Pharmacokinetics Flashcards
What is Pharmacokinetics?
This is what the body does to the drug
The processes which determine the changes in concentration of a drug in the body over time
The knowledge of the fate of a drug, its disposition (drug disposition)
What is pharmacodynamics?
This is what the drug does to the body
What is the pneumonic that describes the disposition of a drug?
ADME
What does ADME stand for?
Absorption- drugs enters the blood plasma following administration
Distribution- drug distributed throughout body tissues and fluids
Metabolism- tissue enzymes convert the drug to different form (hepatic metabolism)
Excretion- removal of the drug from the body (renal excretion)
What is the meaning of absorption? (pharmacologically)
Drug absorption is the movement of drug molecules across biological membranes
The gastrointestinal tract is a biological membrane for oral drugs. The GI tract is a barrier to what kind of drugs?
Barrier to more water soluble drugs
The GI tract is a biological membrane for oral drugs. The GI tract is permeable to what kind of drugs?
Lipid- soluble drugs
What are the 4 ways by which small molecules are able to cross cell membranes?
Diffusion (through lipid membrane)
Membrane transporter
Aquaporins (pores formed by aquaporin proteins)
Pincocytosis (cells engulf molecules into special membrane bound vesicles)
What factors related to drugs affect absorption
- lipid (can it cross membrane) or water solubility(will it dissolve)
- particle size- smaller?
- degree of ionisation- unionised form can cross bilayer much easier
- physical form- suspension is easier than a coated tablet
- chemical stability- broken down by gastric acid, enzymes, bacteria
- drug concentration- higher concentration, better diffusion
What factors related to the body can affect absorption?
- area of absorption (intestines with villi are better than stomach)
- vascularity (more blood vessels to carry the drug)
- Effect of pH- ion trapping, pH of environment (most drugs are weak acids?)
- Gut motility (diarrhoea will result in poor absorption)
- Diseases- integrity of absorptive surface
- pre-systemic (first pass metabolism)
Where does first pass metabolism (pre-systemic metabolism) occur?
Gut wall and liver
Many drugs are weak acids or weak bases and this they exist in equilibrium of what forms ?
Ionised and unionised forms
What is pH?
how many free H+ ions are available in a solution
What is pKa?
Dissociation constant
how a molecule (drug) will react in a solution at a specific pH at which the acid/base exists as ionised (50%) and unionised (50%) form in equal amount (equilibrium)
Give an example of a drug that is a weak acid
Aspirin
How will aspirin behave in the stomach?
It is able to cross the membrane into the plasma
This is because the stomach is acidic therefore there will be more of the unionised form of the drug (HA).
How will aspirin behave once it has entered the blood plasma
More of the active ionised form (A-) is formed due to the fact that the plasma is more neutral and hence will encourage formation of H+ ions
How will aspirin behave in the urine?
Urine has a more basic pH (8). This will encourage formation of H+ ions and therefore also the ionised (A-) active form.
The ionised form is not able to cross the lipid membrane to the plasma and hence it is trapped in the urine and excreted
Give an example of a drug that is a weak base
Pethidine
How will a drug such as Pethidine behave in the stomach?
Pethidine is trapped in the stomach and does not reach the plasma. This is because the stomach is an acidic environment hence the reaction will shift to making the ionised form which cannot cross the lipid membrane
How does Pethidine behave in the urine?
Urine has a pH of 8. This will encourage the formation of H+ ions and thus the formation of the unionised (B) form which is able to cross the lipid membrane. Pethidine as such is not excreted in the urine as it can be absorbed back into the plasma
What is bioavailability (F)?
The proportion of the drug does that reached the systemic circulation.
Unless drugs are administered ___________, most drugs are absorbed incompletely.
Intravenously
An F value of 0% indicates that …
none of the drug dose have entered the systemic circulation
An F value of 100% indicated that…
All of the drug dose has been absorbed into systemic circulation
What is the bioavailability value of intravenously administered drugs?
100%
What is the bioavailability of drugs administered intramuscularly?
75 to =<100
What is the bioavailability of drugs administered subcutaneously?
75 to =<100
What is the bioavailability of drugs administered rectally?
30 to <100
What is the bioavailability of drugs administered orally?
5 to <100
What is the bioavailability of drugs that are inhaled?
5 to <100
What is the bioavailability of drugs that are administered transdermally?
80 to <= 100
What is the drug nicarpidine used to treat?
High blood pressure
A calcium channel blocker
What is the effect of grapefruit on orally administered Nicardipine?
It increases the bioavailability of nicardipine.
It inhibits the action of CYP450 enzymes
This reduces pre-systemic clearance that drugs administered orally have to undergo
How is bioavailability (F) calculated?
F= AUCoral/AUCiv X Div/Doral
AUC- area under the curve
D- dose
Where is the main site of metabolism for orally administered drugs?
Liver
What other site metabolises orally administered drugs?
Intestinal wall
What is first pass metabolism?
This is when drugs pass from GI tract to the liver via the hepatic portal vein before entering main circulation
Following metabolism, drugs are prepared for ________
elimination
Briefly describe the bioavailability of orally administered drugs
Reduced drug bioavailability
What is a prodrug?
This is a pharmacologically inactive compound that is converted into a pharmacologically active compound after metabolism.
What is the active compound of Enalapril and what is it used to treat?
Enalaprilat
Hypertension
The prodrug of aciclovir is _______
Valaciclovir
Antiviral drug
What is the active compound for the aspirin prodrug and what is its use?
Salicylic acid
Pain relief
Describe, briefly, the absorptive quality of prodrugs
Prodrugs have good absorption
The concentration (amount) of a drug can be calculated by…
Mass(bioavailability)/volume (plasma volume)
Systemic circulation refers to …
Blood plasma
How do drug molecules exist?
Bound or free form
In what form are drugs able to move through body fluid compartments?
Free drug
What does the volume of distribution take into consideration?
Other body compartments outside of the blood plasma
What is the equation for drug concentration when taking into account other body compartments?
C=M(mass/bioavailability)/Vd (volume of distribution- body compartments)
What is the definition of the volume of distribution?
It is the apparent volume the drug is dissolved in
Calculate the volume of distribution for a patient who was given 10mg IV bolus
Blood= 5L
Plasma= blood- cells= 2.5L
C= 10mg/2.5L= 4mg/L
Calculate the volume of distribution after an hour of administering 10mg IV bolus to a patient
At time 0= 4mg/L ( calculated in another Q card)
After an hour
10mg/(2.5L+7.5L)= 1mg/L
What happens to the volume of distribution for a drug that cannot cross the vascular endothelium?
Volume of distribution decreases and the concentration of the drug in the plasma increase
What happens to the volume of distribution for a drug that can cross the vascular endothelium easily?
An apparent large volume of distribution
Volume of distribution increases
Concentration in plasma decreases
Suggest some reasons as to why a drug might be confined to the plasma
Drug too large to cross vascular endothelium
Drug strongly bound to plasma proteins
Suggest some reasons as to why a drug might be confined to the extracellular space
Polar drugs cannot enter the cells
Large macromolecules which access cell membrane receptors
What kinds of drugs are difficult to remove during overdose?
Drugs restricted to total body water (readily crosses cell membranes inside and outside cells)
Drugs that extensively dissolve in far or bound to a proteing
What does the phrase “apparent volume of distribution mean”?
this refers to the fact that all of the body equilibrated with the drug do not have equal concentrations
It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration
List some reasons why the volume of distribution would not necessarily correspond to any physical compartment
- binding to tissues
- binding to plasma proteins
- partitioning into fat
- adsorption onto bone
- blood flow
Na+ K+ ATPase enzyme is essential for all cells. What tissues contain large quantities of the enzyme?
Muscle
Nervous Tissue
Kidneys
What is the MOA of digoxin, a medication used to treat heart failure.
It inhibits the Na+/K+ ATPase enzyme.
This increases intracellular Na+ and therefore causes an influx of Ca2+ ions in the heart
This leads to increased contractility
The amount of a drug that is bound to a protein is dependent on what 3 factors?
- concentration of the free drug
- its affinity for the protein binding sites
- the concentration of the protein
Albumin mainly binds to what kinds of drugs?
Weak acids such as warfarin
Weak bases such as Lignocaine bind to what plasma protein?
alpha 1/2 acidic glycoproteins
The unbound form of a drug is described to be …
Pharmacologically active
As a first approximation, the binding reaction can be regarded as a _____________ of the drug molecules with a finite population of binding sites.
simple association
What fraction of a drug undergoes metabolism in the liver and other tissues?
the unbound fraction
The fraction of unbound drug can be altered by a number of variables such as… (list them)
- concentration of drug in the body
- the amount and quality of plasma protein
- other drugs that bind to the plasma protein
When drugs accumulate in certain tissues, these tissues act as _____ of extra drug. What do these tissues do?
reservoirs
They slowly release the drug into the bloodstream
Briefly describe the fat:water partition coefficient of most drugs
Relatively low
What is the lipid: water coefficient of morphine? What is the consequence of this?
0.4
Sequestration into tissues is very little
What is the lipid: water coefficient of thiopental, an ultrashort acting depressant on the CNS?
10
There is a _______ correlation between blood flow in tissue and distribution of drugs
Positive
What effect does low blood supply have on the accumulation of drugs in fat and bone
Low blood supply will limit accumulation of the drug in fat and bone
What is the effect of high blood supply on drugs?
This increases metabolism and clearance in liver and kidneys
What is the effect of enzymatic activity on the pharmacological activity of many drugs?
Pharmacological activity is reduced or abolished by enzyme activity
What is the main site of drug metabolism?
Liver hepatocytes- smooth endoplasmic reticulum
Drugs administered ______ and _______ enter the liver to undergo “first pass metabolism” before reaching systemic circulation.
Orally
Rectally
(enter GI tract and travel to liver via portal vein)
Why do we metabolise drugs?
this is to decrease lipid solubility of the drug (increase water solubility) and therefore increase renal elimination of drug in the urine
What does the smooth endoplasmic reticulum of the hepatocytes contain that is relevant to pharmacokinetics?
They contain the cytochrome P450 enzyme superfamily
How many different CYPs have been found in humans?
more than 50
What is the function of CYP enzymes?
metabolise foreign substances (xenobiotics- including drugs)
What are the 2 sets of chemical reactions utilised by CYP enzymes for metabolism to occur?
- Phase I metabolism- CYP450 enzymes
- Phase II metabolism- conjugation reactions
Phase I reactions are often catabolic (breaks down). Give examples of phase I reactions.
Oxidation
Reduction
Hydrolysis
How do phase I reactions make use of CYP450 enzymes?
These enzymes are oxidases and they are used to unmask or introduce polar groups (-OH’s/-Os) on the drug
What is the overall effect of phase I metabolism on drugs?
Decrease lipid solubility and therefore increase renal elimination (due to making them more polar)
In phase I reactions, reactive groups (functionalisation) are introduced for _________
Conjugation
What is an isoenzyme?
an enzyme that differs in amino acid sequence but catalyses the same chemical reaction
Elucidate the nomenclature of CYP 3A4
3- family
A- subfamily
4- isoenzyme
What is the most common P450 isoenzyme?
accounts for 50% of isoenzyme
CYP3A4
What is the second most common P450 enzyme?
CYP2D6
accounts for 20% of P450 isoenzymes
Polymorphisms of CYP2D6 lead to either ______ or _______ metabolism
fast
slow
CYP1A2 metabolises which drugs?
Caffeine
paracetamol (NAPQI)
tacrine
theophylline
CYP2B6 metabolises which drugs?
cyclophosphamide
methadone
CYP2C8 metabolises which drugs?
paclitaxel
repaglinide
CYP2C19 metabolises which drugs?
omeprazole
phenytoin
CYP2C9 is used to metabolise which drugs?
warfarin
ibuprofen
tolbutamide
CYP2D6 is used to metabolise which drugs?
codeine
debrisoquine
S- metoprolol
CYP2E1 metabolises…
alcohol
paracetamol
CYP3A4, 5, 7 metabolise which drugs
Nifedipine (calcium channel blocker)
simvastatin
ciclosporin (immunosuppresant)
Indinavir
An example of a substrate (drug) for CYP3A4 enzyme is …
Midazolam (sedative)
Give an example of an inhibitor of CYP3A4
fluconazole (anti-fungal)
Carbamazepine (anti-convulsant) acts as an ________ of CYP3A4 enzyme
Inducer
What is the effect of an inhibitor of a CYP450 enzyme?
decreases metabolism of the target drug (increase in t1/2-half-life); increases the plasma drug concentration
This increases the effect of the drug as well as drug toxicity
What is the meaning of t1/2 (half-life)?
the amount of time required to reduce drug level to half of its initial value (plasma concentration)
What is the effect of an inducer on CYP450 enzymes?
Increases synthesis or decreases degradation of CYP450 enzymes
Increases metabolism of the drug (reduces its half-life)
There is a decrease in plasma concentration of the drug
The effect of the drug is decreased
Inducer activity is ______ whilst inhibitor activity is _________. How long does inducer activity take?
Slow
Rapid
inducer activity takes 1-2 weeks
Drugs such as suzamethonium are metabolised by …
Plasma cholinesterases
Salbutamol is metabolised by enzymes in the ______ system
GI
Short acting B-adrenoceptor (SABA)
Ethanol is metabolised by which enzymes? Where are these enzymes located
Alcohol dehydrogenase
these are often cytoplasmic enzymes
Prostanoids in the lungs have a role in the metabolism of drugs. True or false
True
Give examples of other oxidases (outside of CYPs) that can metabolise drugs
Noradrenaline
Tyramine
5-HT- monoamine oxidases
Phase II reactions are _______
Anabolic (build up)
What is the function of phase II reactions
use enzymes (transferases) to attach small endogenous polar molecules to the drug
this makes them more likely to undergo renal elimination in the urine
Phase II reactions are also known as …
Conjugation reactions
Where do conjugation reactions take place
Mainly liver
other tissues such as lungs and kidneys are involved
Give examples of chemical groups inserted in conjugation reactions
glucuronyl
sulfate
methyl
acetyl
What is the most common enzyme that catalyses the conjugation (phase 2) reactions?
UDP-glucoronosyltransferase
What is the function of UDP-glucoronosyltransferase
Glucoronic acid binds making the drugs very water soluble (hydrophilic)
Briefly describe how phase I and phase II metabolism work in tandem
during phase I, CYP isoenzyme (oxidase) introduces or unmasks a polar group
A larger molecule can attach to polar group such as -OH or -O; for instance, UDP-glucoronosyltransferase can add glucuronyl group making it very polar.
The water soluble drug is now more easily filtered and excreted through kidneys.
Drugs undergoing extensive first- pass metabolism exhibit pronounced inter-individual variability in drug disposition. List some reasons for this.
- genetic variation- polymorphism in enzymes- CYP2D6 fast and slow metabolisers of codeine
- induction and inhibition of drug metabolising enzymes
- food can increase hepatic flow, increasing bioavailability of drug (propanolol)
- drugs can increase or decrease hepatic flow, increase of decrease bioavailability of drugs (hydralazine increases propanolol)
- liver disease increases bioavailability of drug (morphine)
- Age
Describe the CYP450 activity in the elderly and in newborns
Elderly- livers capacity for CYP450 metabolism is reduced >30%, higher levels of drug and prolonged half-life can lead to increased toxicity
Newborns- have partially developed CYP450 enzyme systems and hence can also have difficulty metabolising many drugs and can lead to toxicity
What is the primary metabolic pathway for paracetamol
90% glucoronidation
What enzymes metabolise paracetamol into NAPQI metabolite
CYP3A4 and CYP2E1
NAPQI metabolite build up can cause …
liver damage
In an adult, how much of the therapeutic paracetamol dose produced NAPQI
10%
How is NAPQI inactivated?
by conjugation with glutathione
Briefly describe what happens in a paracetamol overdose
glutathione runs out
NAPQI cannot be inactivated
build up of NAPQI can lead to liver toxicity
When is there a good prognosis for paracetamol overdose?
If treatment is within 8 hours with the antidote acetylcysteine
What is the function of acetylcysteine in a paracetamol overdose?
replenishes livers gluthathione
Allows NAPQI to be metabolised safely
Give examples of tranferase reactions that can occur in phase II metabolism
methylation
acetylation
glucuronidation
sulphation
mercaptopuric acid formation
gluthathione conjugation
Elimination is a combination of …
Metabolism by liver
Excretion by kidneys , hepatobiliary system, lungs
___% of drugs undergo metabolic degradation whilsyt ___% are renally excreted as their unchanged active form in the urine
66%
33%
Of the 66% of drugs metabolically degraded, ___% undergo renal elimination of the inactive drug and ___% undergo hepatobiliary elimination of the inactive drug
33%
33%
Metabolic degradation of the drug leads to the elimination of what form of the drug?
The inactive form
What is the definition of elimination?
process that removes drugs from the body- clearance
What is clearance?
Volume of plasma that is cleared of drug per unit time (volume: CL=mL/min)
What is the rate of elimination?
the is the mass of drug eliminated per unit time (AMOUNT: rate of elimination; ug/min)
What is used to determine the rate of elimination?
Clearance
Rate of elimination= clearance x [Drug]plasma (ug/min=mL/min x ug/mL)
Clearance occurs through any organ that has access to the outside world. Give examples of this
Kidney can excrete drugs into the urine
Liver can excrete drugs into the bile
Lungs can excrete drugs into the air
How would you calculate total clearance CLtotal?
CLtotal= CLrenal + CLliver + CLlungs
What organ is involved in the elimination of virtually every drug or drug metabolite?
Kidney
How is the kidney involved in the elimination of drugs or drug metabolites?
- glomerular filtration- free drug enters the glomerular filtrate
- proximal tubular active secretion
- passive distal tubular reabsorption (lipid soluble, unionized drug)
Ionised, lipid insoluble drug enters into the urine
What part of the kidney is the main site for interactions?
Proximal tubular active secretion
What is the first step in making urine?
Glomerular filtration
What is glomerular filtration?
The process that your kidneys use to filter excess fluid/ waste/ DRUGS out of the blood and into the urine via the collecting ducts of the kidney
What kinds of drugs are cleared by filtration?
Free water soluble drugs (low molecular weight)
In the case that a drug is bound to a plasma protein that has a high molecular weight, what happens?
Protein bound drug remains in circulation
What is the glomerular filtration rate?
This is the flow rate of filtered fluid through the kidney
Why is creatinine clearance a useful measure for approximating GFR
Creatinine is a by product of muscle metabolism that is excreted unchanged by the kidney
How does active secretion in the proximal tubules take place?
Active secretion of drugs from blood into the urine against its concentration gradient
It requires transporter proteins on the plasma membrane of the proximal convoluted tubule
Give an example of a drug that is secreted via active secretion in the proximal tubules
Penicillin
The secretion of free-drug perturbs the equilibrium of free and protein-bound drugs. What is the consequence of this?
This allows some protein-bound drug to become available which is then later secreted
Different drugs may compete for the same transporters. True or false
True
Transporters involved in active secretion at proximal tubules can not become saturated. True or false
False
They can
List some drugs that inhibit proximal tubular secretion of penicillin, azidothymidine and indometacin by competing for the same transporter proteins
Probenecid
Sulfinpyrazone
Phenylbutazone
Sulfonamides
Aspirin
Thiazide diuretics
Indometacin?
List some drugs that inhibit proximal tubular secretion of dioxin by competing for the same transporter proteins
Verapamil
Amiodarone
Quinidine
List some drugs that inhibit proximal tubular secretion of furosemide (frusemide) by competing for the same transporter proteins
Indometacin
List some drugs that inhibit proximal tubular secretion of methotrexate by competing for the same transporter proteins
Aspirin
NSAIDs
Passive reabsorption occurs in the _______ of the kidney
Distal tubule
The renal tubule behaves like a lipid barrier. What does it seperate?
High drug concentration in the tubular lumen
Low drug concentration in the blood plasma
If a drug is lipid soluble (unionised), what occurs in the distal tubule of the kidney
It will go down its concentration gradient and back into the plasma
What affects tubular reabsorption?
Urine flow rate
A low urine flow rate causes a _______ in reabsorption of the drug back into the plasma
low urine flow rate will cause an increase in reabsorption
A high urine flow rate causes a _______ in reabsorption of the drug back into the plasma
a decrease in reabsorption
For a weak base drug, how is reabsorption through the distal tubule affected by an increasing/high pH
high pH- less H+ ions present
unionised (B) form is produced
more of the drug is reabsorbed back into the blood plasma
For a weak acid drug, how is reabsorption through the distal tubule affected by a decreasing/low pH
low pH- more H+ ions
unionised (AH) form is produced
More AH is reabsorbed back into the blood plasma
For a weak base drug, how is reabsorption through the distal tubule affected by an decreasing/ low pH
low pH- more H+ ions
less of unionised (B) is formed and more BH+ ionised form is produced
less B is reabsorbed back into the plasma
If elimination is entirely renal (not metabolic) and the drug is filtered but not reabsorbed or secreted, what is the clearance of that drug roughly
125ml/min
GFR
If elimination is entirely renal and drug is filtered and secreted but not reabsorbed, what is the rough clearance of that drug?
625ml/min
renal plasma flow
If elimination of a drug is both via renal and hepatic mechanisms the clearance value …
exceeds 625ml/min
