0111101230 1330 - Mfm Ii - Pharmacodynamics Iii & Iv (Meibohm)

Front 1

Therapeutic Index

Back 1

ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in an experimental population.

Therapeutic Index = TD50/ED50 or LD50/ED50

Front 2

What must the Therapeutic Index (safety margin) be in order for a drug to be usable?

Back 2

must be at least 1, but ideally will be much greater than 1.

ex. Digoxin has a TI of 2
Penicillin has a TI of > 100

Front 3

Therapeutic range (probability based)

Back 3

ideally large range of drug concentration where efficacy exists (starts at EC50), but toxicity does not (ends where toxicity effects begin to increase).

note that since Emax, EC50, and n are different for all individuals, the therapeutic range is good for MOST patients

Front 4

What is the significance of the efficacy of Theophylline?

Back 4

> 5 ug/ml = bronchodilatory effect
10-20 ug/ml = TR for anti-asthmatic (target 10-15)
5-10 ug/ml = TR for apnea therapy in children (target 7.5)

different therapeutic ranges for different indications

Front 5

What is the significance of the toxicity of Theophylline?

Back 5

5-20 ug/ml - headache, sausea, tremor, sleeplessness
15-35 ug/ml - vomiting, diarrhea, stomach pain, nervousness, tachychardia
> 35 ug/ml - convulsions, cerebral hypoxia, arrhythmia, cardiac arrest, death

Front 6

What is the defined therapeutic range of Theophylline?

Back 6

10-20 ug/ml

Front 7

Type A adverse drug reactions (ADR)

Back 7

"side effects"
dose-related, predictable, expected, accepted to occur

Front 8

Type B adverse drug reactions (ADR)

Back 8

non-dose related, unespected, allergic reaction, carcinogenic, teteratogenic, idiosyncratic

Front 9

What are all the types of ADR (adverse drug reactions?

Back 9

Type A - side effects
Type B - bizarre effects
Type C - chronic effects
Type D - delayed effects
Type E - end-of-treatment effects

A and B are the most important and will be discussed in detail

Front 10

What is idiosyncratic?

Back 10

individually peculiar with respect to known character

Front 11

What affects the frequency and severity of Type A ADRs?

Back 11

therapeutic range and selectivity

Front 12

What is the difference between silenafil, vardenafil, and tadalafil?

Back 12

All are phosphodiesterase inhibitors for the treatment of erectile dysfunction.

silenafil - viagra
vardenafil - levitra
tadalafil - Cialis

The difference is that there are PDE1 - PDE11 throughout the body and they all target PDE5 with the same potency, but have different potency for other PDEs, so they offer different side effects because of the altered potency.

Front 13

What affects the frequency and severity of Type B ADRs?

Back 13

genetics of an individual

Front 14

Common examples of Type B ADRs

Back 14

1) Hepatotoxicity because of toxic intermediates that some individuals are sensitive to
2) Nephrotoxicity
3) Pancreatitis
4) Hypersensitivity I, II, III, and IV (allergic) reactions - immunologically mediated manifesting as urtikaria, rhinitis, bronchial asthma or angioedema

Front 15

What is the mechanism of a Type I hypersensitivity reaction and what Ab mediates this reaction?

Back 15

IgE mediated, anaphylactic reaction and Ag-Ab reaction causing systemic anaphylaxis, caused by penicillin and cephalosporins

Front 16

What is the mechanism of a Type II hypersensitivity reaction and what Ab mediates this reaction?

Back 16

IgG, IgM mediated cytotoxic, Ag-Ab reaction producing hemolytic anemia caused by penicillin and quinine

Front 17

What is the mechanism of a Type III hypersensitivity reaction and what Ab mediates this reaction?

Back 17

IgG, IgM mediated immune complex or immune complex-Ab reactions producing serum sickness caused by penicillin, cephalosporins, isoniazid, pheytoin

Front 18

What is the mechanism of a Type IV hypersensitivity reaction and what Ab mediates this reaction?

Back 18

T-cell mediated delayed hypersensitivity which takes > 12 hrs to respond with Ag-T-cell interactions producing topical (not systemic) problems. usually rashes

Front 19

tolerance

Back 19

diminishing effect to a repeated stimulus (drug in dose). can be metabolic or functional.

Front 20

metabolic tolerance

Back 20

time-dependent change in PK parameters (clearance)

Front 21

functional tolerance

Back 21

time-dependent change in pharmacodynamic parameters such as
1) decrease in receptor number or
2) receptor desensitization

Front 22

graphically, how does functional tolerance present?

Back 22

as a clockwise hysteresis loop

Front 23

What phenomenon does ranitidine provide in pt populations?

Back 23

functional tolerance with constant rate infusion not being able to provide constant correlated 1:1 control over gastric pH

Front 24

receptor desensitization

Back 24

a cause of functional tolerance where receptor number does not change, but affinity for agonist is reduced, resulting in a rightward shift of the binding curve. transduction is reduced and effect changes.

Front 25

does Emax change in receptor desensitization?

Back 25

nope, the curve is just shifted to the right because more [agonist] is needed.

Front 26

receptor down-regulation

Back 26

a cause of functional tolerance where proteolytic degredation of receptor occurs. receptors are interalized by use of endosomes and lysosomes -> net loss in total receptors -> Emax decreases, but Kd remains the same. makes sense.

Front 27

tachyphylaxis

Back 27

special case of functional tolerance. happens rapidly (minutes to hours) and is rapidly reversible.

Front 28

What are two examples of tachyphylaxis?

Back 28

1) indirect sympathomimetics (Amphetamines, Ephedrin) because the repeated exposure depletes neurotransmitter storage. these drugs simple cause release of these NTs. when they run out. they run out. give it some time, and they will come back.
2) Nitrates (Nitroclycerin) - converting nitrates to NO (the whole point of nitrates) uses SH-groups that are of limited supply. once the SH pool is replenished, the nitrates will regain their potency

Front 29

dependence

Back 29

1) rewardive psychological dependence - if it feels good, do it
2) withdrawal physiological dependence - it feels bad if you don't do it

Front 30

neuroadaptation related to dependence

Back 30

adaptive mechanisms initiated by the brain to restore physiological homeostasis when a drug is introduced that can lead to physiological dependence

Front 31

receptor down regulation related to dependence

Back 31

happens with an agonist drug
1) receptor down regulation with repeated exposure
2) recovery after removal of drug where receptors must slowly up-regulate (withdrawals)

Front 32

Three ways that receptors respond that effects dependence.

Back 32

1) downregulation
2) affinity
3) upregulation

Front 33

receptor up regulation related to dependence

Back 33

happens with an antagonist drug
1) antagonist blocks normal action
2) cell up regulates to provide receptors for normal ligand interaction
3) when drug is removed cell must slowly down regulate to return to homeostasis

Front 34

affinity related to dependence

Back 34

affinity changes with use of drug
1) receptor changes affinity in order to interact with drug, but changes so that is not interactive with normal ligand
2) drug is removed and receptor can no longer interact with normal ligand
3) affinity must change to be viable to use with normal ligand when drug is gone for a length of time

Front 35

what happens with cyclosporin in pediatric pharmacodynamics?

Back 35

as age increases, the EC50 increases which reflects a decreased efficacy relative to dose as age increases

Front 36

what happens with warfarin in pediatric pharmacodynamics?

Back 36

the effect is 2x in pediatrics which corresponds to potency and sensitivity is 2x in pediatrics compared to adults

Front 37

what happens with Sotalol in pediatric pharmacodynamics?

Back 37

effects of the drug are neonates > infants > adolescents

Front 38

elderly

Back 38

elderly are more sensitive to drugs, rather because of receptor differences, their sensitivity is different. the examples that he gave showed a higher sensitivity

Front 39

FDA food and drug administration

Back 39

established in 1938 by Federal Food Drug and Cosmetic Act

Front 40

3 roles of the FDA

Back 40

1) New drug application (NDA)
2) Abbreviated new drug application (ANDA) - for generic or bio-equivalence of preexisting drugs
3) Investigational New drug application (IND) - first time use in humans

Front 41

of every 10,000 compounds submitted to the FDA how long does it take and how many are accepted?

Back 41

~15 years for 1 drug

Front 42

What are the preclinical stages of producing a drug through the FDA?

Back 42

1) discovery
2) preclinical dev I - animal in vivo and in vitro trials, manufacturing procedure established
3) preclinical dev II - establish PK and PD relationships and animal toxicology trials in rodent and nonrodent categories (mouse and monkey) at least 2 species, risk assessment, plan for human trial
4) Preclinical to clinical transition - IND application
5) Clinical Phase 1 - <100 subjects, efficacy is not an objective, just introducing it into human targets
6) Clinical Phase 2 - perform in pts with illness, prove therapeutic value, identify best demographic and dosing regimens
7) Clinical Phase 3 -

Front 43

what is the transition between preclinical and clinical phases of drug development?

Back 43

4) Preclinical to clinical transition - IND application

Front 44

What are the clinical stages of producing a drug through the FDA?

Back 44

5) Clinical Phase 1 - <100 subjects, efficacy is not an objective, just introducing it into human targets
6) Clinical Phase 2 - perform in pts with illness, prove therapeutic value, identify best demographic and dosing regimens
7) Clinical Phase 3 - confirm efficacy and safety >1000 pts, detect adverse reactions with two independent double blind randomized placebo controlled trials, fill out NDA
8) Clinical Phase 4 - post approval, marketing, refine efficacy in different populations, further adverse reaction study,