Pharmacokinetics and oharmacodynamics Flashcards
Define pharmacokinetics
Study of what the body does to the drug
Define pharmacodynamics
Study of what the drug does to the body
Define pharmacogenetics
The effects of genetic variability on the pharmacokintics or dynamics of a drug on an individual
What are the four main mechanisms involved in pharmacokinetics?
AbsorptionDistributionMetabolismElimination
Define systemic entry
Entry of a substance so that the whole body is affected
What can systemic entry of drugs be affected by?
- GI motility- Splanchnic blood flow (blood flow to visceral organs)- Molecular size- pH levels- Presence of active transport systems
Define first pass metabolism
Any metabolism that occurs before the drug enters the systemic circulation.
Where can first pass metabolism occur?
- Liver and portal venous system2. Within the gut lumen (gastric acid, proteolytic enzymes)3. In the gut wall (P-glycoprotein efflux transports drugs back into the lumen from the intestinal enterocyte)
Define bioavailability
The amount of drug which enters the systemic circulation in an unchanged form, relative to that is administered via IV.
How can you calculate bioavailability?
Amount of drug reaching systemic circulation / total amount of the drug administered
What is bioavailability affected by?
- Intestinal motility- Food (lipid-soluble or water-soluble)- Age- First-pass metabolism. - Vomiting/malabsorption- Drug formulation
Define drug distribution
The ability of a drug to “dissolve” in the body
What are the two main factors that affect the distribution of a drug?
LipophilicityProtein binding
How does lipophilicty affects a drug’s distribution?
The more lipophillic a drug is, the more likely it will mvoe from the blood to tissues with a higher lipid content
Describe where you mainly find lipid-insoluble drugs
Are mainly confined to the plasma and interstitial fluid
Describe where you would mostly find lipid soluble drugs
Are able to reach all the body compartments and will accumulate in fat
How does protein binding affect the distribution of a drug?
A drug must be in an unbound states in order for it to be able to interact with receptors.
Give some proteins that bind drugs and which kind of drugs d they bind to
Albumin - acidic drugsGlobulins - hormonesLipoproteins - basic drugsAcid glycoproteins - basic drugs
Define an object drug
The number of molecules administrated which are lower than the number of binding sites
Define a precipitant drug
The number of molecules administered are higher than the number of binding sites
Give an example of an object drug
Warfarin
Give some examples of precipitant drugs
PhenytoinAspirinSulphonamides
What effects do object and precipitant drugs have on each other?
Precipitant drugs will displace the binding of an object drug.
What can cause changes to protein binding?
- hypoalbuminaemia- pregnancy- renal failure- displacement by other drugs
When can the displacement of other drugs be an issue?
Where there is:- high proteins binding- Low vol of distribution- a narrow therapeutic ratio
What compartments make up the extracellular fluid of the body?
PlasmaInterstitial fluidTranscellular fluidFat
Define the volume of distribution
A measure to see how well a drug distributes throughout the body systems
How do you measure the volume of distribution?
Total amount of drug in the body / concentration of the drug in the plasma
When would you have a high volume of distribution?
When the drug is able to move through a large number of the bod compartments
When would you have a low volume of distribution?
When the drug is confined to one body compartment and cannot travel to others.
Give the Vd of a drug which is confined to the plasma
around 0.1l.kg-1 or less than 5 litres
Give the Vd of a drug which is confined to the extracellular fluid
around 0.4l.kg-1 or less than 15 litres
Give the Vd of a drug which is able to travel throughout the body compartments
greater than 1l.kg-1 or more than 15 litres
What can tissue distribution be affected by?
Lipid solubilityProtein bindingDisease statesRegional blood flowSpecific receptor sites in tissuesDrug interactions
Define drug metabolism
The enzymatic conversion of one chemical entity to another within the body. It is made up of two phases.
Define Phase 1 reactions
Catabolic. Involves producing products which are chemically reactive. Allows for drugs to be conjugated.
Define Phase 2 reactions
Anabolic and involve conjugation. This produces inactive products.
Where do the phase 1 and phase 2 reactions occur?
In the liver
Give some characteristics of phase 1 reactions
Are dependent on cytochrome P450 enzymes and NADPH
What is happening when you calculate a volume of distribution which is greater tan the body weight of the patient?
Tissue binding is occurring- the drug is accumulating in the circulation- usually very lipophillic drugs which are binding to adipose tissue
Give two characteristics of CYP450 and NADPH
Can be induced and inhibited. Often by other drugs of chemicals.
Give some drugs that induce CYP450
PhenytoinCarbamezepineBarbituatesRifampicinAlcohol (chronic)Sulphonureas and St Johns WortPC BRAS
Give some drugs the inhibit CYP450
Grapefruit juiceOmeprazoleDisulframErythromycinValroateIsonazidCimetidine ane CiprofloxacinEthanol (acutely)Sulphonamides
What happens in phase 2 metabolism?
The reactive intermediate is conjugated with a polar molecule to form a water soluble complex by conjugation
What are some common conjugates?
Glucoronic acidSulphonamidesGlutathione
What is needed in order for phase 2 reactions to occur?
Specific enzymes and Uridine Diphosphate Glucuronic Acid (UDPGA)
Why do drugs undergo phase 2 metabolism?
Makes them water soluble and less lipid soluble, so that the drug can be excreted by via the kidneys in the urine.
Give some routes by which drugs can be excreted
KidneyLungBreast milkSweatTearsGenital secretionsBileSaliva
What three components determine the rate of renal excretion of a drug?
GFRPassive tubular resorptionActive tubular secretion
Define Clearance
Is a measure of both hepatic clearance and renal clearance
What causes a decrease in renal clearance?
GFR which has the effect os increasing the half life of the drug
By what mechanism are drugs transported into urine?
There are organic anion and cation transporters which are renal transporters to actively transport drugs from the plasma into the lumen of the nephron
Where do you find organic anion and cation transporters?
In the proximal convoluted tubule and have parallels with CYP450s as they are able to transport a wide range of molecules
What factors affect clearance?
Heart - affects blood flow to main elimination organsRenal Hepatic
Define half life
The amount of time taken for a drug to reach half the concentration which it had been when measured.
What factors affect half life?
HeartRenalHepatic
How can you calculate half life?
(0.693 x Vd) / clearance
Define 1st order kinetics
The rate of elimination if proportional to drug level. A constant fraction is eliminated in unit time and you are able to define a half life.
What kind of curve do you get with 1st order kinetics?
Linear curve- against a logarithmic scale
Define zero order kinetics
The rate of elimination is constant and you cannot define a half life. Drug monitoring is ESSENTIAL
What type of curve do you get with zero order kinetics?
A straight line curve- the half life decreases with decreasing concentration
What differences do you get the elimination kinetics with varying concetrations of that drug?
At therapetic levels - linear kinetics are seen as the CYPs and liver are able to deal with the drug effectively. At higher levels - elimination will become saturated and show zero order kinetics
Give some drugs which show saturated kinetics on overdose
AspirinPhenytoinVerapamilFluoxetine
Which drugs are more likely to result in toxicity?
Zero order drugsDrugs which have:- long half life- narrow therapeutic window- drugs likely to have drug:drug interactions
Define therapeutic window
The concentration within which a drug has a therapeutic effect without giving unacceptable adverse effects
Define steady state concentration
The concentration at which elimination and administration are equal and the drug concentration stays within set values
How long does it take to reach a steady state?
4-5 half lives
What occurs when you want to reach the steady state quickly?
You will give a loading does so that you are able to reach the steady state and therapeutic window quickly.
Define Cmax
The maximum concentration of a drug
