Kaplan Pharmacology - Section 1 - General Principles (2)

Front 1

What does phase II of biotransformation involve?

Back 1

Conjugation with endogenous compounds via the activity of transferases.

Front 2

What types of conjugation reactions are there?

Back 2

(1) Glucuronidation
(2) Acetylation
(3) Glutathione (GSH) conjugation

Front 3

You see reduced activity of this phase II conjugation reaction in neonates. What is it?

Back 3

Glucuronidation

Front 4

Why do you see "Grey baby syndrome" with chloramphenicol?

Back 4

The neonate has a relative inability to metabolize chloramphenicol due to low levels of glucuronosyl transferase.

Front 5

In acetylation you have __________ variation. Explain.

Back 5

Genotypic variation. You have fast and slow metabolizers (acetylators). If you're a slow metabolizer, you can accumulate certain drugs (e.g., drug-induced SLE).

Front 6

A woman on isoniazid therapy develops a fever with pain in inspiration. She develops pain in her joints and a rash upon exposure to sunlight. What might be going on?

Back 6

Slow acetylator.

Isoniazid, procainamide and hydralazine may induce drug-induced SLE, especially in these patients.

Front 7

With acetaminophen you deplete this molecule. What is it?

Back 7

Glutathione

Front 8

Give two examples of drugs that undergo glucuronidation.

Back 8

Morphine and chloramphenicol.

Front 9

What does drug elimination mean?

Back 9

It's when you terminate the action of a drug.

Front 10

What are some major modes of drug elimination?

Back 10

(1) Biotransformation to inactive metabolites
(2) Excretion via the kidney
(3) Excretion via other modes, e.g., bile duct, lungs, and sweat.

Front 11

There are different orders of elimination rate. What does zero order mean?

Back 11

A constant amount of drug is eliminated per unit time, independent of plasma concentration or amount in the body.

[In a nutshell: Saturation of elimination mechanisms (at Vmax)]

Front 12

What drugs undergo zero-order elimination?

Back 12

(1) Ethanol (except low blood levels)
(2) Phenytoin (at high therapeutic doses)
(3) Salicylates (toxic doses)

Front 13

What order of elimination is this?

80 mg ----4 hr----> 70 mg ----4 hr----> 60 mg ----4 hr----> 50 mg

Back 13

Zero-order. Notice the constant rate independent of concentration.

Front 14

What is first order elimination?

Back 14

A constant fraction of a drug is eliminated per unit time.

Front 15

Most drugs follow _________ (zero/first/second) order elimination rates.

Back 15

first (i.e., enzymes are not working at their Vmax)

Front 16

What order of elimination is this?

80 mg ----4 hr----> 40 mg ----4 hr----> 20 mg ----4 hr----> 10 mg

Back 16

First-order, notice the constant fraction (1/2) eliminated.

Front 17

Draw plots of zero order kinetics using units of drug and log units of drug as function of time.

Back 17

Front 18

Draw plots of first order kinetics using units of drug and log units of drug as function of time.

Back 18

Front 19

Write down renal elimination (clearance) as an equation.

Back 19

Rate of elimination = GFR + active secretion - reabsorption

Front 20

What is renal clearance defined as?

Back 20

The volume of blood cleared of drug per unit time.

Front 21

Renal clearance is ___________ (variable/constant) in first order kinetics.

Back 21

constant

Front 22

A drug is not secreted or reabsorbed. It has a significant fraction that is protein bound. What clearance equation can you write down for this?

Back 22

Clearance = Free fraction x GFR

Front 23

Considering rate of elimination equation, what is going on with a drug if the clearance is lower than the GFR? What is going on if the clearance is higher than the GFR?

Back 23

Cl < GFR means reabsorption has occurred. Cl > GFR means that secretion has occurred.

Front 24

What is steady state?

Back 24

Steady state is the point at which the amount of drug being administered equals the amount being eliminated, such that the plasma and tissue levels remain constant in the case of IV administration and fluctuate around a mean in the case of oral fixed dosage.

Front 25

The time it takes to reach steady state is dependent only on?

Back 25

the elimination half life of a drug

(It's independent of dose size and frequency of administration)

Front 26

What is the therapeutic window?

Back 26

Marked in orange.

("Effective, but not toxic")

Front 27

What is clinical steady state?

Back 27

95% of the "way" to steady state

Front 28

How many half lives does it take to reach clinical steady state?

Back 28

4-5 half lives

Front 29

How many steady states is required to reach mathematical steady state?

Back 29

Greater than 7

Front 30

How much do you decrease the time to steady state by increasing the rate of infusion (K0)?

Back 30

Steady state is irrespective of rate of infusion. You reach a higher concentration at steady state, but it takes the same amount of time to reach steady state.

Front 31

Sometimes you can't wait long enough to reach steady state. What can be done?

Back 31

Give a higher dose called a loading dose to more rapidly achieve effective blood levels. Such dosings are often one time only and is estimated to put the amount of drug in the body that would be there at steady state. It's potentially dangerous.

Front 32

Equation of loading dose.

Back 32

LD = Cp x Vd

Front 33

To maintain a loading dose you follow it up with a?

Back 33

Maintenance dose

Front 34

Half life eqation?

Back 34

t1/2 = 0.7 x Vd/Cl

Front 35

Infusion rate equation?

Back 35

K0 = Cl x C^ss

Front 36

Maintenace dose (MD) equation?

Back 36

MD = [Cl x Css x tau (dosing interval, how frequently)]/f

Front 37

Loading dose equation?

Back 37

LD = [Vd x Cd]/f

Front 38

What is an agonist?

Back 38

A drug is called an agonist when binding to the receptor results in a response.

Front 39

What is an antagonist?

Back 39

A drug is called an antagonist when binding to the receptor is not associated with a response. It has an effect by preventing an agonist from binding to the receptor.

Front 40

The affinity of a drug is inverse to the ____.

Back 40

Kd (like the Km)

Front 41

When you think about the efficacy of a drug this is very similar to _______ (biochemistry).

Back 41

Vmax

Front 42

What can you say about these two drugs?

Back 42

The slope is parallel, it means they work on the same receptors. Drug A has higher affinity than drug B (shifted to left). Due to this we can also say A has better potency than B. Both drugs have same efficacy (100%).

Front 43

What plot is this?

Back 43

Graded (Quantitative) Dose Response (D-R) curves

Front 44

What can you say about these two drugs?

Back 44

They work on different receptors (not parallel slopes). X is more potent than Y (left shift). X has a greater efficacy than Y.

Front 45

What does potency mean?

Back 45

The dose required to produce a particular effect.

Front 46

What is a full and partial agonist?

Back 46

Full: Produce a maximal response; they have maximal efficacy.

Partial: Are incapable of eliciting a maximal response; they are less effective than full agonists.

Front 47

Which drug(s) is/are a full agonist and which drug(s) is/are partial agonists?

Back 47

B = Full agonist
A & C = Partial agonists

Front 48

Which drug is more potent, A or C?

Back 48

A

Front 49

True or false: We can compare curves A and B.

Back 49

False, the curves will cross if you extrapolate. However at certain doses we can compare, e.g. stippled line.

Front 50

What can we say about potencies of A and B?

Back 50

A is more potent than B at low doses. If you extrapolate A to cross B, then B will have higher potency than A at doses above that point.

Front 51

Describe the concept of duality of partial agonists.

Back 51

It means that a partial agonist can act as an antagonist (duality, two properties) in the presence of a full agonist, because it displaces the full agonist and the response is reduced.

Front 52

Give an example of a partial agonist.

Back 52

Pindolol

Front 53

Most drugs that are antagonist are _____________?

Back 53

competitive

Front 54

Five important noncompetitive drugs?

Back 54

(1) Phenoxybenzamine
(2) Digoxin
(3) Allopurinol
(4) PPIs
(5) Aspirin

"Dig APAP"

Front 55

True or false: In the presence of a noncompetitive antagonist, adding more agonist allows to generate a full response.

Back 55

False.

Front 56

What antagonism is added that results in the yellow curve and white curve?

Back 56

Yellow = Competitive (reduced potency)
White = Noncompetitive (reduced efficacy)

Front 57

What example can you think of that might fit this curve shift?

Back 57

GABA as control with addition of benzodiazepines.

Front 58

What's the difference between pharmacologic antagonism vs. physiologic antagonism?

Back 58

Physiologic: Two agonists with opposing action antagonize each other.

Pharmacologic: Same receptor.

Front 59

Give an example of physiologic antagonism.

Back 59

Vasoconstrictor (phenylephrine) and vasodilator (nitroglycerin)

Front 60

What is chemical antagonism?

Back 60

Formation of a complex between effector drug and another compound.

Example: Protamine binds to heparin to reverse its action.

Front 61

What type of dose-response curve permit estimation of median effective dose (ED50)?

Back 61

Quantal (Cumulative) D-R Curves.

Front 62

What is the ED50?

Back 62

Dose that's effective in 50% of the population

Front 63

What does therapeutic index mean?

Back 63

It's an evaluation of the relative safety of a drug as it compares the toxic dose (TD50) or lethal dose (LD50) to the effective dose (ED50).

TI = TD50/ED50 or LD50/ED50

("TILE")

Front 64

Calculate therapeutic index. What does the number tell you?

Back 64

TI = TD50/ED50
TI = 10/2
TI = 5

If you take five times the recommended dose on average in the population, you are going to experience toxicity.

Front 65

Low therapeutic index means that a drug is _______ (safe/unsafe).

Back 65

unsafe... it means that a low number of recommended dosages will lead to toxicity.

Front 66

Give a list of four drugs with a low therapeutic index.

Back 66

(1) Theophylline
(2) Digoxin
(3) Warfarin
(4) Lithium

Front 67

What curve is therapeutically preferred and more safe?

Back 67

The orange. It is steeper and it reflects a lower patient variability. The purple curve would overlap the therapeutic range with the toxic range (not preferred).

Front 68

Pharmacologic responses elicited via modification of gene expression (steroids) are usually __________ (faster/slower) in onset but ____________ (longer/shorter) in duration than many other drugs.

Back 68

slower; longer

Front 69

Give four examples of molecules that work by intracellular receptors.

Back 69

(1) Thyroid hormones
(2) Glucocorticoids
(3) Testosterone
(4) Vitamin D

Front 70

True or false: Membrane receptors coupled to ion channels utilize second messengers. Give an example.

Back 70

False. These receptors are directly coupled to ion channels.

Nicotinic receptor for ACh

Front 71

The GABA_A receptor in the CNS is coupled to?

Back 71

Chloride channels.

Front 72

How do receptors that are coupled to intracellular enzymes via coupling proteins look like?

Back 72

"Serpentine" with 7 transmembrane spanning domains, the third of which is coupled to the G protein effector mechanism.

Front 73

Binding of an agonist linked to Gs proteins will do what?

Back 73

Increase cAMP production.

Front 74

What receptors are coupled to an increase in cAMP?

Back 74

Beta1, Beta2, D1, H2, V2

Front 75

Glucagon, similar to beta receptors, are linked to what coupling proteins?

Back 75

Gs

Front 76

Binding of an agonist linked to Gi proteins will do what?

Back 76

Binding of agonists linked to Gi proteins decreases cAMP production.

Front 77

These receptors are linked to Gi proteins.

Back 77

Alpha2, M2, D2

Front 78

How are receptors linked to Gq proteins different than receptors linked to Gs proteins?

Back 78

Gq use the effector phospholipase C, and not adenylyl cyclase. Activation of phospholipase C releases second messengers IP3 and DAG from the membrane phospholipid PIP2. IP3 releases CA++ from SR, which together with DAG activates protein kinase C.

Front 79

What receptor types are linked to Gq proteins?

Back 79

Angiotensin II, Alpha1, M1, M3, H1, V1

"Tense and HAVe 1 M&M"

Front 80

cGMP is a second messenger in _____________ that __________.

Back 80

vascular smooth muscle; dephosphorylates myosin light chains

Front 81

cGMP activates what?

Back 81

Protein kinase G

Front 82

What are some molecules that can increase NO synthesis by endothelial cells?

Back 82

(1) Nitrates
(2) Bradykinin
(3) M agonists
(4) Histamine

Front 83

These receptors function as transmembrane enzymes.

Back 83

Receptors for insulin and growth factors such as EGF and PDGF.

Front 84

This is a guanylyl cyclase associated receptor ligand.

Back 84

ANP

Front 85

Receptors for cytokines are _________ and on activation can activate a distinctive set of ______________.

Back 85

membrane-spanning; cytoplasmic tyrosine kinases (JAKs).

Front 86

What is the role of JAKs?

Back 86

JAKs phosphorylate signal transducers and activators of transcription (STATs). STATs dimerize, then dissociate, cross nuclear membrane and modulate gene transcription.

Front 87

Drug development and testing involves what phases?

Back 87

Preclinical, Phase 1, Phase 2, Phase 3, Phase 4

Phase 1,2,3,4 = Clinical trial

Front 88

What does preclinical testing of a drug involve?

Back 88

Involves 2 different animal species. Purpose is to evaluate safety and biologic activity prior to trying it out in humans in clinical trial.

Front 89

What happens in phase 1 of drug development and testing?

Back 89

~50 healthy volunteers are given the drug. The question we are posing now is "Is the drug safe?". (Safety & Dosage)

Front 90

What happens in phase 2 of drug development and testing?

Back 90

The drug is tested on ~200 patients with the disease. Now we evaluate effectiveness of the drug.

Drugs often fail in phase 2.

Front 91

What happens in phase 3 of drug development and testing?

Back 91

~2000 patients are exposed to the drug. We confirm effectiveness of the drug as well as common side-effects. This is an expensive phase.

Front 92

What happens between phase 3 and 4 of drug development and testing?

Back 92

Drug company applies for a new drug application with the FDA.

Front 93

What happens in phase 4 of drug development and testing?

Back 93

Post-marketing surveillance (after FDA approval). We discover common as well as rare side-effects (higher number of people).

Front 94

FDA classification of drugs and pregnancy considering teratogenicity.

Back 94

Front 95

What category of drugs are the safest in pregnancy?

Back 95

A

Front 96

How safe are category B drugs for use in pregnancy?

Back 96

Some animal models have shown risks, however, none in humans, so B category is considered safe.

Front 97

How safe are category C drugs for use in pregnancy?

Back 97

This is the unknown category. We don't have any data, only for animals.

Front 98

These categories of drugs have a definite risk for use in pregnancy.

Back 98

D and X

"Benefits outweigh the risk":
- E.g. pregnant woman taking anticonvulsant with known teratogenic effects because this anticonvulsant is the only one that treats her seizures adequately.