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
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
3
Q
Harris-Kefauver Amendments
A
- Effectiveness required (in addition to safety)
- Rigorous testing requirements for new drugs
- Thalidomide (caused birth and fetal deaths)
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
5
Q
Hatch Waxman Act 1984
A
Increased availability of generic drugs
6
Q
Dietary Supplement Health and Education Act 1994
A
- Restricted the labeling of supplements
- Not required to go through FDA
7
Q
What are the stages of new drug development
A
Pre-clinical testing
Clinical Testing
Marketing
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
toxPharmocokinetic properties –animals, metabolism Pharmacology – Mechanism (how this works, how selective its going to be, and efficacy
9
Q
How long does pre-clinical testing take
A
Takes 1-5 years
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
11
Q
What happens during phase 1 of clinical testing?
A
PK, safety, dose
- Subjects: Healthy Volunteers
- N = 20-80
- Takes 1 year
12
Q
What happens during phase 2 of clinical testing?
A
Effects and Safety
- N= 100-300
- Subjects: patients
- Takes 2 years
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
14
Q
How long does clinical testing take
A
Takes 4-6 years
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
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
17
Q
What are the three main drug names?
A
- Chemical name
- Generic name
- Brand name
18
Q
Generic Name
A
- Use the most
- Example: Acetaminophen
- Many professionals advocate for the universal use of generic names
19
Q
Brand Name
A
Tylenol is the brand name for acetaminophen
20
Q
Name factors that influence intensity of drug response during administration?
A
- medication error
- patient adherence
21
Q
Name factors that influence the intensity of drug response for pharmacokinetics?
A
ADME
22
Q
Name factors that influence the intensity of drug response for pharmacodynamics?
A
- drug receptor interactions
- patients functional state
- placebo effects
23
Q
What are the sources of variation
A
- Physiological variable
- Pathologic variable
- Genetic variable
- Drug interactions
24
Q
What are ligands?
A
molecules that bind to receptors
Drug is a ligand
25
What are receptors?
macromolecule to which a drug (ligand) binds to produce effect
26
Give examples of exogenous ligands
Hormones
Neurotransmitters
Regulatory molecules
27
What happens when a ligand binds to a receptor?
it will either mimic or block what is suppose to happen
biological response
clinical effect
28
What are the 4 primary receptor families?
- Cell membrane- embedded enzyme
- Ligand gated ion channel
- Transcription factors
- G protein coupled receptors
29
Cell membrane embedded enzyme
-Activation occur in seconds
-Agonist drug or endogenous ligand
Example: insulin
30
Ligand gated ion channel
-Activation are extremely fast and occur in milliseconds
-Agonist drug or endogenous ligand
Example: ACH, GABA
31
Transcription factors
- Activation can take 4 hours to days
- Nucleus
- Requires lipid solubility to reach the cell nucleus
* Example: Thyroid hormones, steroids
32
G-protein coupled:
- Activation occurs rapidly
- Receptor ----G protein---- effector
-Agonist drug or endogenous ligand
*Example: NE, Serotonin, Histamine and
other peptide hormones
33
What are the drug-receptor components?
Drug types
| Binding sites
34
What are the 2 general types of drugs
Agonist
| Antagonist
35
What is the binding site
Lock and key
Reversible: ligand is removed or substituted
Irreversible: bound to enzyme, receptor until that receptor is no more
36
How do drugs produce limited effects in certain parts of the body?
Receptor selectively
| Receptor distribution/location
37
Receptor selectively
- How can we make drugs selective for an enzyme in specific organs?
- We want to keep drugs where we want it.
38
Receptor distribution/location
Where is receptor located?
39
# Define agonist
What is affinity and intrinsic activity
- 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
Define antagonist
-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
What is a partial agonist?
- 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
Give an example of partial agonist
- 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
What is a competitive antagonist
- 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
What is a noncompetitive antagonist
- 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
Give an example of noncompetitive antagonist
Omeprazole decreases gastric acid
46
What types of drugs don't work via a receptor?
- Antacid (not absorbing, just neutralizing stomach acid)
- Osmotic laxatives (retain water in stool to soften it to increase bowel movements)
- chelating agents, resins (
47
Describe characteristics of the dose-response curve.
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
Why is steeper slope less safe
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
What is ED50?
Is a median dose that 50% will experienced maximal response
50
What is flatter slope safe?
More wiggle room, less room for toxic levels
51
What is efficacy.
Maximal response produced by drug
52
Does efficacy matter
Yes
53
What is potency
Dose of drug required for a given response
54
Compare efficacy and potency for 2 drugs.
Look at notebook
55
For drugs with equal efficacy, does potency matter?
No, it is not an important quality in a drug
Does not imply nothing about its maximal efficacy.
56
What are the drug effects for population of patients?
VARIABILITY it varies
57
What is the difference between TD50 and ED50
Therapeutic index
58
What is TD50
median toxic dose that 50% of individuals will exhibit toxic response
59
What is ED50 (quantal dose-response)
Median effective dose that 50% of individuals will exhibit maximal response
60
Narrow Therapeutic Index Window
As we make small adjustments we see big effects. We get it from a therapeutic window to a toxic window
61
What is side effects of drugs.
- 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
Define adverse effect of drugs (toxicity)?
Adverse effect due to an excessive dose
Can range from annoying to life threatening
63
Define adverse effect of drugs (toxicity)?
Adverse effect due to an excessive dose
Can range from annoying to life threatening
64
Dose-dependent adverse effect
As we increase dose, we expect different responses
65
Idiosyncratic reaction
- Uncommon response resulting from a genetic deposition
| - What happened, don't know what happened
66
What are the special types of toxicity
Mutatagenicity (DNA)
Carcinogenicity (Cancer)
Teratogenicity (pregnancy)
Hypersensitivity (allergies rxn, someone can be allergic to pork derived insulin)
QT Prolongation (electrocardiogram)
67
Why do all drugs have toxicity?
- 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
What are the combination of drugs?
- Additive
- Synergetic
- Antagonistic
- Potentiation
69
Additive
sum of individual effects
| When we add two drugs together we have a 20% response
70
Synergetic
When we put two drugs together
| *we get responses great than additive effects
71
Antagonistic
When we put drugs together the
| *effect goes down less than individual drugs
72
Potentiation
one drug (w/negligible or no effects alone)
But when we put two drugs together it enhances effects
73
Example of Synergetic
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
What can continuous drug-receptor of antagonist interaction lead to?
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
What can continuous drug-receptor of agonist interaction lead to?
If you use agonist drugs continuously, receptors will become less response.
Down regulating the number of receptors
Desensitize
76
Pharmacodynamic tolerance
- 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
Metabolic tolerance
- 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
Tachyphylaxis tolerance
- Reduction in drug responsiveness brought on by repeated dosing over a short time
- happens quickly
- nitroglycerin is administered using transdermal patch
79
What is pharmacogenetics
how genetic variations can affect individual responses to drugs
Alterations in genes code for drug metabolizing enzymes and drug targets
80
Describe how genetic variants can alter pharmacodynamic response.
- Under or over expression of receptor
| - structural/fxnl variation in drug receptor
