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Pharm > Section 1 > Flashcards

Section 1 Flashcards

1
Q

In vitro studies

A

Identification of a new drug target
Screening for a lead compound

Target validation -> target identification -> lead compound ID -> Candidate Optimization

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2
Q

Pre-clinical Testing

A

Animal Testing
2-4 years
Tests: Efficacy, Selectivity, Mechanism

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3
Q

Clinical Testing: Phase I

A

Phase I: is it safe? What are the pharmacokinetics?

20-100 people

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4
Q

Clinical Testing: Phase II

A

Does it work in patients with the disease?
100-200 patients
Usually conducted in special clinical centers
Measures: safety and efficacy “proof of concept”

Phase II: have the highest rate of drug failures

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5
Q

Lipinski Rule of 5

A 
No more than 5 H-bond donors
No more than 10 H-bond acceptors
Molecular mass of less than 500 Da
Octane-water partition coefficient NOT greater than 5
 (Solute in octanol / solute in water)
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6
Q

Preclinical Testing

A

Tests acute toxicity: determines maximum tolerated dose
Determines dose that is lethal in 50% of animals

Subacute Toxicity:
- determines the biochemical and physiological effect

Effect on reproductive performance
Carcinogenic Potential
Mutagenic Potential

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7
Q

Limitations of Preclinical Testing

A

Expensive and time consuming (2-6 years)

Large number of animals needed
Extrapolations of therapeutic index Anand toxicity data from animals

Rare and adverse effects are unlikely to be detected in preclinical testing

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8
Q

Confounds to clinical testing:

A

Variable hx of disease = overcome by large population evaluated over time

Presence of other diseases/risk factors = over come by cross over technique

Subject/observer bias =

  • placebo responses = overcome by single blind, crossover design
  • observer bias = double-blind design
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9
Q

IND

A

Investigational new drug application filed with the FDA

Includes:

  • info on composition/source of drug
  • chemical information
  • all data from preclinical
  • proposed clinical trial plans
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10
Q

Phase I Clinical Trial

A

20-100 healthy volunteers

Effects of drug as function of dosage for expected toxicity

To find the maximum tolerated dose so that a dose can be recommended for phase II

Pharmacokinetics measured
- absorption, distribution, 1/2 life, metabolism, excretion

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11
Q

Dose Escalation Methods of a Phase I Clinical Trial

A

Amount of drug in dose is increased with each cohort added

  • each cohort is called a “dose cohort” (~10)
  • new dose cohort cannot be initiated before safety in previous cohort has been fully assessed

Modified Fibronacci Series: add previous dose to the current one to get the new dose

With dose increases, the action between 2 consecutive doses get smaller

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12
Q

Phase 0 Clinical Trial

A

To test to see how much of a drug is present in tumor, blood, tissue after one dose —> to see if the drug actually got INTO the tumor

To check whether there is a problem with how the drug is:
Absorbed, distributed, metabolized

Pharmacokinetics and dynamics

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13
Q

Phase II Clinical Trial

A

In patients with the targeted disease (n = 100)

To determine efficacy = proof of concept

Evaluates safety, tolerability, efficacy

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14
Q

Phase III Clinical Trial

A

Evaluated in larger patients (1000-6000)

Performed in settings similar to those anticipated for ultimate use of the drug

  • formulated as intended for the market
  • usually expensive due to large number of patients

Safety and Efficacy

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15
Q

NDA

A

New Drug Application

  • if phase III trial meets expectations, NDA is filled out to market agent
    (For biological, a BLA is filed)

Takes months/years for FDA to review
Number of subjects avg 5000

Priority review for breakthrough drugs -> accelerated approval might be granted

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16
Q

Orphan Drug Program

A

Gives incentives for drugs that treat rare disease
(If less than 200,000 puts or R+D costs do not expect to be recovered)

Eg. Gleevec - oral treatment for CML

Accelerated Approval of NDA: use surrogate endpoints for effectiveness
- bio markers that are likely to predict clinical benefits

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17
Q

Phase IV Clinical Trial

A

Post marketing surveillance begins
NDA approved

Delienate treatment risks, benefits and use under “actual use” conditions
Efficacy Study

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18
Q

Patent Rights

A

20 year term for a drug patent filed after 1995

  • sometimes the patents expire after the drug is approved

Post expiration of the patent = any company can produce the equivalent
- file a ANDA (abbreviated new drug application) to market a generic version

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19
Q

MW of drugs

A

100-1000 Da

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20
Q

Agonist

A

Drugs that mimic actions of endogenous compounds

Agonist interacts with receptor to produce a pharmacological response

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21
Q

Partial Agonist

A

Agonist that produces a partial response when the receptor is fully saturated

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22
Q

Inverse Agonism

A

Binds to the same receptor as an agonist but produces the opposite effect

Requires that the receptor has a basal level of activity in absence of ligand

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23
Q

Antagonist

A

Interferes with action of an agonist/partial agonist/inverse agonist by binding to the receptors

  • they bind to the receptor and do not produce a pharmacologic response
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24
Q

Total number of receptors on a cell determines…

A

Maximal drug effect that the drug might produce

E = [D] x Emax/[D] + EC50

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25
Q

Binding of different agonists to the same receptor:

A

Plotted on semi log
Sigmoidal curve
EC50 corresponds to the inflection point on the graph

Two drugs will show the same Emax, yet different EC50

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26
Q

Low EC50

A

High Potency

Less drug needed to reach half of maximal response

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27
Q

High EC50

A

Low potency
Need more concentration to reach 1/2 max

High drug is not desirable, since adverse effects are likely to increase

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28
Q

Potency Ratio

A

Differences in potency between two drugs

EC50 of Drug A/EC50 of Drug B = potency ratio

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29
Q

What determines the efficacy of the drug?

A

Emax

Agonist versus partial agonist behavior = PA shows lower efficacy

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30
Q

How are drugs selected?

A

On efficacy or Emax

The amount of drug given is based on the determination of the potency factor

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31
Q

Antagonists

A

Drugs that block actions of endogenous agents
Carry no activity

Observing Effects:

  • plot dose-response curve of an agonist
  • determine how that curve is affected by differing antagonist concentrations
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32
Q

Competitive Antagonists

A

One whose effects can be overcome by adding more agonist

Agonist and antagonist compete with one another

Commonly observed if they have reversible binding property to receptor

By adding more:

  • curve shifts to the right (EC50 increases)
  • Emax is unchanged

Better antagonist = tighter binding to the receptor

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33
Q

Non Competitive Antagonists

A

Prevents agonist from reaching maximum effect

Irreversible binding = like a covalent modification

Antagonist bound receptors are effectively removed from the pool of agonist targets

By adding more non-competitive antagonist:

  • Emax is reduced
  • EC50 remains unchanged

Makes the agonist look like a PARTIAL agonist (Emax lowered, EC50 unchanged)

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34
Q

Space receptors

A

Increase sensitivity of tissue to the drug (use little bc the target is larger)

Agonist can produce max response without binding to all of the available receptors

35
Q

Irreversible Antagonists in Spare Receptor Situation

A

IA decrease the number of spare receptors

  • increase EC50
  • Emax left unchanged

Once all space receptors are quenched, further addition of antagonist no longer effects the EC50

  • EC50 remains unchanged
  • Emax decreases
36
Q

Therapeutic Dose

A

ED50

37
Q

Lethal Dose

A

LD50

Toxic dose

38
Q

Dose Response Curves

A

Difficult to construct when pharm response is an “either-or” event

Inter-individuality limits the applicability of 1 dose-response relationship to another

39
Q

Quantal Dose Response Curve

A

Y axis = number of individuals responding

X axis = concentration of drug (log[D])

Median effective dose = 50% of individuals exhibit the quantal response

40
Q

Therapeutic Index

A

Margin of safety to be expected for a drug

Therapeutic Index = TD 50/ED 50

On Dose-Response Quantal Curve, it is the range of dose between TD50 and ED50

41
Q

What is the major route of elimination in drugs?

A

Excreted through the kidney unchanged

42
Q

Lipophillicity of most drugs:

A

Facilitates cross through membrane

Renal excretion of lipophillic drugs are POOR due to reabsoportion through the tubular membranes

43
Q

What is the 2nd Major Route of Drug Elimination?

A

Bio transformation of drugs in hydrophilic metabolites

  • making them more polar is critical for the termination of biological activity and excretion through the body
44
Q

What are Phase I Reactions in Xenobiotic Metabolizing System?

A

Introduce/exposes a polar functional group
- OH, COOH, NH2, SH on compound

Enzymes that Catayzle Phase I Functionalization Rxns exist on ER membrane

45
Q

What are Phase II Enzymes in Metabolism?

A

Phase II Rxns (Conjugation Reactions)

Conjugation of compounds to yield even more polar conjugated
Located in the cyto soul

46
Q

Where is the main site of drug metabolism/biotransformation?

A

Liver = principal organ

GI tract, lungs, skin, kidneys = secondary

47
Q

Cytochrome 450

A

Involved in Phase I reactions

Oxidative Rxns require:

  • molecular oxygen
  • NADPH - reducing agent
  • Cytochrome 450
48
Q

CYPs

A

Large capacity to metabolize large number of diverse chemicals
Not high specificity

Major Form:
CYP3A4

49
Q

Phase II Conjugation Reactions in Drug Metabolism

A

Functional group by Phase I makes compound reactive
- neutralize functional group, make more soluble

Phase II

  • involve specific transferases located in the cytosol
  • couples a endogenous substance + exogenous

HIGHLY POLAR NATURE OF CONJUGATES PROMOTE elimination

50
Q

Glucuronidation (Phase II reaction of Metabolism)

A

Endogenous reactant = UDP-Glucuronic Acid

Uses UDP-glucuronosyltransferase (UGT)

51
Q

Glutathione Conjugation in Phase II Reactions

A

Major detoxification pathway
- conjugates reactive electrophillic compounds with tripeptide glutathione

Glutathione S Transferase
Endogenous Reactant = Glutathione

52
Q

Sulphation in Phase II Conjugation Reaction

A

Sulphotransferase

Endogenous reactant = PAPS

53
Q

The metabolic products are…

A

Often less active than the parent drugs

- they might have enhanced ability (inactive prodrugs might convert to metabolically active drugs

54
Q

Drug metabolism…

A

Increases clearance

Decreases 1/2 life

55
Q

Before a New Drug Application…

A

Route of metabolism and enzymes involved must be known

56
Q

Isoniazid (INH)

A

Is the exception where Phase II reactions precede Phase I reactions

Acetylation (Phase II) occurs 1st
Hydrolysis (Phase I) occurs 2nd

57
Q

Induction of metabolizing Enzymes

A

Increases the number of enzymes
Induces Cytochrome P450 gene (of which makes more enzyme)
- increases metabolism rate of some drugs

58
Q

Inhibiting Metabolizing Enzyme

A

Decreases the amount of enzymes

Grapefruit juice
Alcohol

Might impair elimination of the drug, prolong its effects, increased incidence of drug toxicity

59
Q

Liver dysfunction

A

Affects the liver function and diminishes they metabolism of some drugs
- increases the half life of drugs

60
Q

As one ages, there is..

A 
Decrease in:
liver mass
Hepatic enzyme activity
Hepatic blood flow
P450 activity

Females: decreased oxidation of estrogens and benzodiazepines

61
Q

Oral Route Absorption of Drugs

A

Absorption of drug from H2O across the GI epithelium

GI -> Blood

62
Q

Drug Lipophillicity

A

Factor involved in absorption
- lipid/water partition coefficient is the best predictor of drug entry measured by octanol/water

  • higher the coefficient means that the drug will leave the water phase and cross into the GI epithelium
63
Q

PkA or Ka of a adrug

A

Factor involved in absorption

Most drugs are weak bases or weak acids

64
Q

Uncharged weak acid

A

Protonated form

Can move across the biological membrane

65
Q

Uncharged form of weak base

A

Unprotonated form

Can move across the biological membrane

66
Q

Lipid/Water Partition Coefficient

A

Best predictor of drug entry into body

If above one, or higher, the drug will more readily leave the water phase and cross the GI epithelium

67
Q

10 (pH-pKa) =

A

[A-]/[HA]

For carboxlyic acids, they are ionic in the deprotonated state.

68
Q

1O (pH-pKa) = (for amines)

A

[B]/[BH+]

69
Q

Partitioning of Drug

A

Distribution of a drug will proceed until the uncharged form of drug achieves equal concentration in both water compartments

At equilibrium, the total drug concentration is higher in compartment with higher pH-dependent ionization.
-> if it is ionized, it is stuck in place!

70
Q

Oral Bioavailability of a drug is:

A

Fraction of the drug that gains access to systemic circulation in chemical all unaltered forms
- if it is absorbed well and survives the liver metabolism

Mouth -> GI -> liver (1st pass metabolism)

71
Q

Infusion Rate

A

R = CL (body) x CL (plasma)

72
Q

Half Life Equation

A

T1/2 = .693 x Vd / CL(body)

Vd = L/kg
This means that you need to correct for Kg of the patient
Vd = 1.5L/Kg x 70kg

73
Q

What is the time for a drug to reach steady state concentration?

A

Four 1/2 lives

Eg:
(8 hr half-life)(4) = 32 hours to reach steady state

74
Q

To create an IV regimen, you begin with twice the effective dose of the drug. Then what?

A

Repeat with the effective dose every 1/2 life of the drug.

Only works if:

  • half-life is between 8-24 hrs
  • 2 fold fluctuation in the drug is acceptable

Example:
Loading dose = 500 mg
Maintenance Dose = 250 mg/8 hours

75
Q

Switch from IV -> Oral Considerations:

A

Maintenance Dose in IV is 100mg/2x day

Oral Dose with a bioavailability of 50% = 200mg/2x

76
Q

Fixed Dose and Fixed Time Regimen = most common pattern of administration

A

Drugs are eliminated exponentially
- some of the 1st dose is present at the time of the 2nd dose

Drug accumulates until its concentration increases to a SS point where the rate of input = rate of output

77
Q

When is steady state reached?

A

After 4 half lives, the amount of drug lost during the dosing interval is exactly what is being put in

78
Q

Volume of Distribution (Vd)

A

Vd must be normalized by body weight (L/Kg)

Vd = total amount of drug in the body/plasma concentration of drug
Vd = Ab / Cpl
79
Q

Clearance (CL)

A

Volume of plasma from which all drug is removed

CL(body) = L/hr, mL/min
- should be normalized for body weight

CL(renal)+CL(hepatic)=CL(body)

80
Q

Clearance of drug at an organ

A

CLorgan = Organ Plasma Flow (OPF) x Extraction Ratio (ER)

Extraction Ratio: fractional decline in drug concentration from arterial->venous side of the organ

81
Q

Half Life

A

Time it takes for plasma concentration or amount of drug in body to be reduced by half

T1/2 = .693 x Vd/CLbody

As Vd goes up, so does the half-life

82
Q

IV infusion

A

Continuous administration at a constant rate

Upon infusion, plasma concentration rises until the rate of loss = rate of input
- Cpl-ss = therapeutic level / efficacious level

83
Q

At the steady state, the rate of the infusion =

A

R = CLbody x Cpl-s

84
Q

Increase in Rate, changes SS-level in what way?

A

2R will cause the steady state level to double

Therefore, increasing rate does not allow SS to be reached faster

2 in 2R controls where you end up, not how fast you get there.

Pharm (6 decks)

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