Exam 1 - Lecture 1 & 2 Flashcards
Describe the drug development process
Steps involved in the marketing of drugs are:
- preclinical testing (animal models),
- Clinical testing phases
- I (Safety),
- II (Efficacy- does it work) &
- III (Double-blind studies) [all phases drug metabolism],
- NDA (FDA New Drug Application) and
- Phase IV or post-marketing surveillance.
To be approved for marketing by the Food and Drug Administration (FDA), a drug must be shown by studies to be “safe and effective”, terms that are relative to each particular drug.
Results from post-marketing surveillance have revealed rare but serious adverse reactions to drugs not reported during the investigational stages.
This may result in a “warning” added to the drug literature (e.g., torsade’s de pointes with thioridazine) or even withdrawal of the drug from the market (such as seen with Seldane, Vioxx, Redux, etc.
When a new drug is approved for marketing in the USA its conditions for use are detailed in the package insert the compilation of scientific data submitted by the manufacturer for FDA review and approval “indications.”
However, many drugs, once marketed, often find therapeutic utility for different purposes or in populations other than those described in the package insert.
Such drugs are used for “unlabeled” purposes.
What does phase I clinical testing test?
I (Safety),
Phase I clinical evaluation is the first testing of a new compound in subjects, for the purpose of establishing the tolerance of healthy human subjects at different doses; defining its pharmacological effects at anticipated therapeutic levels; and studying its absorption, distribution, metabolism, and excretion patterns in humans.
What does phase II clinical testing look for?
II (Efficacy- does it work)
Phase II clinical evaluation is controlled studies performed on patients with the target disease or disorder to determine a compound’s potential usefulness and short-term risks.
A relatively small number of patients, usually no more than several hundred subjects, are enrolled in phase II studies.
What does phase III clinical testing look for?
III (Double-blind studies) [all phases drug metabolism]
Phase III trials are controlled and uncontrolled clinical trials of a drug’s safety and efficacy in hospital and outpatient settings.
Phase III studies gather precise information on the drug’s efficacy for specific indications, determine whether the drug produces a broader range of adverse effects than those exhibited in the small study populations of phases I and II studies, and identify the best way of administering and using the drug for the purpose intended.
Woo, Teri Moser; Robinson, Marylou V (2015-08-03). Pharmacotherapeutics For Advanced Practice Nurse Prescribers (Page 39). F.A. Davis Company. Kindle Edition.
What is an IND?
An investigational new drug (IND) application is filed with the FDA prior to human testing.
What is an NDA?
New Drug Application
Regulatory Review: New Drug Application To market a new drug for human use, a manufacturer must have a new drug application (NDA) approved by the FDA. All information about the drug gathered during the drug discovery and development process is assembled in the NDA. During the review period, the FDA may ask the company for additional information about the product or seek clarification of the data contained in the application.
The FDA has 60 days to determine whether the NDA will be filed for review. Once the FDA files the NDA, a team is assigned to review the drug sponsor’s research on the safety and effectiveness of the drug.
Usually, the FDA requests additional information, and the manufacturer needs from 1 to 5 years to complete any additional well-controlled trials necessary to support the claimed indications or prove the drug’s safety.
What is a phase IV clinical trial?
Clinical trials conducted after a drug is marketed (referred to as phase IV studies in the United States) are an important source of information on as-yet undetected adverse outcomes, especially in populations not included in the premarketing trials (e.g., children, the elderly, pregnant women), and the drug’s long-term morbidity and mortality profile.
Regulatory authorities can require companies to conduct phase IV studies as a condition of market approval.
Clinical experience with a new drug may include no more than 1,000 to 2,000 patients. The detection of rare (less than 1 in 1,000) adverse drug reactions is not reliable until hundreds of thousands of patients have taken the drug.
Woo, Teri Moser; Robinson, Marylou V (2015-08-03). Pharmacotherapeutics For Advanced Practice Nurse Prescribers (Page 40). F.A. Davis Company. Kindle Edition.
What is bioavailability?
Bioavailability is the percentage of the dose of the drug administered by any route reaches the systemic circulation.
What is bioequivalence?
Bioequivalence is “equivalent release of the same drug substance from 2 or more drug products or formulations.”
Two different dosage forms of the same drug are considered to be bioequivalent when they produce AUC, Cmax and Tmax values that are neither clinically nor statistically different.
Levothyroxine and certain brands of phenytoin sodium are examples of drugs where the bioequivalence of various brands of the drug are questionable.
Sustained-release dosage forms may not be bioequivalent because of differences in the sustained-release formulation (e.g., niacin).
What is a drug indication?
Drugs condition for use.
What is drug use for unlabeled purpose?
Unlabeled Purpose: the therapeutic utility for different purposes or in populations other than those described in the package insert (discovered after marketing).
What are orphan drugs?
The Orphan Drug Act of 1983 provides incentives for the development of drugs for treatment of diseases affecting fewer than 200,000 patients in the US, or for research using commonly available (nonpatentable) chemicals for treatment of specific diseases.
The incentives (usually tax breaks) are to encourage companies to do research for which they are unlikely to recoup their costs.
Generic vs. Trade Drugs
Must prove equivalence “bioavailability” or equivalence
Controls required for Scheduled I drugs:
- No accepted medical use
- No legal use permitted
- For registered research facilities only
Examples:
Heroin, LSD, mescaline, peyote, marijuana
Controls required for Scheduled II drugs:
- No refills permitted
- Written prescriptions only (no telephone orders)
- Prescription expires in 72 h if not filled
Examples:
Narcotics (morphine, codeine, meperidine, opium, hydromorphone, oxycodone, oxymorphone, methadone)
Stimulants (cocaine, amphetamine, methylphenidate), hydrocodone,
Depressants (pentobarbital, secobarbital)
Controls required for Scheduled III drugs:
- Prescription must be rewritten after 6 mo or 5 refills
- Telephone prescription okay
Examples:
Stimulants (benzphetamine, chlorpheniramine, diethylpropion)
Depressants (butabarbital),
Testosterone
Controls required for Class IV drugs:
- Same as schedule III
- Penalties for illegal possession are different
- Prescription must be rewritten after 6 mo or 5 refills
- Telephone prescription okay
Examples:
Pentazocine, propoxyphene, phentermine, benzodiazepines, meprobamate
Controls required for Class V drugs:
- Same as all prescription drugs
- May be dispensed without a prescription unless regulated by the state.
Example:
Loperamide, diphenoxylate
Describe Schedule I Drugs:
Schedule I: Addictive substances with no approved medical use, no legal use, and only used in medical research facilities (e.g., heroin)
Describe Schedule II Drugs:
Schedule II:
No refills permitted,
No telephone orders
Unless emergency and written order to be provided within 7 days,
Electronic prescribing permitted with certain software
(Woo & Robinson, 2016). (e.g., morphine)
Describe Schedule III Drugs:
Schedule III: Prescription must be rewritten after 6 months or 5 refills, and a telephone or fax prescription is acceptable.
Describe Schedule IV drugs:
Schedule IV: Has same control requirements as schedule III, but penalties for illegal possession are different (e.g., Benzodiazepines)
Describe Schedule V drugs:
Schedule V: Same as all prescription drugs, and may be dispensed without a prescription unless state regulated. Texas law requires a prescription for Schedule V drugs so essentially, in Texas, there is no difference in prescribing or how schedules III, IV, & V are handled. (e.g., Loperamide)
Pharmacology
•The total knowledge of drugs including history, chemistry, source, biochemical & physical effects, pharmacodynamics (what the drug does to the body), pharmacokinetics (what the body does to the drug), therapeutics, site of action, interactions, distinctive features, etc.
Clinical Pharmacology
•The study of the effect of drugs in man (as compared to animal or comparative pharmacology). (The emphasis is on the drug and its uses.)
Pharmacotherapeutics
•deals with the use of drugs in prevention & treatment of disease, usually to alleviate symptoms or, sometimes, to alter the course of the disease. The emphasis is on the disease and the treatment thereof.
Drug
•any substance which, when introduced into the body, produces a physiological change, a biological change, a decrease in population of resident or invading microorganisms, or a decrease in abnormal tissue development
Toxicology
•deals with adverse effects of drugs
Therapeutic Index
Relative toxicity of a drug;
Most commonly, the ratio of the dose capable of killing 50% of animals (LD50) over that required to achieve a beneficial effect in 50% of the animals (ED50). In clinical terms, a drug that has a “small therapeutic index” has little difference between the therapeutic dose and the dose that causes toxicity (e.g., digoxin).
A drug may have more than one therapeutic index, depending on the specific uses of the drug and the toxic effect being considered. The margin of safety of aspirin for relief of headache is greater than its margin of safety when used for relief of arthritic pain.
Tolerance
Hyporeactivity that occurs from chronic exposure to a drug (such as an opioid or alcohol). When tolerance develops, usually increasing doses are needed to provide a therapeutic effect. This is attributed to neuronal adaptation or cellular tolerance.
Cross-Tolerance
May develop between drugs within a class (e.g., opioids) or between drugs of different classes that produce similar pharmacologic effects (e.g., alcohol & inhaled anesthetics).
Metabolic Tolerance
- Enzyme Induction: decreased response to a dose of a drug which develops because of an increase in rate of elimination of the drug
- Enzyme Inhibition: increased response to a dose of a drug which develops because of a reduced rate of drug elimination
Downregulation
Downregulation: a decrease in the number or sensitivity of receptor sites after continued dosing (may need increased dose)
Example of downregulation: One theory of type 2 diabetes is increased intake of sugar causes release of large amounts of insulin. Continued exposure to high levels of insulin causes the insulin receptors to become less sensitive or down regulation of the receptors.
A change in receptor numbers may also be caused by other hormones. For example, thyroid hormones increase both the number of beta-receptors in heart muscle and cardiac sensitivity to catecholamines). Up regulation and down regulation may contribute to two clinically important phenomena: first, tachyphylaxis or rapid tolerance to the effect of some drugs, and second, the “overshoot” phenomena that follow withdrawal of certain drugs.
Upregulation
Upregulation: an increase in the number of or sensitivity of receptor sites after continued dosing (may need lowered dose)
Example of upregulation: In response to constant depression of receptors (as with beta blockers), the body may either increase the number of receptors or increase the sensitivity of receptors. May have an exaggerated response if the drug is withdrawn.
A change in receptor numbers may also be caused by other hormones. For example, thyroid hormones increase both the number of beta-receptors in heart muscle and cardiac sensitivity to catecholamines). Up regulation and down regulation may contribute to two clinically important phenomena: first, tachyphylaxis or rapid tolerance to the effect of some drugs, and second, the “overshoot” phenomena that follow withdrawal of certain drugs.
IDIOSYNCRASY
describes an unusual effect of a drug. It usually occurs in a very small percentage of patients and may not be related to the dose of the drug
Side Effect
usually describes any action of the drug other than the desired (therapeutic) effect.
Adverse Effect
•any noxious, unintended, and undesired effect that occurs at normal drug doses. The terms “side effect” and “adverse effect” are often uses synonymously but all side effects may not be “noxious”
Toxic Effect
•effect (usually expected) produced by large (toxic) doses of the drug.
Additive Effect
•occur when the effect of 2 drugs administered together is equal to the sum of the effect of the 2 drugs taken separately
Synergistic Effects
•occur when 2 drugs administered together interact in such a way that their combined effects are greater than the sum of the effects for each drug given alone.
Antagonistic Effects
•combination of 2 drugs results in drug effects that are less than the sum of the effects of each drug given separately
Incompatibility
•most commonly used to describe intravenous drugs. An undesirable reaction that occurs between the drug and the solution, container or another drug.
Selectivity
•Drugs may have a high selectivity for one receptor (e.g., acetylcholine) but may produce a number of effects because of the widespread locations of acetylcholine receptors.
Nonselectivity
- On the other hand, diphenhydramine (Benadryl) is classified as an antihistamine although it also has both anticholinergic and sedative effects. Thus it is nonselective in its actions.
- A drug’s desired effect on one occasion may be a side effect on another occasion. (For example, when codeine is used as an analgesic, constipation may be a side effect or untoward effect. Codeine {or a similar drug} may also be used for its constipating effect in the treatment of diarrhea).
Pharmacodynamics
- Studies the relationship between the drug concentration and the patient’s response to the drug… it is what the drug does to the body.
- AKA “pharmacology”
- Variation in drug response is explained by a variation in
- 1) environmental factors
- 2) genetic factors (account for most of the variations in metabolic rates for many drugs)
- Drug + Receptor ⇔ Drug-receptor complex → Response
Drug-Receptor Interactions:
Receptor Theory
- The drug molecule must “fit” into the receptor.
- Like a lock and key mechanism (not always this simplistic)
Drug-Receptor Interactions:
What does “binding” produce?
Once bound, initiates biochemical & physiological changes characteristic of the response to the drug, hormone, or neurotransmitter
Upregulation may lead to:
A.Higher response to a drug
B.Lower response to a drug
C: Exaggerated response if drug is withdrawn
D: No response
C: Exaggerated response if drug is withdrawn
What is Affinity?
(drug-receptor interactions)
- The attraction between a drug and its receptor.
- Determines potency
- HIGHER affinity = HIGHER potency
- LOWER affinity = LOWER potency
What is Intrinsic Activity (Efficacy)?
(drug-receptor interactions)
The ability of a drug to activate a receptor and produce an effect.
What are the two properties that produce an active compound?
Affinity
Intrinsic Activity (Efficacy)
What is the drug response curve?
Depicts the relation between drug dose and magnitude of effect.
Example: 50% of the max response occurs at a dose concentration at which a drug occupies 50% of its receptors.
What happens at doses below the dose-response curve?
Doses do not produce a pharmacological response.
What happens at doses above the dose-response curve?
Doses not produce much additional pharm. response.
It may have unwanted effects → toxicitiy
What is drug efficacy?
- The maximum effect that a drug can produce regardless of dose.
Example: drugs used to treat mild pain will not work on severe pain no matter the dose. Opioids have higher efficacy for pain relief than NSAIDs or Acetaminophen.
What is drug potency?
- “Think amount”
- The amount of a drug that needed to produce a given effect.
- Potency describes the difference in concentration/dosage of different drugs required to produce similar effect.
- Drugs that are more potent may require a lower dosage to produce the same response
What is ED50?
AKA: Median Effective Dose
The concentration or dose of drug that causes 50% of maximum effect.
The dose o a drug to produce a specified intensity of effect in 50% of individuals.
Is determined by affinity of drug for receptor and number of receptors available
What is the median effective dose/ED50?
- The dose o a drug to produce a specified intensity of effect in 50% of individuals.
What determines the potency of a drug?
- Is determined by the affinity of the drug for its receptor and number of receptors available.
What is LD50/Median Lethal Dose?
The dose that is lethal to 50% of animals is the median lethal dose.
In the drug-response curve, what is the x-axis?
x-axis= drug concentration
In the drug-response curve, what is the y-axis?
y-axis = percentage of maximum effect
Which of these is most potent?
(has highest potency)
The red curve.
Which of these drugs has the lowest affinity?
Green curve. This is the least potent (has lowest affinity).
Assuming the following doses all produce an equal effect on a headache, which of these drugs has the highest potency?
A)200mg ibuprofen,
B)325 mg ASA,
C)50 mg ketoprofen
Ketoprofen requires the lowest dose so it has the highest potency.
Review pictograph
Efficacy vs. Potency
Why might a pt. respond to low doses of a drug?
- May have sensitivity to the drug
- May experience placebo effect
Why do different patients have different responses to same drug dose?
Multiple factors may affect pt. response to drug/drug dose:
- Environmental
- Genetic/Ethnic
- Physiologic variations (pregnancy/breastbreastfeeding/children)
- Phenogenomics
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