UNIT 1 Flashcards
(285 cards)
1
Q
study of substances that interact with living systems through chemical processes
A
Pharmacology
2
Q
therapeutic applications may be considered the proper role of __________ used to prevent, diagnose, and treat disease.
A
Medical pharmacology
3
Q
deals with the undesirable effects of chemicals on living systems
A
Toxicology
4
Q
aimed at understanding the actions of drugs as chemicals on individual organisms, especially humans and domestic animals.
A
Medical pharmacology and toxicology
5
Q
Domain of pharmacology that includes the beneficial and toxic effects
A
Medical pharmacology and toxicology
6
Q
deals with the absorption, distribution, and elimination of drugs.
- body to drug
A
Pharmacokinetics
7
Q
concerns the actions of the chemical on the organism.
- Drug to body
A
Pharmacodynamics
8
Q
concerned with the effects of chemicals on all organisms and their survival in groups and as species.
A
Environmental toxicology
9
Q
T/F
Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials
A
T
10
Q
T/F
Around the end of the 17th century, reliance on observation and experimentation began to replace theorizing in physiology and clinical medicine.
A
T
11
Q
T/F
During the prehistory, schools promulgated bizarre notions such as the idea that disease was caused by excesses of bile or blood in the body, that wounds could be healed by applying a salve to the weapon that caused the wound, and so on.
A
12
Q
The science of drug preparation and the medical uses of drugs
A
Materia medica
13
Q
Precursor of pharmacology
A
Materia medica
14
Q
During prehistory, any real understand-ing of the mechanisms of action of drugs was prevented by
A
- absence of methods for purifying active agents from the crude materials
- lack of methods for testing hypotheses about the nature of drug actions
15
Q
developed the methods of experimental physiology and pharmacology
A
François Magendie and his student Claude Bernard
16
Q
T/F
Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and tissue levels.
A
T
17
Q
T/F
real advances in basic pharmacology were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless “patent medicines.”
A
T
18
Q
T/F
Reintroduction of the concepts of rational therapeutics, esp. controlled clinical trials, made it possible to adequately evaluate therapeutic claims
A
T
19
Q
the use of receptor identification methods has led to the discovery of
A
Orphan receptors
20
Q
receptors for which no ligand has been discovered and whose function can only be guessed.
A
Orphan receptors
21
Q
biologic substrate of drug action
A
Drug receptor
22
Q
T/F
Studies of the local molecular environment of receptors have shown that receptors and effectors function in isolation
A
F; receptors and effectors DO NOT function in isolation
23
Q
T/F
Receptors and effectors are strongly influenced by other receptors and by companion regulatory proteins.
A
T; strongly influenced by other receptors and regulatory proteins kasi they cannot function alone
24
Q
the relation of the individual’s genetic makeup to his or her response to specific drugs
A
Pharmacogenomics
25
Decoding of the genomes of many species—from bacteria to humans—has led to the recognition of unsuspected relationships between
1. Receptor families
2. How receptor proteins evolved
26
Discovery that small segments of RNA can interfere with protein synthesis with extreme selectivity has led to investigation of _______ as therapeutic agents
1. small interfering RNAs (siRNAs
2. micro-RNAs (miRNAs)
27
short nucleotide chains, synthesized to be complementary to natural RNA or DNA
antisense oligonucleotides (ANOs)
28
can interfere with the readout of genes and the transcription of RNA.
ANOs
29
T/F
all substances can under certain circumstances be toxic
T
30
T/F
the chemicals in botanicals (herbs and plant extracts, “nutraceuticals”) are no different from chemicals in manufactured drugs except for the much greater proportion of impurities in botanicals
T
31
T/F
Manufactured drugs have lower impurities than botanicals
F; there are more impurities in botanicals
32
T/F
all dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety as conventional drugs and medical therapies.
T
33
T/F
there should be no artificial separation between scientific medicine and “alternative” or “complementary” medicine.
T
34
all nutritional and botanical substances should be tested by _________ as synthetic compounds.
Randomized controlled trails (RCTs)
35
any substance that brings about a change in biologic function through its chemical actions.
Drug
36
In most cases, the drug molecule interacts as an _____________ with a specific target molecule that plays a ________ role in the biologic system.
Agonist or antagonist; regulatory
37
What is the target molecule called as
Receptor
38
39
drugs known as ____________ may interact directly with other drugs
Chemical antagonists
40
Drugs that interact almost exclusively with water molecules
Osmotic agents
41
Example/s of drugs SYNTHESIZED WITHIN the body
Hormones
42
Ex/s of drugs that are NOT SYNTHESIZED within the body
Xenobiotics; substances foreign to the body
43
drugs that have almost exclusively harmful effects
Poisons
44
“the dose makes the poison,” meaning that any substance can be harmful if taken in the wrong dosage.
Paracelsus (1493–1541)
45
defined as poisons of biologic origin
- synthesized by plants or animals
Toxins
46
What are considered for drug molecules to chemically interact with its receptors
1. size
2. electrical charge
3. shape
4. atomic composition.
47
T/F
drug is often administered at a location distant from its intended site of action
T
48
T/F
useful drug must have the necessary properties to be transported from its site of admin- istration to its site of action.
T
49
T/F
a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration.
T
50
These factors often determine the best route of administration.
If the drug is solid, liquid, or gaseous (physical nature of drugs)
51
T/F
various classes of organic compounds (carbohydrates, proteins, lipids, and smaller molecules) are all represented in pharmacology.
T
52
T/F
oligonucleotides, in the form of small segments of RNA, have entered clinical trials and are on the threshold of introduction into therapeutics.
T
53
T/F
Many organic drugs are weak acids or bases.
T
54
T/F
pH differences in the various compartments of the body may alter the degree of ionization of weak acids and bases
T; regarding many organic drugs
Most of organic drugs = weak acids or bases
55
molecular size of drugs range
MW 7 - 59,050
Lithium ion - MW 7
Alteplase - MW 59, 050
Thrombolitic agents - MW 50,000
56
most drugs have molecular weights between
MW 100 - 1000
57
MW for selective binding
100 MW
58
MW for transversing to different barriers of the body (from the site of administration to site of action)
1000 MW
59
If the drug has >1000 MW…
1.Drug cannot move within the body
- cannot diffuse readily between compartments of the body
2. Drug is given directly at the site of action
60
To have a good “fit” to only one type of receptor, a drug molecule must be
Unique in shape, charge, and its other properties to prevent binding to other receptors
61
62
T/F
very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect.
T
63
A clot-dissolving enzyme, administered directly into the vascular compartment by intravenous or intra-arterial infusion.
Alteplase
64
Drugs interact with receptors by means of
Chemical forces/bonds
65
3 major types of bonds in drug-receptor bonds
1. Covalent
2. Electrostatic
3. Hydrophobic
66
- Very strong bonds
- generally irreversible under biologic conditions
Covalent
67
Covalent bonding between the acetyl groups of aspirin and cyclooxygenase
- covalent bond formed is not readily broken.
- platelet aggregation–blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the blood- stream (about 15 minutes)
- reversed only by the synthesis of new enzyme in new platelets, a process that takes several days.
68
Ex of drugs that are:
- highly reactive
- covalent bond forming
DNA-alkylating agents used in cancer chemotherapy
69
- much more common than covalent bonds in drug-receptor interactions
- weaker than covalent
- between cation and anion
- vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces
Electrostatic bonds
70
- usually weak
- important in the interactions of highly lipid-soluble drugs
- interacts with the lipids of cell membranes
- interacts with the internal walls of receptor “pockets.”
Hydrophobic bonds
71
T/F
drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds
T;
Weak bonds = more selective
72
T/F
Covalent bonds are less selective and can bind to multiple receptors
T;
Covalent bonds = less selective
73
T/F
weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur.
T; kasi nga selective sila
74
T/F
if we wished to design a highly selective short-acting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose a molecule that forms weaker bonds.
T
75
T/F
the drug’s shape must be complementary to that of the receptor site in the same way that a key is complementary to a lock.
T
76
T/F
more than half of all useful drugs are chiral molecules; that is, they can exist as enantiomeric pairs.
T
77
Drugs with two asymmetric centers have ___ diastereomers
Four;
Ex. ephedrine, a sympathomimetic drug.
78
T/F
The more active enantiomer at one type of receptor site may not be more active at another receptor type, eg, a type that may be responsible for some other effect.
T
79
T/F
drug transporters may be stereoselective.
T
80
T/F
the duration of action of one enantiomer may be quite different from that of the other.
T
81
T/F
administration of the pure, active enantiomer decreases adverse effects relative to those produced by racemic formulations has been established.
F; not yet established
82
implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor.
Rational design of drugs
83
IUPHAR
International Union of Pharmacology
84
T/F
drugs were developed through random testing of chemicals or modification of drugs already known to have some effect.
T; receptor cannot predict drug design
85
actions of the drug on the body
Pharmacodynamics
86
actions of the body on the drug
Pharmacokinetics
87
govern the absorption, distribution, and elimination of drugs
Pharmacokinetics
88
T/F
For drugs to take effect, it must bind to a receptor
T
89
different ways a drug can interact with a receptor and produce a biological effect
• Drug (D) + receptor-effector (R) → drug-receptor-effector complex → effect
• D + R → drug-receptor complex → effector molecule → effect
• D + R → D-R complex → activation of coupling molecule → effector molecule → effect
• Inhibition of metabolism of endogenous activator → increased activator action on an effector molecule → increased effect
90
T/F
In the diff ways a drug binds to its receptor, the final change in function is accomplished by an effector mechanism.
T
91
T/F
The effector may be part of the receptor molecule or may be a separate molecule.
T
92
A very large number of receptors communicate with their effectors through
Coupling molecules
93
Agonist drugs bind to and _________ the receptor
Activate
94
T/F
Binding of agonists drug to receptors may bring direct or indirect effect
T
95
Some receptors incorporate effector machinery in the same molecule
Causing direct effect
96
Drugs that compete with and prevent binding by other molecules.
Antagonist
97
T/F
Some antagonists bind very tightly to the receptor site in an irreversible or pseudoirre- versible fashion and cannot be displaced by increasing the agonist concentration
T
98
T/F
You can overcome the effect of antagonists by increasing the dosage of agonists
T; in competitive antagonists
99
Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are
Allosteric modulators
100
Allosteric modulators may…
Enhance or inhibit the action of the agonist molecule
101
T/F
Allosteric inhibition is not usually overcome by increasing the dose of agonist.
T
102
T/F
Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist.
T
103
Absence of agonist
Constitutive activity
104
T/F
Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the activated form some of the time and may produce the same physiologic effect as agonist-induced activity.
T; constitutive activity
105
Agonists have a much ________ for the activated receptor configuration and stabilize it
Higher affinity
106
The recognition of constitutive activity may depend on:
1. Receptor density
2. Concentration of coupling molecules (if coupled system)
3. Number of effectors
107
when administered at concentrations sufficient to saturate the receptor pool, can activate their receptor- effector systems to the maximum extent of which the system is capable
Full agonists
108
bind to receptors and activate them in the same way but do not evoke as great a response, no matter how high the concentration.
Partial agonists
109
do not stabilize the activated receptor configuration as fully as full agonists
Partial agonists
110
Have low intrinsic efficacy
Partial agonist
111
T/F
Intrinsic efficacy is independent of affinity (as usually measured) for the receptor.
T
112
T/F
partial agonists can also prevent access by full agonists.
T
113
the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect.
Neutral antagonism
114
What will happen if a drug has a much stronger affinity for the Ri than for the Ra state and stabilizes a large fraction in the Ri–D pool?
Reduce in any constitutive activity
115
If a drug strongly prefers the inactive (Ri) receptor state and stabilizes it, it will reduce any existing receptor activity, including constitutive activity. This effect is opposite to that of a conventional agonist, and such drugs are called
Inverse agonist
116
prevents excessive activation when agonist molecules continue to be present for long periods.
Desensitization mechanisms
117
T/F
Effect of drugs that bind covalently to the receptor site may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized
T
118
To function as a receptor, endogenous molecule must be…
1. Selective - avoids constant activation of the receptor
2. Change its function - to alter the function of the biologic system, necessary to cause a pharmacologic effect
119
T/F
Not all of endogenous molecules are regulatory molecules
T
120
Site where a drug can bind to but will not cause any detectable change in the biologic system
Inert binding site
121
T/F
Inert binding sites are completely useless
F; it affects the distribution of drugs within the body and determines the amount of free drug in the circulation (important in pharmacokinetics)
122
- inactive precursor chemical that is readily absorbed and sitributed
- converted to active form when in the body
Prodrug
123
Diffusion that occurs within:
- larger aqueous compartments of the body (interstitial space, cyto- sol, etc)
- across epithelial membrane tight junctions
- endothelial lining of blood vessels through aqueous pores
Aqueous diffusion
124
T/F
The capillaries of the brain, the testes, and some other tissues are characterized by the absence of pores that permit aqueous diffusion. These tissues are therefore protected or “sanctuary” sites from many circulating drugs.
T; protected from many circulating drugs because the drugs can't easily diffuse (spread) out of the bloodstream and into these tissues due to the lack of pores in the capillaries.
125
usually driven by the concentration gradient of the permeating drug
Aqueous diffusion
126
T/F
Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous pores
T
127
most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body
Lipid diffusion
128
determines how readily the molecule moves between aqueous and lipid media.
lipid:aqueous partition coefficient
129
the ability to move from aqueous to lipid or vice versa varies with the ________ , because charged molecules attract water molecules.
pH of the medium
130
The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by
Henderson-Hasselbalch equation
131
Exist for substances that are too large or too insoluble in lipid to diffuse passively through membranes
Special carriers
132
bring about movement by active transport or facilitated diffusion
Special carriers
133
Diffusion that is selective, saturable, and inhibitable
Facilitated diffusion or active transport
134
ABC transporter
ATP-binding cassette
135
ABC family includes…
P-glycoprotein or multidrug resistance type 1 (MDR1) transporter found in the brain, testes, and other tis- sues, and in some drug-resistant neoplastic cells
136
Transport molecules that play important roles in:
- the excretion of some drugs or their metabolites into urine and bile
- resistance of some tumors to chemotherapeutic drugs
multidrug resistance-associated protein (MRP)
137
SLC
Solute carrier family (transport molecule)
138
Transporter family that do not bind ATP
but use ion gradients
SLC
139
important in the uptake of neurotransmitters across nerve-ending membranes.
SLC
140
- substance is bound at a cell-surface receptor
- engulfed by the cell membrane
- carried into the cell by pinching off of the newly formed vesicle inside the membrane
Endocytosis
Bound > engulf > carried to cell = substance can then be released into the cytosol by breakdown of the vesicle membrane
141
142
responsible for the transport of vitamin B12
Endocytosis
143
T/F
iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the binding proteins must be present for this process to work.
T
144
responsible for the secretion of many substances from cells
Exocytosis
145
process that allows nerve cells to release neurotransmitters from their storage vesicles into the synaptic cleft, enabling communication between cells.
Exocytosis
146
mechanism by which cells release substances from inside the cell into the extracellular space.
Exocytosis
147
T/F
many neurotransmitters substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm
T
148
describes how substances move from areas of high concentration to areas of low concentration (diffusion)
Fick’s law
149
T/F
in lipid diffusion, the lipid:aqueous partition coefficient is a major determinant of mobility of the drug because it determines how readily the drug enters the lipid membrane from the aqueous medium.
T
150
The electrostatic charge of an ionized molecule ______ water dipoles and results in a ______, relatively _____________ complex.
Attract; polar; water-soluble and lipid-soluble
151
T/F
Because lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes.
T
152
T/F
very large percentage of the drugs in use are weak acids or weak bases
T
153
For drugs, a WEAK ACID is best defined as a neutral molecule that can _________ into an _______
Reversibly dissociate; anion and proton
154
A WEAK BASEcan be defined as a neutral molecule that can form a _______ by combining with a ______.
cation; proton
155
Antimalarial drug that undergoes association-dissociation process
pyrimethamine
156
the protonated form of a weak acid is the _____, more _________
Neutral; lipid-soluble form
157
unprotonated form of a weak base is the ______.
Neutral form
158
requires that reactions move to the left in an acid environment (low pH, excess protons available) and to the right in an alkaline environment.
Law of mass action
159
relates the ratio of protonated to unprotonated weak acid or weak base to the molecule’s pK and the pH of the medium
Henderson-Hasselbalch equation
160
T/F
Henderson-Hasselbalch equation only applies to acidic drugs
F; both acidic and basic drugs
161
the lower the pH relative to the pKa
the greater will be the fraction of drug in the protonated form
162
High ph = less protonated
Low ph = more protonated
Acidic drugs = more lipid soluble at lower ph
Basic drug = more lipid soluble at higher ph
163
adjusting urine pH to make certain that most of the drug is in the ionized state =
accelerates excretion of drug
164
Ionized form of drug =
Less lipid soluble = less likely to be reabsorbed;
ionizing drugs traps it in the urine to accelerate excretion
165
T/F
weak acids are usually excreted faster in alkaline urine
T
166
167
T/F
weak bases are usually excreted faster in acidic urine
T
168
Other body fluids in which pH differences from blood pH may cause trapping or reabsorption are the contents of the
- stomach (normal pH 1.9–3)
- small intestine (pH 7.5–8),
- breast milk (pH 6.4–7.6),
- aqueous humor (pH 6.4–7.5),
- vaginal and prostatic secretions (pH 3.5–7).
169
a large number of drugs are weak bases. Most of these bases are _________ molecules.
amine-containing
170
one carbon and two hydrogens bonded to N
Primary amine
171
Two carbon and one hydrogens bonded to N
Secondary amine
172
Three carbon and NO hydrogens bonded to N
Tertiary amine
173
Four carbon, NO hydrogen bonded to N
Quaternary amines
174
Diff quaternary amines with other amines
- always charged (+)
- poorly lipid-soluble = cannot accept proton and become uncharged
175
Similarity of primary, secondary, and tertiary amines
- can change their charge (reversible protonation)
- can vary their lipid solubility depending on the pH of their environment
176
177
T/F
A truly new drug imply mimic the structure and action of previously available drugs
F; one that does not simply mimic the structure and action of previously available drugs
178
T/F
Developing a new drug requires the discovery of a new drug target, ie, the pathophysiologic process or substrate of a disease
T
179
T/F
the development of new drugs usually takes place in industrial laboratories whereas,
discoveries of new drug target are usually made in public sector institutions (universities and research institutes), and molecules that have beneficial effects on such targets are often discovered in the same laboratories.
T;
Drug target = public sector institutions
Development = industrial labs
180
the multibillion- dollar corporations that specialize in drug development and marketing.
big pharma
181
The development of a new drug usually begins with…
- the discovery or synthesis of a potential new drug compound
- elucidation of a new drug target.
182
T/F
- relevant biologic effects
- drug metabolism
- pharmacokinetic profiles
- relative safety of the drug
must be characterized in vivo in animals before human drug trials can be started
T
183
T/F
With regulatory approval, human testing may then go forward (usually in three phases) before the drug is considered for approval for general use
T
184
T/F
A fourth phase of data gathering and safety monitoring follows after approval for marketing.
T
185
T/F
Highly toxic drugs may be used by practitioners provided that they have undergone special training in their use and who maintain detailed records.
T
186
Most new drugs or drug products are discovered or developed through the following approaches:
1. screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules
2. chemical modification of a known active molecule, resulting in a “me-too” analog
3. identification or elucidation of a new drug target
4. rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure.
1/2= industry
3/4 = acad research labs
187
involves the preclinical and clinical steps,
Translational research
188
involves a variety of assays at the molecular, cellular, organ system, and whole animal levels to define the pharmacologic profile, ie, the activity and selectivity of the drug.
Drug screening
189
The type and number of initial screening tests depend on the
Pharmacologic and therapeutic goal
190
T/F
The selection of compounds for development is most efficiently conducted in animal models of human disease.
T
191
T/F
Effects on cell function determine whether the drug is an agonist, partial agonist, inverse agonist, or antagonist at relevant receptors.
T
192
The desired result of this screening procedure
Lead compound
193
T/F
All chemicals are toxic in some individuals at some dose.
T
194
T/F
no chemical can be certified as completely “safe” (free of risk)
T
195
objective is to estimate the risk associ- ated with exposure to the drug candidate and to consider this in the context of therapeutic needs and likely duration of drug use.
preclinical toxicity testing
196
- identifying potential human toxicities
- designing tests to further define the toxic mechanisms
- predicting the most relevant toxicities to be monitored in clinical trials
preclinical toxicity studies
197
the maximum dose at which a specified toxic effect is not seen
no-effect dose
198
the smallest dose that is observed to kill any experimental animal
minimum lethal dose
199
the dose that kills approximately 50% of the animals in a test group
median lethal dose; estimated from the smallest number of animals possible
200
T/F
no-effect dose, minimum lethal dose, and median lethal dose are used to calculate the initial dose to be tried in humans
- usually taken as one hundredth to one tenth of the no-effect dose in animals.
T
201
________ may be required to collect and analyze data on toxicity before the drug can be considered ready for testing in humans.
2-6 yrs
202
T/F
Extrapolations of toxicity data from animals to humans are reasonably predictive for many but not for all toxicities.
T
203
T/F
For statistical reasons, rare adverse effects are unlikely to be detected in preclinical testing.
T
204
205
T/F
the design and execution of a good clinical trial require includes basic scientists, clinical pharmacologists, clinician specialists, statisticians, and others.
T
206
T/F
A good experimental design takes into account the natural history of the disease
T
207
- Further protection against errors of interpretation caused by disease fluctuations is sometimes provided by using a crossover design,
- consists of alternating periods of administration of test drug, placebo preparation (the control), and the standard treatment (positive control)
Crossover design
208
T/F
Known and unknown diseases and risk factors (including life- styles of subjects) may influence the results of a clinical study.
T
209
T/F
some diseases alter the pharmacokinetics of drugs and other drugs and some foods alter the pharmacokinetics of many drugs.
T
210
usually quantitated by administration of an inert material with exactly the same physical appearance, odor, consistency, etc, as the active dosage form.
Placebo response
211
involves use of a placebo, administered to the same subjects in a crossover design, if possible, or to a separate control group of well-matched subjects.
Single-blind design
212
Observer bias can be taken into account by disguising the identity of the medication being used—placebo or active form—from both the subjects and the personnel evaluating the subjects’ responses
Double-blind design
213
a third party holds the code identifying each medication packet, and the code is not broken until all the clinical data have been collected.
Double-blind design
214
Confirmation of compliance with protocols, also
Adherence
215
designed to answer specific, usually single, questions under tightly controlled laboratory conditions
- does drug x inhibit enzyme y?
The basic question may then be extended
- if drug x inhibits enzyme y, what is the concentra- tion-response relationship?
Basic research
216
usually reproducible and often lead to reliable insights into the mechanism of the drug’s action.
Basic research
217
- include phase 1–3 trials
- results often reveal unpredictable benefits and toxicities but do not generally test a prespecified hypothesis and cannot prove cause and effect.
First-in-human studies
218
consist of observations designed to test a specified hypothesis
- eg, that thiazolidinedione antidiabetic drugs are associated with adverse cardiovascular events.
Analytic epidemiological studies
219
utilize populations of patients that have (exposed group) and have not (control group) been exposed to the agents under study and ask whether the exposed groups show a higher or lower incidence of the effect.
Cohort epidemiologic studies
220
utilize populations of patients that have displayed the end point under study and ask whether they have been exposed or not exposed to the drugs in question.
Case-control epidemiologic studies
221
- utilize rigorous evaluation and grouping of sim- ilar studies to increase the number of subjects studied and hence the statistical power of results obtained in multiple published studies
- cannot prove cause and effect.
Meta-analyses
222
designed to answer specific questions about the effects of medications on clinical end points or important surrogate end points, using large enough samples of patients and allocating them to control and experimental treatments using rigorous randomization methods
Large randomized controlled trials (RCTs)
223
best method for distributing all foreseen confounding factors, as well as unknown confounders, equally between the experimental and control groups.
RCTs
224
critical factor in evaluating the data regarding a new drug
access to all the data.
225
falsely exaggerates the benefits of new drugs because negative results are hidden.
missing data phenomenon
226
oversees the drug evaluation process in the USA and grants approval for marketing of new drug products
The Food & Drug Administration
227
responsible for certain aspects of food safety, a role it shares with the US Department of Agriculture (USDA)
FDA
228
To receive FDA approval for marketing, the originating institution or company must submit evidence of ________
safety and effectiveness
229
a reaction to deaths associated with the use of a preparation of sulfanilamide
Federal Food, Drug, and Cosmetic Act of 1938
230
result of a teratogenic drug disaster involving thalidomide.
Kefauver-Harris Amend- ments of 1962
231
“nontoxic” hypnotic and pro- moted as being especially useful as a sleep aid during pregnancy.
- withdrawn from sale worldwide due to phocomelia
Thalidomide
232
condition involving shortening or complete absence of the arms and legs.
phocomelia
233
234
T/F
thalidomide is a relatively safe drug for humans other than the fetus.
T
235
approved by the FDA for limited use as a potent immunoregulatory agent and to treat certain forms of leprosy.
Thalidomide
236
IND
Notice of Claimed Investigational Exemption for a New Drug
237
IND includes
1. composition and source of the drug
2. chemical and manufacturing information
3. all data from animal studies
4. proposed plans for clinical trials
5. the names and credentials of physicians who will conduct the clinical trials,
6. compilation of the key preclinical data relevant to study of the drug in humans that have been made available to investigators and their institutional review boards.
238
FDA often requires _____ of clinical testing to accumulate and analyze all required data.
4-6 years
239
Testing in humans is begun only after _____ have been completed
sufficient acute and subacute animal toxicity studies
240
241
______ in animals, including _______ , is usually done concurrently with clinical trials.
Chronic safety testing; carcinogenicity studies
242
T/F
In each phase of the clinical trials, volunteers or patients must be informed of the investigational status of the drug as well as the possible risks and must be allowed to decline or to consent to participate and receive the drug.
T
243
IRB
interdisciplinary institutional review board
244
review and approve the scientific and ethical plans for testing in humans.
IRB
245
- 20-100 volunteers
- may be nonblind or “open”; both the investigators and the subjects know what is being given
- may be “blinded” and placebo controlled
Phase 1
246
Many predictable toxicities are detected in this phase
Phase 1
247
- Pharmacokinetic measurements of absorption, half-life, and metabolism are often done.
Phase 1
248
determine the probable limits of the safe clinical dosage range.
Phase 1
249
- usually performed in research centers by specially trained clinical pharmacologists
Phase 1
250
drug is studied in patients with the target disease to determine its efficacy (“proof of concept”), and the doses to be used in any follow-on trials.
Phase 2
251
- 100-200 volunteers
- single -blind design with an inert placebo medication and an established active drug (positive control) in addition to the investigational agent.
Phase 2
252
- usually done in special clinical centers (eg, university hospitals)
Phase 2
253
- broader range of toxicities may be detected in this phase.
- have the highest rate of drug failures, and only 25% of innovative drugs move on to phase 3.
Phase 2
254
drug is evaluated in much larger numbers of patients with the target disease—usually thousands—to further establish and confirm safety and efficacy.
Phase 3
255
designed to minimize errors caused by placebo effects, variable course of the disease, etc.
- double-blind and crossover techniques are often used.
Phase 3
256
257
usually performed in settings similar to those anticipated for the ultimate use of the drug.i
Phase 3
258
Certain toxic effects, especially those caused by immunologic processes, may first become apparent in
Phase 3
259
Marketing approval requires submission of
NDA
260
T/F
If phase 3 results meet expectations, application is made for permission to market the new agent.
T
261
Biological approvals are submitted to
Biological License Application (BLA)—to the FDA.
262
T/F
If problems arise, eg, unexpected but possibly serious toxici- ties, additional studies may be required and the approval process may extend to several additional years.
T
263
T/F
In cases of urgent need (eg, cancer chemotherapy), the process of preclinical and clinical testing and FDA review may be accelerated
T
264
T/F
For serious diseases, the FDA may permit extensive but controlled marketing of a new drug before phase 3 studies are completed
T
265
T/F
for life-threatening diseases, it may permit controlled marketing even
before phase 2 studies have been completed.
T
266
FDA programs that are intended to speed entry of new drugs into the marketplace.
- Fast track
- priority approal
- accelerated approval
267
additional special category of “_____” products (eg, for cystic fibrosis) was approved for restricted marketing after expanded phase 1 trials
breakthrough
268
usually granted with the requirement that careful monitoring of the effectiveness and toxicity of the drug be carried out and reported to the FDA.
*Unfortunately, FDA enforcement of this requirement has not always been adequate.
Accelerated approval
269
Once approval to market a drug has been obtained
Phase 4
270
monitoring the safety of the new drug under actual conditions of use in large numbers of patients
Phase 4
271
T/F
low-incidence drug effects are not generally detected before phase 4 no matter how carefully phase 1, 2, and 3 studies are executed.
T
272
No definite duration
Phase 4
273
The time from the filing of a patent application to approval for marketing of a new drug may be
5 years and above
274
FDA review process duration for evaluation of an NDA
300-500 days
275
provides for 12 years of patent protection for new drugs
Patient Protection and Affordable Care Act of 2010
276
277
278
After expiration of the patent, any company may produce the drug, file an abbreviated new drug application (ANDA), demonstrate required equivalence, and, with FDA approval, market the drug as a _____ without paying license fees to the original patent owner.
generic product
279
drug’s proprietary trade name and is usually registered; this registered name may be legally protected as long as it is used.
Trademark
280
claimed to be the fourth leading cause of death
adverse drug reactions
281
In cases of adverse drug reactions, Events that are both serious and unexpected must be reported to the FDA within
15 days
282
ability to predict and avoid adverse drug reactions and optimize a drug’s therapeutic index
Precisions medicine
283
Drugs for rare disease
Orphan drugs
284
T/F
Funding for development of drugs for rare diseases or ignored diseases that do not receive priority attention from the traditional indus- try has received increasing support via philanthropy or similar funding from not-for-profit foundations
T; Cystic Fibrosis Foundation, the Michael J. Fox Foundation for Parkin- son’s Disease, the Huntington’s Disease Society of America, and the Gates Foundation.
285
provides incentives for the development of drugs for treatment of a rare disease or condition defined as “any disease or condition which
(a) affects less than 200,000 persons in the USA (b) affects more than 200,000 per- sons in the USA
Orphan Drug Amendment of 1983
