therapeutic benefit is optimal
At steady state the infusion = elimination
Rate of administration
(Dose x bioavailability)/ dose interval (how often given per day)
Stead state concentration equation
(Maintenance dose x bioavailability) / (dose interval x clearance)
Loading dose
CSS x Vd
Why is adrenaline often do-administered
Acts on alpha 1 receptors for vasoconstriction, reducing the blood flow and rate of absorption
- keeps the anaesthetic in the desired area
How to increase rate of steady state concentration
Increase the rate of infusion by:
- increasing dose
- increase bioavailability
- decrease dose interval
