3. Pharmacodynamics

Question 1

What are drug interactions and the 4 types of them?

Answer 1

A situation in which a substance affects the activity of a drug

Interactions between 2 drugs- drug-drug interaction between 2 drugs metabolized by same CYP isoform
Between a drug and a food item- drug-food interactions are metabolized by CYP enzymes and grapefruit juice for example
Between drug and herbs- drug-herb interactions metabolized by CYP and St. John’s wort for example
Other interactions- with blood electrolytes for example

Slides 67-70 general principles

Question 2

What are pharmacodynamic drug-drug interactions?

What are pharmacokinetic drug-drug interactions?

Answer 2

Pharmacodynamic- 2 drugs affecting the same system
Ex: 2 sedative drugs will produce more sedation, alcohol and a sedative drug

Pharmacokinetic- one drug changes the absorption, distribution, metabolism, excretion (ADME) of another
Ex: absorption- antacids reduce absorption of tetracycline
Distribution- competition for plasma protein binding by non-steroidal anti-inflammatory drugs
Metabolism- one drug affecting the metabolism of another drug is most common reason for drug drug interactions

Question 3

What is the most common metabolizing enzyme responsible for drug-drug interactions?

Answer 3

Two drugs metabolized by the same enzyme can compete for the enzyme CYP3A4

Question 4

Why is it important to check for liver and kidney diseases before administering a drug?

Answer 4

Liver and kidney affect the metabolism and excretion and plasma levels of many drugs
Doses of drugs with high hepatic extraction ratio have to be reduced in chronic liver and kidney disease (ex: antidepressants)

Question 5

What are the 4 cases to watch out for drug-drug interactions (DDIs) in?

Answer 5

The elderly
Receiving more than 2 drugs
Receiving warfarin, NSAIDs
New signs/ symptoms after starting a new drug

Question 6

What is a receptor?

What is affinity?

Answer 6

Receptor- macromolecule whose biological function changes when a drug binds to it
Drug receptor binding triggers signal transduction

Affinity- measure of propensity of a drug to bind receptor; the force of attraction between drug and receptor

Question 7

What happens if we put 2 drugs acting at the same receptor?

Answer 7

They will compete for the receptor due to the transient binding
The drug with higher concentration will have a greater chance at binding

Slide 82 general principles

Question 8

What is Kd and it’s equation?

Answer 8

Kd- concentration of a drug that occupies 50% of the total number of receptors at equilibrium
Kd=K2/K1
The lower the Kd, the more affinity the drug has for the receptor

Slide 83 general principles

Question 9

What can be derived from dose response and quintal curves graphs?
What is efficacy?

Answer 9

Slide 84 graph of % contraction over dose of drug (mg)

Emax- maximal effect produces by a drug. It is a measure of efficacy of a drug
EC50- dose or concentration of a drug that produces 50% of maximal response

Efficacy (intrinsic activity)- ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but not efficacy

Question 10

What is an agonist?
What is a partial agonist?
What is an antagonist?

Answer 10

Agonist- drug that binds to the receptor and produces an effect
Affinity and intrinsic activity

Partial agonist- has affinity for a receptor but less intrinsic activity (lower efficacy and lower Emax compared to an agonist acting at the same receptor)

Antagonist- drug which binds (competes for binding against other ligands) but does not activate the receptor
Has affinity but no intrinsic activity
Can be competitive or non competitive

Slides 87-88

Question 11

How does a partial agonist work?

What’s a clinical example?

Answer 11

Partial agonist produces less than full effect when given alone

Partial agonist acts as an antagonist in the presence of a full agonist (blocks the full effect of an agonist)

Antagonist properties of a partial agonist can be useful; they provide some agonist activity and at the same time block them endogenous full agonists

Pindolol for high blood pressure and abnormal heart rhythms (reduces excessive stimulation due to norepinephrine in a person with high sympathetic nervous system activity)

Question 12

What is competitive antagonism?

Answer 12

Slides 92-93 general principles
In presence of a competitive (reversible) antagonist a higher dose of agonist is required to produce the same effect
When the agonist is alone a lower dose can produce maximal effect

Question 13

What is non-competitive (irreversible) antagonism?

Answer 13

Slides 94-95 general principles
In the presence of an irreversible (non-competitive) antagonist even a higher dose of agonist cannot produce maximal effect
When the agonist is alone, a lower dose can produce maximal effect

Question 14

What is inverse agonist?

Answer 14

Some receptors have intrinsic (constitutive) activity even when no ligand is bound to them
When a ligand binds to them, their basal activity is reduced, these are inverse agonists

Are like competitive antagonists but on their own they reduce receptor activity whereas competitive antagonists have no effect on their own
Slide 97 general principles

Question 15

What is allosteric interaction?

What is an example?

Answer 15

Slides 98-100 general principles

When a ligand B binds to a site close to the site of an agonist A on a receptor, it can affect the binding and/or response to agonist A, this is allosteric interaction

Benzodiazepine drugs potentiate the response to gama aminobutyric acid (GABA) when they bind to GABAa receptor

Question 16

What is the quantal dose response curve?

What are the 2 types?

Answer 16

Indicates sensitivity of a given population to the doses of a drug for a given effect

Frequency distribution- each bar shows number of people responding to dose, excludes people responding to lower doses

Cumulative frequency- each bar shows the number of people responding to that dose and to lower doses

Slides 101-102

Question 17

What is the therapeutic index?

Answer 17

Therapeutic index= TD50/ED50 or LD50/ED50
TD50- toxic dose in 50% of people
ED50- effective dose in 50% of people
LD50- lethal dose in 50% of people

Higher the ratio, safer the drug

Question 18

What is the therapeutic window?

Answer 18

The difference between the minimum effective concentrations for a desired response and an adverse response

Reflects plasma concentration range that provides efficacy without unacceptable toxicity

Question 19

What’s the difference between. An dose-(concentration)-response curve and a quantal dose curve?

Answer 19

Dose-(concentration)-response curve shows graded responses in a single individual, produced by increasing concentrations of a given drug

Quantal dose-response curve shows a specific response (quantal-all or none, present or absent) in a group of individuals produced by a drug

Question 20

What are the 4 signal transduction mechanisms?

Answer 20

1. G protein coupled receptor systems (GPCRs, metabotropic receptors)
   Half of all known drugs work through GPCRs
2. Ion-channel receptors (ionotropic receptors)
3. Enzymes as receptors- tyrosine kinase, serine/threonine kinase
4. Nuclear receptors

Slides 107-108

Question 21

What are enzyme receptors?

Answer 21

Receptor is a pair of protein molecules (monomers) that are separate when inactive
Agonist causes them to interact and form a diner

The interaction phosphorylates tyrosines in the intracellular region of the receptor and the receptor becomes an active enzyme

Question 22

What are ion channel receptors?

Answer 22

The receptor is a protein with a channel in the centre. An agonist causes the channel to open and allows specific ions to cross the cell membrane to the other side

Question 23

What are nuclear receptors?

Answer 23

These receptors are mostly in the cell cytosol
Agonist enters the cell and binds to the receptor
Drug-receptor complex then enters the nucleus and stimulates gene transcription
This leads to synthesis of new proteins and enzymes
Slide 111 general principles

Question 24

How do receptors get desensitized?

Answer 24

Agonists tend to desensitize receptors- frequent stimulations of a receptor by its agonist results in a decreased response (desensitization)

Question 25

How are receptors up regulated?

Answer 25

Antagonists upregulate receptors
Example: treatment with β-receptor antagonist causes a withdrawal rebound effect when the antagonist treatment is stopped suddenly. This is because the receptor number has increased and when the antagonist is suddenly removed from the receptor, there are more receptors available for the agonist resulting in a rebound response

Question 26

What is homologous desensitization compared to heterologous desensitization?

Answer 26

Homologous- desensitization to one agonist at a receptor will also desensitize other agonists at the same receptor

Heterologous- desensitization to one agonist at a receptor will also desensitize other agonists at different receptors to produce the same response

Slide 114 general principles

Question 27

What is the stance of drug use during pregnancy?

Answer 27

First trimester is most important when the fetal development is most sensitive to drugs

More prevalent than expected

Category D and X have been used during pregnancy

Question 28

What placental expression protects the fetus?

Where’s it located?

Answer 28

Placental expression of drug transporters such as P-glycoprotein protects the fetus by efflux of drug from the fetal to maternal circulation
Located apical
Slide 122 general principles

Question 29

What is the classification (risk level) of drugs for their use during pregnancy?

Answer 29

A- safe; lots of data
B- likely safe; animals OK
C- uncertain; risk vs benefit
D- likely unsafe; risk vs benefit
X- unsafe, do not use

Question 30

What are the principles of drug use in children?

Answer 30

Pharmacokinetics of most drugs are not well defined in children

Variability in pharmacokinetics is greatest when the body is changing
Drug clearance values do not vary linearly with either body weight of body surface area

Question 31

What is the maturation level of CYP3A4 in newborns?

Answer 31

CYP3A4 is expressed within 1 week
So any drug that is metabolized by CYP3A4 is likely to produce toxicity of administered to a newborn or 1-2 day old infant

Question 32

At what age does GFR levels reach adult values in infants?

Answer 32

GFR increases to adult levels by 8 to 12 months

Slide 128 general principles

Question 33

What is one pharmacodynamic (drug response) difference between adults and children?

Answer 33

Antihistamines and barbiturates cause sedation in adults but they cause hyperactivity in children

Question 34

What are the common physiologic changes that take place in elderly people that affect pharmacokinetic and pharmacodynamic responses to drugs?

Answer 34

Reduction in lean body mass
Reduction in serum albumin
Reduction in total body water
Increase in percentage of body fat
Kidney and liver function should be carefully assessed

Question 35

What are the changes in GFR values I’m elderly?

Answer 35

Starts to decline after 30, accelerated decline after 65 to 70

Elderly people over age of 75 can expect to have significantly reduced rental clearance of drugs