Pharmacology- pharmacokinetics

Question 1

what is the acronym for the components of pharmacokinetics?

Answer 1

Absorption
Distribution
Metabolism
Elimination

Question 2

name 4 classes of receptors that drugs can act upon

Answer 2

ligand gated ion channels
G protein coupled receptors
tyrosine kinase receptors
intracellular receptors

Question 3

what are some of the cellular responses responsible for tachyphylaxis?

Answer 3

Tachyphylaxis can be a rapid response to a drug.

1) receptor internalisation (can’t be activated if they are intracellular.)
2) phosphorylation of receptors that decrease activity
3) down regulation of receptors

This means that an increased dose of a drug cannot illicit a greater response.

Question 4

what are some of the cellular responses responsible for tolerance?

Answer 4

up regulation of the metabolic enzymes result in the more rapid metabolism of drugs.

This process can be overwhelmed by an increasing dose of the drug- enzymes get over saturated and you can still cause the desired response.

Question 5

define bio availability

Answer 5

bio availability is the fraction of administered drug that reaches systemic circulation in its unchanged form.

first pass effect in the pre-systemic metabolism or elimination of a drug that reduces its bio availability.

Question 6

what are the 2 phases of metabolism?

Answer 6

phase 1- cytochrome P450 oxidation, reduction, hydrolysis

phase 2- conjugation (sulfation, methylation, acetylation, glucuronidation)

geriatric patients tend to have more phase 2 metabolism.

Question 7

Describe volume of distribution

Answer 7

The theoretical volume occupied by a drug compared to the plasma concentration.

This is calculated by the amount of drug/plasma concentration.

highly protein bound drugs generally have a low Vd (large and charged)
Drugs distributed into the tissue compartments have a high Vd.

Question 8

how can half life be calculated in drugs subject to first order elimination

Answer 8

In first order eliminated drugs (where rate of elimination is proportional to drug concentration)

is (0.7xvolume distribution) / clearance.

Question 9

what is zero order elimination? name some drugs that are eliminated in this manner.

Answer 9

zero order elimination is where the rate of elimination of a drug is at a constant rate (vs dependent on concentration as in first order)

Examples of drugs are aspirin, ethanol and phenytoin.

Question 10

what is elimination? what is a formula that can calculate this?

Answer 10

elimination is the volume of body cleared of a drug over a unit time.

volume distribution x elimination constant.

Question 11

how long does a drug subject to first order elimination take to reach steady state?

Answer 11

4 to 5 half lives.

clearance and dose determine the magnitude of the steady state but the time to reach it is subject to the drugs half life.

Question 12

list some of the modalities of absorption

Answer 12

1) passive diffusion- flows down concentration gradient (drug needs to be small and hydrophobic for this to occur to pass the lipid membrane).

2) facilitated diffusion- protein channels provide an opening for the drug to pass through if the drug is large and hydrophilic. Still a passive process.

3) Active transport- a protein pump uses ATP to in order to transport a drug across the membrane.

4) Bulk transport- drug binds several small receptors which then facilitates endocytosis of the drug into the cell, which can be used in If very large molecule (like vitamin B12)

Question 13

Describe how pH affects drug absorption

Answer 13

1) pH- if the drug is a weak acid it can donate hydrogen/protons, which results in a negative charge which makes it more difficult to pass the lipid membrane. so an acidic environment would prevent this initial donation preventing the creation of the polarised formulation of the drug.

As in HA-> H+ + A- (A being the drug).

The opposite is true for weak bases (less of the ionised form is present when the environment is more alkaline)

Question 14

Describe how blood flow affects drug absorption

Answer 14

decreasing blood flow reduces the perfusion to the region of the body responsible for absorbing the drug (ie skin for dermal, GIT for PO).

Question 15

how does surface area and contact time effect absorption?

Answer 15

total surface area- less surface area= less of a region for the drug to be absorbed. (i.e Coeliac disease or IBD).

contact time- as in diarrhea/GIT hyper motility there is less time for the drug to be absorbed at the relevant area of the GIT as the peristalsis is moving the contents forward. the opposite is true for constipation- there is a greater amount of time for the drug to be absorbed.

Question 16

name some factors effecting drug absorption.

Answer 16

route of administration
drug dose
drug properties (molecular size, pH)
blood flow
environment pH
total surface area
contact time

Question 17

what are some of the drug properties that effects the bio availability?

Answer 17

1) solubility- small, hydrophobic (lipid soluble) drugs pass the lipid membrane easier than larger and hydrophillic molecules meaning the latter have less bio availability.

2) stability- if oral administration it needs to be able to survive the acidic environment of the stomach in order to be absorbed )as in penicillin G). proteases from the pancreas can also cause significant drug breakdown prior to absorption as in the case of insulin.

3) first pass effect- oral drug dosing is absorbed to the portal venous system which passes through the liver where it is subject to initial metabolism.

Question 18

what are some of the factors affecting excretion

Answer 18

filtration- drug needs to be small enough to pass through the glomerular membrane.
Dependent on renal function and adequate kidney perfusion.

Secretion
in the peritubular capillaries (after the Glomerulus) secretion can occur where drugs that did not pass through the glomerulus can be transported into cell membranes and then into the tubules.
by similar methods as absorption, small hydrophobic and non polar ions are are to pass via diffusion, whilst large polar hydrophilic molecules require active transport.
secretion is dependent on the drug concentration and not having the transporters saturated/inhibited by poly pharmacy.

Re absorption
in the distal convoluted tubule drugs that had initially passed into the tubule are subject to re absorption to systemic circulation.
again small, non polar hydrophobic drugs can easily pass through the cell membrane. - drugs with these structures need to be metabolised to become more polar so this doesn’t continue indefinitely.

Question 19

define drug clearance

Answer 19

clearance is a pharmacokinetic measurement of the volume of plasma from which a substance is completely removed per unit time. Usually, clearance is measured in L/h or mL/min.

clearance is equal to rate of elimination divided by plasma concentration of the drug.
alternatively it is also equal to (volume of distribution x 0.7)/ half life. (for drugs under first order elimination kinetics where half life is constant.)

This is a combination of metabolism and excretion.

Question 20

describe the drug properties that would fit in with a single compartment model of drug distribution.

Answer 20

In order to remain in a single compartment a drug must have little to no tissue penetration.
Highly hydrophilic drug classes such as aminoglycosides (including gentamycin) fall into this category.

Question 21

describe the concentration/time graph of the 2 compartment model of drug distribution and describe the phases

Answer 21

there are 2 phases; distribution and elimination.

The distribution phase is the initial rapid decline in serum drug concentration caused by the drug shifting from the central compartment to the peripheral.
The elimination phase is the slow decline in drug concentration, sustained by redistribution of drug from tissue stores

Question 22

describe the 3 compartments of the 3 compartment model.
describe the concentration/time curve of a highly lipophilic drug.

What are the stages observed in the graph?

Answer 22

The 3 compartments are serum, fat and lean tissue.

In the case of a fat soluble drug; lean muscle contains little fat and is therefore a poor storage reservoir for the drug. The fat compartment however soaks up a large amount of the drug. After a while, much of the drug has been cleared from the circulating blood and lean tissue; at this stage the fat compartment begins to act as a source of the drug, topping up the serum levels as elimination takes place.

The graph has 3 phases; distribution, elimination and slow tissue release.

Question 23

draw the 3 compartment model

Answer 23

the volumes are predictably identified as V (V1 to V3 for the three-compartment model).

the effect site, which is a tiny compartment but which does contribute something (it is after all the drug target) and which is conventionally represented as Ve.

The kinetics of distribution from one compartment to another are usually described as Kxy, where x is the compartment from which the drug is distributing, and y is the compartment to which the drug is going. In this manner, distribution of a bolus from the central compartment V1 to the peripheral compartment V2 would be labeled as K12.

Question 24

What are some of the limitations of compartment modelling?

Answer 24

1) it is assumed that the central compartment is the only compartment from which a drug is eliminated; this is often not the case.

2) mathematical modelling may include compartments from which the confirmation of drug concentration would be near impossible in human subjects (i.e brain).