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Pharmacokinetics > Drug Development > Flashcards

Drug Development Flashcards

1
Q

Name the different drug legislations in the USA

A
  • Food Drug and Cosmetic Act 1938
  • Harris-Kefauver Amendments
  • Controlled Substance Act 1970
  • Hatch Waxman Act
  • Dietary Supplement Health and Education Act 1994
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2
Q

Food Drug and Cosmetic Act 1938

A
  • First legislation to address drug safety
  • All new drugs must undergo testing for safety

1937 – contaminated sulfanilamide kills 107 people

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3
Q

Harris-Kefauver Amendments

A
  • Effectiveness required (in addition to safety)
  • Rigorous testing requirements for new drugs
  • Thalidomide (caused birth and fetal deaths)
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4
Q

Controlled Substance Act 1970

A
  • Set rules for manufacture and distribution of drugs considered to have potential for abuse
  • Schedule 1, 2, 3, 4, 5 based on potential abuse
  • Opioids (schedule 2)
  • Hand written prescription, no refill
  • Document waste of medications.

Enforced by DEA

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5
Q

Hatch Waxman Act 1984

A

Increased availability of generic drugs

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6
Q

Dietary Supplement Health and Education Act 1994

A
  • Restricted the labeling of supplements

- Not required to go through FDA

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7
Q

What are the stages of new drug development

A

Pre-clinical testing
Clinical Testing
Marketing

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8
Q

What happens during the pre-clinical testing

A
  • in vitro, tested on animals
  • Required before a new drug may be tested in humans
  • Evaluating for :
    Toxicities - mutagenicity,
    carcinogenicity, reproductive, chronic
    tox
          Pharmocokinetic properties –animals, 
      metabolism

      Pharmacology – Mechanism (how this 
      works, how selective its going to be, 
       and efficacy
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9
Q

How long does pre-clinical testing take

A

Takes 1-5 years

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10
Q

What happens during the clinical testing?

A
  • Tested on humans
  • occurs in four phases
  • The first three are done before a new drug is marketed
  • The fourth is done after marketing has begun
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11
Q

What happens during phase 1 of clinical testing?

A

PK, safety, dose

  • Subjects: Healthy Volunteers
  • N = 20-80
  • Takes 1 year
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12
Q

What happens during phase 2 of clinical testing?

A

Effects and Safety

  • N= 100-300
  • Subjects: patients
  • Takes 2 years
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13
Q

What happens during phase 3 of clinical testing?

A

Safety and Effectiveness

  • Rigorous design (double blind, placebo controlled)
  • Subjects: thousands of patients
  • Takes 3 or more years
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14
Q

How long does clinical testing take

A

Takes 4-6 years

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15
Q

What happens during phase 4 of Marketing

A
  • Postmarking surveillance
  • New drug is released for general use, permitting observation of its effects in a large population
  • Low incidence of AEs
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16
Q

What is the prescribing label?

A
  • Based on preclinical, clinical, post marketing
  • Highlights approved indications, contraindications, black box and other warnings, AE
  • Off label use - FDA indication/ not FDA approved, we do this all the time and it is not wrong
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17
Q

What are the three main drug names?

A
  • Chemical name
  • Generic name
  • Brand name
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18
Q

Generic Name

A
  • Use the most
  • Example: Acetaminophen
  • Many professionals advocate for the universal use of generic names
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19
Q

Brand Name

A

Tylenol is the brand name for acetaminophen

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20
Q

Name factors that influence intensity of drug response during administration?

A
  • medication error

- patient adherence

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21
Q

Name factors that influence the intensity of drug response for pharmacokinetics?

A

ADME

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22
Q

Name factors that influence the intensity of drug response for pharmacodynamics?

A
  • drug receptor interactions
  • patients functional state
  • placebo effects
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23
Q

What are the sources of variation

A
  • Physiological variable
  • Pathologic variable
  • Genetic variable
  • Drug interactions
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24
Q

What are ligands?

A

molecules that bind to receptors

Drug is a ligand

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25
Q

What are receptors?

A

macromolecule to which a drug (ligand) binds to produce effect

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26
Q

Give examples of exogenous ligands

A

Hormones
Neurotransmitters
Regulatory molecules

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27
Q

What happens when a ligand binds to a receptor?

A

it will either mimic or block what is suppose to happen

biological response
clinical effect

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28
Q

What are the 4 primary receptor families?

A
  • Cell membrane- embedded enzyme
  • Ligand gated ion channel
  • Transcription factors
  • G protein coupled receptors
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29
Q

Cell membrane embedded enzyme

A

-Activation occur in seconds

-Agonist drug or endogenous ligand
Example: insulin

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30
Q

Ligand gated ion channel

A

-Activation are extremely fast and occur in milliseconds

-Agonist drug or endogenous ligand
Example: ACH, GABA

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31
Q

Transcription factors

A
  • Activation can take 4 hours to days
  • Nucleus
  • Requires lipid solubility to reach the cell nucleus
    * Example: Thyroid hormones, steroids
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32
Q

G-protein coupled:

A
  • Activation occurs rapidly
  • Receptor —-G protein—- effector

-Agonist drug or endogenous ligand
*Example: NE, Serotonin, Histamine and
other peptide hormones

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33
Q

What are the drug-receptor components?

A

Drug types

Binding sites

34
Q

What are the 2 general types of drugs

A

Agonist

Antagonist

35
Q

What is the binding site

A

Lock and key

Reversible: ligand is removed or substituted

Irreversible: bound to enzyme, receptor until that receptor is no more

36
Q

How do drugs produce limited effects in certain parts of the body?

A

Receptor selectively

Receptor distribution/location

37
Q

Receptor selectively

A
  • How can we make drugs selective for an enzyme in specific organs?
  • We want to keep drugs where we want it.
38
Q

Receptor distribution/location

A

Where is receptor located?

39
Q

Define agonist

What is affinity and intrinsic activity

A
  • Activates receptors
  • Endogenous ligand (hormones, neurotransmitters)

-Both affinity and high intrinsic activity
* Affinity: has strong attraction between
drug and receptor. Allows agonist to
bind to receptors

        *Intrinsic activity: Allows the bound 
         agonist to activate or turn on receptor 
         function
40
Q

Define antagonist

A

-Blocks receptor activation

-Even though it doesn’t cause receptor activation, it produces pharmacological effects by blocking effects of endogenous ligand
•Beta-blocker blocks effects of NE
•Naloxone antidote in morphine
overdose

-Has affinity because it allows the antagonist to bind to receptors, but lacks intrinsic activity, prevents the bound from causing receptor activation

41
Q

What is a partial agonist?

A
  • Agonist with only moderate intrinsic activity
  • The maximal effect that partial agonist can produce is lower than that of a full agonist.
  • Act with a little bit of agonist action and a little touch of antagonist
42
Q

Give an example of partial agonist

A
  • Pentazocine is administered by itself, it occupies opioid receptors and products moderate relief of pain.
  • If I am taking high does of another opiod (morphine) and you give me a large dose of pentazocine –pentazocine is acting as both an agonist (producing moderate pain relief) and an antagonist (blocking the higher degree of relief that could have been achieved with meperidine by itself)
43
Q

What is a competitive antagonist

A
  • Reversible
  • Produce receptor blockade by competing with agonists for receptor binding
         • beta blocker such as proprandolo
     •if there are more agonist than 
     antagonist, agonist will occupy space, 
     ices versa
44
Q

What is a noncompetitive antagonist

A
  • Irreversibility
  • Reduces number of receptors available for activation by agonist
  • Reduces the maximal response that agonist can elicit
  • Less common, long duration
  • Has to rely on your body’s natural process of breaking down old receptors and making new ones
45
Q

Give an example of noncompetitive antagonist

A

Omeprazole decreases gastric acid

46
Q

What types of drugs don’t work via a receptor?

A
  • Antacid (not absorbing, just neutralizing stomach acid)
  • Osmotic laxatives (retain water in stool to soften it to increase bowel movements)
  • chelating agents, resins (
47
Q

Describe characteristics of the dose-response curve.

A

S-shaped (as dose increases, response increases)

Response increase w/dose

Levels off (drugs level off at higher doses, so that further increases in dosage lead to minor increases in effectiveness)

Steeper vs. Flatter slope

48
Q

Why is steeper slope less safe

A

Doesn’t increase gradually

Minor changes in dose might create a major change in dose response so that will result in narrow therapeutic window

Can reach toxic level

49
Q

What is ED50?

A

Is a median dose that 50% will experienced maximal response

50
Q

What is flatter slope safe?

A

More wiggle room, less room for toxic levels

51
Q

What is efficacy.

A

Maximal response produced by drug

52
Q

Does efficacy matter

A

Yes

53
Q

What is potency

A

Dose of drug required for a given response

54
Q

Compare efficacy and potency for 2 drugs.

A

Look at notebook

55
Q

For drugs with equal efficacy, does potency matter?

A

No, it is not an important quality in a drug

Does not imply nothing about its maximal efficacy.

56
Q

What are the drug effects for population of patients?

A

VARIABILITY it varies

57
Q

What is the difference between TD50 and ED50

A

Therapeutic index

58
Q

What is TD50

A

median toxic dose that 50% of individuals will exhibit toxic response

59
Q

What is ED50 (quantal dose-response)

A

Median effective dose that 50% of individuals will exhibit maximal response

60
Q

Narrow Therapeutic Index Window

A

As we make small adjustments we see big effects. We get it from a therapeutic window to a toxic window

61
Q

What is side effects of drugs.

A
  • Nearly unavoidable secondary effected produced at therapeutic doses
  • Every drug can cause nausea, fatigue, headache. 10% complain of nausea.
  • This information was gathered during clinical
62
Q

Define adverse effect of drugs (toxicity)?

A

Adverse effect due to an excessive dose

Can range from annoying to life threatening

63
Q

Define adverse effect of drugs (toxicity)?

A

Adverse effect due to an excessive dose

Can range from annoying to life threatening

64
Q

Dose-dependent adverse effect

A

As we increase dose, we expect different responses

65
Q

Idiosyncratic reaction

A
  • Uncommon response resulting from a genetic deposition

- What happened, don’t know what happened

66
Q

What are the special types of toxicity

A

Mutatagenicity (DNA)

Carcinogenicity (Cancer)

Teratogenicity (pregnancy)

Hypersensitivity (allergies rxn, someone can be allergic to pork derived insulin)

QT Prolongation (electrocardiogram)

67
Q

Why do all drugs have toxicity?

A
  • All drugs have toxicity because no drug will have 100% specificity.
  • Selective NOT the same thing as specificity
  • Specific is a drug that has a particular effect
  • A drug binds on a particular receptor-target (so its selective), but that target may be expressed in different tissues and thus may exert different biological effects (so no-specific). In that sense, it is very rare (close to impossible) to find a drug that is specific and selective at the same time. This is why selectivity/specificity has been the holy grail of pharmacologists in previous generations
  • Receptor localization
68
Q

What are the combination of drugs?

A
  • Additive
  • Synergetic
  • Antagonistic
  • Potentiation
69
Q

Additive

A

sum of individual effects

When we add two drugs together we have a 20% response

70
Q

Synergetic

A

When we put two drugs together

*we get responses great than additive effects

71
Q

Antagonistic

A

When we put drugs together the

*effect goes down less than individual drugs

72
Q

Potentiation

A

one drug (w/negligible or no effects alone)

But when we put two drugs together it enhances effects

73
Q

Example of Synergetic

A

Bacteria

  • You try one drug (trimethoprim), doesn’t kill all bacteria
  • You try another drug (sulfamethoxazole), doesn’t kill all bacteria

Combine those two drugs boom you kill off majority of bacteria (made a greater effect)

74
Q

What can continuous drug-receptor of antagonist interaction lead to?

A

If you use antagonist drugs continuously cells will regulate receptors to become hypersensitive

If you continue blocking receptors, as a result, your body will make more receptors which will take time. When you take the same does for a period of time, your body gets tired of it and makes more receptors so you need more drugs to bind to those added receptors.

75
Q

What can continuous drug-receptor of agonist interaction lead to?

A

If you use agonist drugs continuously, receptors will become less response.

Down regulating the number of receptors
Desensitize

76
Q

Pharmacodynamic tolerance

A
  • longer term administration of a drug such as heroin and morphine
  • Because increased drug levels are required to produce an effective response, the minimum effective concentration of a drug becomes abnormally high
  • MEC is the plasma drug level below which therapeutic effects will not occur
77
Q

Metabolic tolerance

A
  • Acceleration of drug metabolism
  • Must adjust dose higher of effected drugs to increase concentrations
  • Barbiturates induce synthesis of liver enzymes which cause increase in metabolism of other drugs
78
Q

Tachyphylaxis tolerance

A
  • Reduction in drug responsiveness brought on by repeated dosing over a short time
  • happens quickly
  • nitroglycerin is administered using transdermal patch
79
Q

What is pharmacogenetics

A

how genetic variations can affect individual responses to drugs

Alterations in genes code for drug metabolizing enzymes and drug targets

80
Q

Describe how genetic variants can alter pharmacodynamic response.

A
  • Under or over expression of receptor

- structural/fxnl variation in drug receptor

Pharmacokinetics (6 decks)

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