Pharmacokinetics and Pharmacodynamics

Question 1

What is the life cycle of a drug in the body?

Answer 1

1. Application (drug needs to be administrated)
2. Resorption
3. Distribution –> either has a biological effect straight away or binding to a receptor first
4. a. biotransformation
5. Excretion

Question 2

What is pharmacokinetics (def.) and which factors are involved in it?

Answer 2

Def.: what the body does to the drug

Involved factors:

i. Absorption
ii. Distribution/storage
iii. Exertion/metabolic elimination

Question 3

What is Pharmacodynamics (def.) and which factors are involved in it?

Answer 3

Def.: What the drug does to the body

Involved factors:

i. Dose
ii. Receptor behaviour
iii. Non-receptor mediated effects

Question 4

Examples for interaction between Pharmacokinetics and -dynamics

Answer 4

a. Absorption and distribution affect doses/concentration at the receptor/target tissue
b. excretion determine how long the drug can be active

Question 5

what does dosis mean in pharmacodynamics?

Answer 5

the effective concentration of the drug at the receptor/tissue

Question 6

which statement is correct?

a. all drugs act on receptors
b. Agonists act only on receptors but antagonists can act on both receptors and transporters
c. most drugs (agonists and antagonists) act on receptors but there are also other non-receptor effects such as ion channels, enzymes and transporters
d. Antagonists act only on receptors but agonists can act on both receptors and transporters

Answer 6

c. most drugs (agonists and antagonists) act on receptors but there are also other non-receptor effects such as ion channels, enzymes and transporters

Question 7

what is the function of an agonist?

Answer 7

to fully activate the receptor

Question 8

what is the function of a competitive antagonist?

Answer 8

competes with agonist on the receptor binding site without eliciting a response

Question 9

what is the function of a non-competitive antagonist?

Answer 9

binds to the receptor at a different site from agonist and blocks the receptor from binding agonists

Question 10

what is the difference between drug- affinity and efficacy?

Answer 10

• Affinity is how well a drug binds its receptor. The dissociation constant Kd can be defined as K-1/K+1; which is the concentration at which 50% of the receptors are occupied –> determining affinity
• Efficacy- the conversion of the drug-receptor complex
  (AR) from inactive to active; also called intrinsic activity. –> EC50 is the concentration at which the response is 50% max.

–> 2 drugs may have similar affinity but different efficacy which means that they won’t activate AR equally as good.

–> description of graph- on the x axis- [drug concentration]; on the y axis- effect/binding; curve of Kd in blue is at higher [c] than EC50 –> Kd is at c=100 and EC50 is at 10 –> this means that the effect is reached before 50% of receptors are occupied, which means that the drug has good efficacy.

Question 11

what would be the difference between the affinity and efficacy curves of an agonist and an antagonist?

Answer 11

Antagonists only have affinity, but no efficacy, hence they do not generate a response. thus, Agonists have EC50 (= the [c] where response is 50% max.) AND Kd ([c] in which 50% of the receptors are occupied), whereas antagonists do not have EC50

Question 12

describe the concept of constitutively active receptors

Answer 12

in a ground state, equilibrium is on the inactive side- 90% of the receptors are inactive, however, even then there is a small percentage (10%) of receptors that are active without an agonist bound to them.

Question 13

which of the statement(s) is/are correct?

a. in a ground state equillibrium is on the inactive side with 90% of receptors being inactive
b. in a ground state the equillibrium is on the active side with 80% of receptors being active
c. in a ground state, a small portion of the receptors remain active without agonist bound to them
d. Antagonist bound to receptor stabilises the drug-receptor complex, and thus the % of inactive receptors remain unchanged compared ground state
e. partial agonist bind to receptor only loosely and therefore activates a lower response

Answer 13

a, c, d

Question 14

describe the drug-receptor interaction in the presence of a full agonist

Answer 14

In a ground state, in a ground state, equilibrium is on the inactive side- 90% of the receptors are inactive, and 10% of receptors are active (constitutively active receptors). A full agonist shifts the receptor population completely into the ACTIVE state –> max. efficacy = 100% (or 1)

Question 15

what is the efficacy of a partial agonist?

Answer 15

between 0 and 1

Question 16

The equation to determine efficacy of partial agonist (pA) and what factors does it depend on?

Answer 16

efficacy(pA)= max. effect of pA/ max. effect of fA.

The efficacy of pA depends on intrinsic properties of the substance–> different for each substance; pA may have same affinity as fA but their efficacy may be different due to this intrinsic properties.

Question 17

what would the dose-response curve of a partial agonist (pA) will look like in comparison to full agonist (fA)

Answer 17

• for fA the DR-curve is shifted to the left, i.e. much lower [c] of the substance is needed to achieve a response. T
• pA won’t reach max. response, because the efficacy of pA is <1

Question 18

what is the difference between an antagonist and an inverse agonist?

Answer 18

• An antagonist bind to receptors and the % of inactive receptors won’t change from the ground state–> 90% inactive, 10% active. Antagonist only occupies the receptor without generating a response.
• Inverse agonist binds to receptors and reduce the ground state activity (from 10% to 0%) by stabilising the inactive conformation of the receptor, and thus, actively changes the response from active to inactive –> considered as negative efficacy

–> there need to be some constitutive activity for inverse agonist to work.

Question 19

describe the 2 state model.

Answer 19

• the 2 states model describes 2 conformational states of receptor: R (= inactive) ; and R* (=active)

Question 20

How is the activity of different drug types (agonist, antagonist, inverse agonist..) affects the states of receptors?

Answer 20

usually the equilibrium at ground state is sifted far to the inactive state (R) , with only 10% of R* (active).

• Agonist- has higher affinity to R*, and shifts equilibrium to the active state.
• Antagonist - equal affinity to both R and R*, so equilibrium is not shifted, but since the antagonist is bound to the receptor, it prevents the substrate from binding –> blocks activity
• inverse agonist- higher activity to R (inactive) –> shifts equilibrium to inactive receptors.

Question 21

what are DR-curve useful for?

Answer 21

DR-curves are useful to assess and compare the max. effect that different drugs can produce (Emax) as well as the [c] at which 50% max. response id reached (EC50). –> 2 agonists can have the same Emax, but different EC50, so the dose required to reach the response will be different –> assessment of quality of agonists.

Question 22

in the presence of competitive antagonist, the DR-curve of an agonist will…

a. not change the curve
b. shift the curve to the right, linearly with increasing antagonist [c]
c. change the slope of the curve (max. response won’t be reached)
d. b + c are correct

Answer 22

b

Question 23

what is the effect of irreversible antagonist?

Answer 23

the presence of irreversible antagonist reduces Emax of the agonist, which cannot be overcome by increasing the [c] of the agonist. Increasing the [c] of the irreversible antagonist will further reduce Emax. No shift in curve but the slope of the curve will become shallower.

Question 24

what are allosteric modulators?

Answer 24

molecules that bind to the receptor at a DIFFERENT site than the agonist and modulate the activity

Question 25

what can allosteric modulators cause? (types)

Answer 25

a. modulate affinity of the agonist for the receptor (+/-) –> shifts curve to the left or right
b. modulate the efficacy of the agonist (+/-) –> shift curve to the left/right and affect Emax
c. evoke response themselves

Question 26

types of antagonism

Answer 26

a. Receptor block - 2 drugs binding the same R (competitive antagonism)
b. non- competitive- disruption of receptor effector linkage
c. pharmacokinetic antagonism- one drug affecting the metabolism, absorption or exertion of the other
d. chemical antagonism- interaction in solution
e. physiological antagonism- 2 drugs with opposing phys. effects.

Question 27

what what is desensitisation and what are possible causes for is?

Answer 27

responsiveness of receptors can change overtime.

reasons:
- change in receptors (phosphorylation, oxidation…)
- loss of receptors (endocytosis…)
- exhaustion of mediators
- increased metabolic degradation
- physiological adaptation (tolerance)

Question 28

difference between tachyphylaxis and tolerance

Answer 28

• tolerance is a gradual decrease in responsiveness of receptor over long periods of time (adaptation)
• Tachyphylaxis is a FAST decrease!

Question 29

how do drugs move around the body?

a. bulk flow through blood or via diffusal transfer
b. only through blood
c. specific transporters
d. all of the above

Answer 29

a

Question 30

which statement(s) is/are correct?
a. the unbound (free) drug concentration in blood is pharmacologically active

b. only drugs bound to proteins (albumin) in blood is pharmacologically active
c. plasma concentration of pharmacologically active drug is measure of both bound and unbound drug molecules

Answer 30

a

Question 31

what is the binding of a drug to albumin depending on?

Answer 31

• free drug concentration
• affinity of drug to binding site
• concentration of protein

Question 32

in order to move across the brain drugs should…

a. be able to pass the BBB by specific transporter systems or by hydrophilic properties
b. be lipophilic
c. be hydrophilic
d. be able to pass the BBB by specific transporter systems or by lipophilic properties
e. be negatively charged
f. all of the above

Answer 32

d

Question 33

Give an example to a drug that uses specific transporter system to cross the brain

Answer 33

L-Dopa uses the L-dopa system to cross the brain, and can therefore be used to treat Parkinson’s patients, and can even cross the BBB more easily than Dopamine

Question 34

describe the phase I and phase II biotransformation reactions

Answer 34

• Phase I :
  a. occurs in the liver (mainly)
  b. introduce reactionary groups
  c. enzymatic activity of enzymes from the Cytochrome P450 family
  d. common reactions- oxidation, reduction, hydrolysis…
• Phase II:
  a. occurs in the kidney
  b. conjunction reaction
  c. transferases add functional groups onto reactionary groups from phase I
  d. functional groups are often very polar/negatively charged
  e. common reactions- methylation, glucuronation, sulfatation…

Question 35

why is biotransformation important?

Answer 35

• Many drugs are highly lipophilic (to be able to cross the lipid bilayer or the BBB), and pure renal elimination of such molecules will take very long –> biotransformation of these molecules in the liver helps eliminating them faster.
• Biotransformation is also important for the bioavailability of the drug- some drugs undergo biotransformation prior to entering the plasma, which can affect the plasma concentration–> dtysfunctioning liver enzymes can lead to elevated plasma [c] which can even be toxic.

Question 36

what is pharmacogenetics? + example

Answer 36

pharmacogenetics studies the influence of polymorphism or rare genetic variants on drug metabolism.

example: studying gene variants of the CYP2D6 gene- many variation described, each has a very different phenotype of plasma [c] of drugs (under-expression–> very high plasma [c], over-expression–> very low plasma [c] ; no sufficient drug effect.

Question 37

Pathways for drug elimination

Answer 37

• Renal elimination: mainly small molecules
• Non-renal (hepatic, GI tract, expiration): mainly large molecules.

for either pathway the presence of transport proteins is essential

Question 38

what molecules are eliminated via kidneys? how?

Answer 38

• small, free, non-protein-bound molecules

- several pathways : GFR, tubular secretion, tubular resorption

Question 39

what is bioavailability?

Answer 39

bioavailability is the % of drug that enters the blood stream unaltered

Question 40

what administration way results in the highest bioavailability?

Answer 40

Intravenous - 100% bioavailable

Question 41

what can the AUC tell us?

Answer 41

• information about Cmax- max. [c] reached
• information about t-max - time point when Cmax is reached
• information about clearance (CL = Q/AUC)

Question 42

ways to calculate AUC

Answer 42

AUC = Q/CL

• AUC can give us info about bioavailability of different administration ways (f= AUCos/AUCiv), and of different drugs (f= AUC1/AUC2)

Question 43

what is the significance of volume distribution + equation and example

Answer 43

• VD is the volume required per dose/amount to yield the [c] measured in plasma
• V=D/C with D= administrated dose and C= plasma [c]
• for pharmacological activity, only free, unbound drug molecules count –> thus, if a drug binds more to plasma proteins or fatty tissue, it means that less [c] in plasma is pharmacologically active and thus a larger volume is needed than when all molecules are free in plasma

Question 44

what is half life time?

Answer 44

• the time it takes for the drug [c] in plasma to reduce to 50%.