Pharm 1 - Intro To Med Pharm (Nierenberg) And Dose Response (Sanchez)

Front 1

Things that a generic company doesn't have to match to the previous brand name drug

Back 1

Excipients - they are a secret of the original company.

Must maintain bioavailability within 10%

Front 2

4 stages of pharmacokinetics

Back 2

Absorption, distribution, metabolism, excretion

(ADME)

Front 3

Number of subjects in brand name vs. generic

Back 3

Brand name - 500-3000
Generic - 20 healthy volunteers (medical students often)

Front 4

Things a generic has to match

Back 4

Kinetics - a comparable bioavailability, area under the curve, Cmax and Tmax

All other USP requirement - I think purity is the main one.

Front 5

Area under the curve

Back 5

Select many blood samples over time to measure the overall amount of drug in the bloodstream after a dose.

Front 6

Tmax

Back 6

The time at which Cmax occurs.

Front 7

T/F
The new product must be tested for clinical efficacy in 100-500 patients

Back 7

F

Front 8

T/F
The new product must match (+/- 10%) the original drug in AUC – this is bioavailable for its absorbability

Back 8

T

Front 9

T/F
C. The new product must match (+/- 10%) the original drug in F

Back 9

T

Front 10

T/F
The new product must match (+/- 10%) the original in Cmax and Tmax

Back 10

T

Front 11

T/F
The new product must contain the same active ingredient as the original drug, in exactly the same salt and dose

Back 11

T

Front 12

T/F
The new product must contain exactly the same excipients as the original drug, and be the same color and shape as well so patients will not be confused

Back 12

F

Front 13

T/F
The new product must be sold at a price that is at least 50% less than the original product

Back 13

F

Front 14

Drug class ibuprofen

Back 14

NSID
Analgesic, antipyretic, anti-inf, anti-gout, anti-dysmennorhea

Front 15

Pharmacodynamics Ibuprofen

Back 15

Inhib of PG synth via COX-1,2

Front 16

Pharmacokinetics Ibuprofen

Back 16

F=80%
Extensive metab in liver and some excreted unchanged in urine.

Front 17

Toxicity Ibuprofen

Back 17

Allergies (Asthma, nasal polyps, etc.)
Caution in pts with renal compromise or ulcer disease.
Fluid retention in CHF patients.

Front 18

Drug interactions Ibuprofen

Back 18

Warfarin, aspirin, diuretics, antihypertensives

Front 19

Special considerations ibuprofen

Back 19

Greater potential for toxicity in geriatric patients.

Front 20

Route of ibuprofen

Back 20

po

Front 21

Do drugs create effects?

Back 21

No
They only modulate ongoing functions.

Front 22

Do all drugs work through receptors?

Back 22

No, but most of them do.

Exceptions are chelators, antacids)

Front 23

Agonist

Back 23

Ligand interacting with a receptor to initiate a response.

Front 24

Antagonists

Back 24

Ligands that occupy the receptor site but doesn't elicit the response OR INHIBIT THE NORMAL RESPONSE!!!

Front 25

Couple response

Back 25

The receptor for the ligand is also the macromolecule that initiates the biological response.

This is seen with ligand-gated ion channels (e.g. nicotinic ACh receptor)

Front 26

Trans-activation

Back 26

Expression of genes due to a ligand-activated txpn factor

(e.g. glucocorticoid hormone receptor)

Front 27

Weakest type of bond

Back 27

Van der Waals

Most interactions are through H bonds.

Front 28

Are most drugs in active state charged or uncharged?

Back 28

Uncharged

Front 29

Association process

Back 29

First ionic bonds form, then H, and if the fit is really good, the VDW interactions.

Front 30

Frequency of drug interactions is a function of...

Back 30

concentrations of the drug and receptor
and
the drug-receptor affinity.

Front 31

Magnitude of drug interaction is a function of...

Back 31

the concentration of drug-receptor complexes at any moment in time.

Front 32

Dose response curve

Back 32

Response on linear scale, dose on log scale.

Usually sigmoidal curve.

Front 33

Quantal dose response curve

Back 33

All or none phenomena.

Can get ED50 and LD50 from these.

The drug is given to many animals at a number of different doses.

Responses are usually over a narrow dose range.

TELLS YOU ABOUT THE POPULATION (inter-individual variation). Doesn't tell much about an individual.

Good to compare different drugs to each other or response to same drug under different experimental conditions.

Can get a gaussian distribution from this.

Front 34

ED50 and LD50

Back 34

Doses where the drug is effective or lethal for 50% of the population.

Based on a quantal dose response curve.

Front 35

Graded/continual dose-response

Back 35

More common clinically

Individual demonstrated incremental response to increasing doses of a drug.

Tell nothing about the population.

Mid-point of this curve represents (but is not) the Kd and the upper limit indicates saturation.

Front 36

Are side effects necessarily bad?

Back 36

No

Front 37

If you are sensitive/resistant to the ED are you also the same for the LD?

Back 37

Yes, likely.

Front 38

Does LD include undesirable/toxic effects?

Back 38

Yes - the LD50.

Front 39

Therapeutic index

Back 39

LD50/ED50

Bigger is obviously better.
This is a poor predictor of risk since it is baed only on the median point for the population (and we are worried about individuals).

THIS TELLS YOU NOTHING ABOUT THE SLOPE OF A CURVE!!!

Front 40

Margin of safety

Back 40

LD1/ED99

Bigger is better. This is a more conservative index.

Front 41

Protective index

Back 41

ED50 (undesirable) / ED50 (desirable)

Since lethality isn't often the issue clinically, this tells us about side effects.

A high protective index increases compliance.

Front 42

Chronicity index

Back 42

On-dose LD50/Ninety-dose LD 50

In terms of safety (not efficacy), 1 is the best (total clearance) and 90 is the worst (no clearance).

We do this because we rarely give a drug once, so we need to know if it is getting cleared.

But the problem with a CI of 1 is that we can't maintain a steady-state so therapy is problematic.

Front 43

Threshold dose

Back 43

All-or-none phenomena at a specific threshold dose. (e.g. acetaminophen and liver toxicity)

There is a dramatic and quantal leap in toxicity.

Front 44

Acetaminophen toxicity

Back 44

It is metab by P450s and glutathione transferase. But when this system is saturated, it generates reactive metabolites that attack tissues and lead to liver toxicity and failure.

Front 45

Potency

Back 45

The RELATIVE dose required to produce a given effect.

More potent is not better. Because it could be cheaper, have less SEs and be safer.

Potency is usually the dose where 50% of the intrinsic activity is reached.

Front 46

Intrinsic activity

Back 46

This is the magnitude of the maximal response (highest dose)

Front 47

Potency and intrinsic activity

Back 47

Relative characteristics derived from dose-response data.

Front 48

Affinity and efficacy

Back 48

Kinetic constants that describe molecular interactions of the drug and its receptor

Front 49

Affinity is...

Back 49

one component of potency

Front 50

Efficacy is...

Back 50

one components of BOTH POTENCY AND INTRINSIC ACTIVITY.

Front 51

Chemical antagonism

Back 51

Direct interactions
(e.g. chelators or antacids)

Front 52

Functional antagonism

Back 52

Two agonists working on pathways that have opposite effects.

Front 53

Competitive antagonist

Back 53

Binds to a receptor and elicits no response.

This is the most frequent antagonism clinically.

Blocks the agonist

Has two types: Equilibrium (reversible) and non-equilibrium (irreversible).

Front 54

Equilibrium competitive antagonist

AKA reversible

Back 54

Binds the ligand binding site

Comes off the receptor and thus more agonist can make a difference.

Right-shift of the curve. Changes potency.
Does not change intrinsic activity.

Front 55

Non-equilibrium competitive antagonist

AKA non-reversible

Back 55

Stays bound to the receptor (ligand binding site) and doesn't come off.

Flattens the dose-response curve.

Does not change potency. Changes intrinsic activity

Front 56

Non-competitive antagonist

Back 56

Acts at a site other than the site of agonist binding, but affects the same process.

This can include an action downstream of the agonst effects (e.g. calcium channel).

Could also bind another site on the same receptor (allosteric effects)

Has the same kinetic effects as a non-equilibrium competitive agonist (reduces intrinsic activity, maintains potency).

Front 57

Two-state receptor model

Back 57

Active/inactive states are independent of whether there is an agonist present or not.

Agonists shift equilibrium to active state
Inverse agonists shift to inactive
Antagonists interferes with the binding of both of these and maintain the status quo.

Front 58

Partial agonists

Back 58

Low intrinsic activity.
In combo with a full agonist, it has properties of both an agonist and antagonist.

Front 59

Simple synergy

Back 59

Each drug acts alone and the combo is greater than additive.

Front 60

Potentiation

Back 60

A type of synergy.

One or both of the drugs normally has no effect alone but results in synergy when together.