Test #2 Flashcards
1
Q
What the body does to the drug
A
Pharmacokinetics
2
Q
What the drug does to the body
A
Pharmacodynamics
3
Q
Area of pharmacology concerned w/ unusual response to drugs caused by genetic differences b/w individuals
A
Pharmacogenetics
4
Q
Repetitive sequence of experimentation & characterization involving biologic assays ranging from the molecular to organism level
A
Drug screening
5
Q
What is the end result of drug screening process called?
A
Lead compound (a patentable entity)
6
Q
What is the goal of preclinical studies?
A
Identifying potential human toxicities & designing mechanism to monitor for these toxicities in clinical trials
7
Q
What are the 3 types of toxic doses?
A
- No effect: max dose showing no toxicity
- Min. lethal dose: min. dose that kills a subject
- Median lethal dose: kills 1/2 of test subjects
8
Q
What are some limitations of preclinical testing?
A
- toxicity testing is time consuming & expensive
- Large numbers of animal subjects needed
- Extrapolation of animal data to humans may not be accurate
- Rare adverse effects are unlikely to be detected
9
Q
What are 5 confounding factors in clinical trials?
A
- Most ds’s have a variable clinical course
- Presence of other ds & risk factors
- Known & unknown ds/risk factors may influence clinical study results
- Subject & observer bias
- Study design must account for placebo effect
10
Q
The administrative body charged w/ oversight of the drug evaluation process.
A
FDA
11
Q
These trials determine the dose-response relationship of the drug. Subjects are normally healthy volunteers. The main goal is to identify the maximal tolerated dose in the absence of severe toxicity. Pharmacokinetic parameters are determined in these trials
A
Phase I trials
12
Q
During these trials, the drug is studied in a small group of pts w/ the target ds to detemine efficacy. A single blinded protocol is usually used.
A
Phase II trials
13
Q
These trials try to establish safety & efficacy. These trials are designed to minimize potential confounding factors. Often involve double-blind crossover protocols.
A
Phase III Trials
14
Q
These trials involve monitoring drug safety when used by a large number of pts. This relies on the voluntary, timely, & complete reporting of toxicity by prescribers
A
Phase IV trials
15
Q
This Act provided incentives for the investigation & development of drugs for rare ds’s
A
Orphan Drug Act of 1983
16
Q
A reaction to a drug that is harmful or an unintended response. Claimed to be the 4th leading cause of death in the US
A
Adverse Drug reactions
17
Q
A fundamental principle of pharmcodynamics is that drugs only modify what?
A
Normal biochemical & physiologic processes; they don’t endow new capabilities
18
Q
The pharmacologic effect is mediated through what?
A
Drug/receptor binding
19
Q
The most biologically important & common receptors are __________ that bind extracellular molecules (ligands) which results in an intracellular change (transduction).
A
Integral membrane proteins
20
Q
What are the 4 major types of integral membrane proteins?
A
- Ligand gated ion channels
- G-protein coupled receptors
- Enzyme-linked receptors
- Intracellular receptors
21
Q
These channels are responsible for regulation of the flow of ions through the cell membrane. Respond rapidly & have a very short duration of effect. Can open channels or modify the function of ion channels.
A
Ligand gated ion channels
22
Q
Voltage gated ion channels in peripheral nerves are receptor sites for what type of drugs?
A
Local anesthetics
23
Q
Ligand binding to the extracellular receptor site of a G-protein couple receptor leads to what?
A
Activation of the alpha-subunit of the G-protein, the release of bound GDP, & binding of a GTP
24
Q
Stimulation of G-protein coupled receptors results in responses lasting how long?
A
Seconds to minutes
25
Enzyme-linked receptors elicit responses that last how long?
Minutes to hours
26
What is the M/C enzyme type assoc. w/ enzyme-linked receptors?
Tyrosine kinase
27
These hormones pass directly through the cell membrane binding to an intranuclear receptor
Steroid hormones (receptor-steroid complex binds to DNA segment causing altered gene expression)
28
Intracellular receptors elicit responses that can last for how long?
at least 30 minutes but can last for hours to days (b/c it involves new protein synthesis)
29
Binding of a small number of receptors can dramatically alter total cellular metabolism due to what?
Cascade effect
30
Repeated or continous administration of an agonist (or antagonist) may lead to changes in receptor population & thereby responsiveness leading to what?
Receptor desensitization (to protect cell from damage)
31
Normal cytosolic proteins that recognize agonist-activated, phosphorylated receptors & bind them.
Arrestins (binding makes receptor inaccessible for G-proteins)
32
The magnitude of a drugs effect depends on what?
Concentration at the receptor site which is determined by the dose of the drug & the drugs particular pharmacokinetics
33
As the drug's concentration increases the magnitude of the pharmacologic effect increases. This is called what?
Graded dose response
34
A plateau in the drug's effect is reached when what happens?
1. All receptors are occupied
| 2. For receptors w/ a large "spare" population maximal cellular response is attained
35
This is the amount of drug necessary to produce an effect 50% of an agent's max. effect.
Potency
36
A significant contributing factor to potency is what?
Affinity of a drug for the receptor
37
The ability of an agent to produce an effect of a given magnitude, the max. biologic response to a drug.
Efficacy
38
If a drug binds to a receptor & produces a biologic effect that mimics the response of the endogenous ligand it is called what?
Agonist (ex: phenylephrine --> epinephrine; meth --> MAO enzymes)
39
These are drugs which decrease the response of another drug or endogenous ligand.
Antagoinsts
40
What are 4 mechanisms by which antagonists work?
1. Bind to same receptor site as agonists (blocking)
2. Non competitive (allosteric inhibition); bind to different site causing a conformational change
3. Irreversible binds a receptors (ex: ASA --> COX-1)
4. Chemical antagonists; bind w/ another drug making it inactive (ex: Protamine sulfate --> heparin)
41
These drugs have some intrinsic activity by it's less than a full agonist.
Partial antagonists (partial agonists) (Ex: Pentazocine --> morphine; methadone)
42
When a drug binds to a separate receptor but the response opposes the response to an agonist
Functional (Physiologic) antagonism (Ex: epinephrine --> histamine)
43
Type of agonist that inhibits receptors that are active in the absence of an agonist
Inverse agonist (seen in benzodiazepine & cannabinoid receptors)
44
These are used to determine the ability of a drug to produce a response of a predetermined magnitude in a pt population. Useful in determining toxic dose in populations
Quantal Dose-Responses
45
The ratio of the dose that produces toxicity to the dose that produces the desired response
Therapeutic Index
46
A large Therapeutic Index indicates what?
Toxicity requires a much larger dose than required for the desired effect.(penicillin)
47
What does a small Therapeutic Index indicate?
The dose for the therapeutic effect approaches the toxic dose, these drugs are potentially dangerous.(warfarin)
48
Attempts to explain an unexpected drug response via a genetic mechanism. Goal is to understand the role that genetic make-up in responses to drugs, both therapeutic & toxic responses
Pharmacogenetics
49
Identifies genetic differences w/i a population to try to explain observed responses or susceptibilities to drugs or ds processes
Pharmacogenomics
50
What are some characteristics of all anti-anxiety agents?
- Have sedative properties (hypnotics)
- Many possess anticonvulsant properties
- Able to induce anterograde amnesia
- Most potentiate GABA activity
51
What is the target of Benzodiazepines?
GABA receptors
52
How do benzos work?
Reduce anxiety through the promotion of GABAnergic transmission which results in inhibiting neuronal circuits in the limbic system
53
Sedative/hypnotic/anterograde amnesia/anticonvulsant effects of benzos occur because of what?
Larger doses that involve interaction of alpha-1 GABA receptors
54
Muscle relaxant effects of benzos occur because of what?
Large doses that work by increasing pre-synaptic inhibition in the spinal cord via alpha-2 GABA receptors
55
Benzos are most frequently used for what?
Generalized anxiety disorders
56
What type of muscle disorders respond to diazepam (Benzos)?
Muscular disorders resulting spasm particularly spasticity assoc. w/ degenerative disorders of spinal cord dysfunction
57
What is the goal of short acting benzos?
Amnesia (used prior to invasive or unpleasant procedures)
58
How can benzos affect sleep/be used to tx sleep disorders?
- Decrease sleep latency
- Increase stage 2 non-REM sleep
- Decrease both slow wave & REM sleep
59
How are benzos absorbed & distributed?
Benzos are lipophilic & rapidly absorbed/distributed after oral administration
60
How are benzos metabolized?
By hepatic microsomal enzyme systems. Excreted in the urine as glucuronides or oxidized metabolites
61
Abrupt discontinuation of benzos results in what withdrawal symptoms?
- Insomnia
- Anxiety
- Agitation
- Muscle tension
62
What type of benzos are more assoc. w/ withdrawal syndromes?
Short-acting agents
63
What are adverse effects of benzos?
- Drowsiness & confusion (M/C)
- Ataxia
- CNS depression when taken w/ other CNS depressants
- Overdose is seldom lethal unless w/ other CNS depressants
64
What are some types of non-benzo anxiolytic & hypnotic agents?
- Zolpidem (Ambien-lacks anticonvulsant & muscle relaxant properties)
- Zaleplon (Sonata-used for sleep initiation but not maintenance, less side effects than zolpidem)
- Eszopiclone (Lunesta-sedative for insomnia for 6 months)
65
This drug is a GABA receptor antagonist that rapidly reverses the effects of benzos when overdose is suspected
Flumazenil (reverses all effects of benzos & can begin a withdrawal syndrome)
66
Type of agents that used to be used as sedatives but were replaced by benzos b/c they were safer
Barbiturates
67
What are some of the negative effects of barbiturates?
- Induce tolerance, drug-metabolizing enzymes
- Induce physical dependence
- Have severe withdrawal syndrome
68
What is the mechanism of barbiturates?
Enhance GABAnergic transmission through binding to a different site on the GABA receptor
69
Larger doses of barbiturates can cause what to happen?
Impair function of Na+ channels leading to general anesthesia
70
What are actions of barbiturates?
- CNS depression (low dose=sedative/anticonvulsant, high dose=anesthesia)
- Respiratory depression
- Enzyme induction
71
What is the only common therapeutic indication for barbiturates?
Generalized seizures which are resistant to less sedating anticonvulsants (1st-line drug for pediatric seizure disorders)
72
How are barbiturates absorbed/distributed?
Well absorbed across the GI tract & rapidly distributed. Highly bound to plasma proteins & compete w/ other plasma protein bound drugs
73
What are adverse effects of barbiturates?
- Physical dependence
- Rapid withdrawal causes a withdrawal syndrome
- Overdose is a common cause of death
74
What 2 categories are CNS stimulants divided into?
```
Psychomotor stimulants (cause excitement, euphoria, relieve fatigue, & increase motor activity
Psychomimetic drugs (hallucinogens; produced profound changes in thought patterns & mood)
```
75
What are examples of psychomotor stimulants?
```
Methylxanthines
Nicotine
Cocaine
Amphetamines
Methylphenidate (Ritalin)
```
76
Theophylline, Theobromine, & Caffeine are examples of what type of psychomotor stimulant?
Methylxanthines
77
What are the proposed mechanisms of Methylxanthines?
1. Translocation of extracellular calcium
2. Increase in cAMP & cGMP d/t phosphodiesterase inhibition
3. Blockade of adenosine receptors (most likely the main effect at common plasma levels)
78
What actions does caffeine have on the body?
CNS: decrease fatigue & increased alertness. Can produce anxiety & tremors
CV: may cause symptoms of cardiac ischemia/arrhythmias
Renal: mild diuretic
Gastric mucosa: it stimulates secretion HCl
79
How is caffeine absorbed & distributed?
Absorbed orally & rapidly distributed throughout the body including the brain
80
What are adverse effects of caffeine?
Moderate doses cause insomnia, anxiety, & agitation.
Higher doses can cause emesis & convulsions.
Lethal dose is 10g (100 cups of coffee) d/t arrhythmias
81
Bruprpion (Zyban) is an antagonist to what drug?
Nicotine
82
How does nicotine work (mechanism)?
Low does causes ganglionic stimulation by depolarization
| High doses it causes ganglionic blockade
83
What actions does nicotine have on the body?
- CNS: Rapidly crosses the BBB, low doses produce aroused relaxation, improves attention, learning, problem solving, & reaction time. High doses produce medullary paralysis causing respiratory/CV failure
- Peripheral: stim. sympathetic system results in increased BP/HR. Stim parasym. increases intestinal motility. High doses result in hypotension/GI paralysis
84
What are the pharmokinetics of nicotine?
Highly lipid soluble so absorption occurs across any mucosa. 90% of inhaled nicotine is absorbed across the alveolar membrane. Clearance involves metabolism in the lung/liver ending w/ urinary excretion. Tolerance to toxic effects develops rapidly.
85
What are the adverse effects of nicotine?
CNS: irritability & tremors
| Intestinal cramps, diarrhea, HTN, tachycardia.
86
What are withdrawal symptoms of nicotine?
Physical dependence develops rapidly. Withdrawal is charac. by irritability, anxiety, restlessness, difficulty, concentrating, HAs, & insomnia
87
What is the mechanism of action of cocaine?
Central & peripheral action is the blockade of reuptake of monoamines (NE, 5-HT & DA) into presynaptic terminals which causes them to be more potent especially DA. This leads to intense sublime euphoria.
88
What are the actions of cocaine?
- CNS: produces an acute increase in awareness & euphoria, higher doses cause hallucinations, delusions & paranoia; tremors, convulsions followed by respiratory & vasomotor depression
- Symp. nervous system: increases action of norepi. producing fight or flight syndrome
- Hyperthermia: impairs thermoregulation
89
What is a therapeutic use of cocaine?
Topical anesthetic
90
Explain the pharmacokinetics of cocaine
- Nasal administration results in peak levels at 15-20 mins.
- IV or inhalation (smoking) peaks w/i seconds but wears off faster
- Rapidly de-esterfied & de-methylated to be exreted in urine
91
What are the adverse effects of cocaine?
- Anxiety: includes HTN, tachycardia, sweating, paranoia
- Depression: major component of withdrawal
- Cerebrovascular ds: fatal arrhythmias, MI, seizures, stroke, intracranial hemorrhage
92
What is the mechanism of action of Amphetamines?
Effects on CNS & PNS involving elevated levels of neurotransmitters in the synaptic space by promoting release of intracellular stores of catecholamines & inhibition of monoamine oxidase
93
The major behavioral effects of amphetamines are d/t the release of what?
Dopamine
94
What are the effects of amphetamines?
Stimulates the entire neuraxis resulting in increased alertness, insomnia, decreased appetite, & decreased fatigue. In symp. nervous system, it prolongs action of NE in adrenergic system
95
What are therapeutic uses of amphetamines?
ADHD tx: Dextroamphetamine/methylphenenidate (Ritalin), Atomoxetine (strattera)
Narcolepsy
96
Explain the pharmacokinetics of amphetamines?
Completely absorbed from the GI tract, metabolized in the liver & excreted in the urine. Duration of action is 4-6 hours
97
What are adverse effects of amphetamines?
- Causes addiction & drug seeking behavior
- CNS: insomnia, irritability, weakness, tremor, confusion, delirium, panic states, suicidal tendencies, acute schizo episode
- CV: palpitations, tachyarrthymias, HTN, acute coronary ischemia, CV collapse
- GI: Nausea, vomiting, ab cramps, diarrhea
98
What is the mechanism of action of Methylphenidate (Ritalin)?
Potent dopamine elevator (better than cocaine) but enters brain slower than cocaine so produces less of a high
99
What are the therapeutic uses of Methylphenidate (Ritalin)?
ADHD
| Nacrolepsy
100
Explain the phamacokinetics of Methylphenidate (Ritalin)
Rapidly absorbed after oral administration & is concentrated in the brain. Excreted in the urine
101
What are adverse reactions of Methylphenidate (Ritalin)?
Ab pain, nausea, anorexia are M/C
| Insomnia, irritability, may increase seizure freq. in pts w/ seizure disorders
102
What is the mechanism of antidepressants?
Increase the cnetral actions of NE &/or serotonin (5-HT)
103
SSRIs specifically inhibit what?
5-HT (serotonin) reuptake at the presynaptic terminal
104
What are the therapeutic uses of SSRIs?
```
Endogenous depression (primary use)
OCD
Panic disorder
Generalized anxiety
Premenstrual dysphoric disorder
Bulimia nervosa
```
105
Explain the pharmacokinetics of SSRIs
- Well absorbed after oral abministration
- Undergo extensive P450 metabolism & conjugation
- Excretion is primarily through kidneys
106
What are adverse effects of SSRIs?
- Sleep disturbances
- Sexual dysfunction
- Increased suicidal ideation in young people
- Overdose may cause Serotonin Syndrome
107
What is the Serotonin Syndrome Triad?
```
Cognitive effects (confusion, hypomania, hallucinations, etc)
Autonomic effects (shivering, sweating, hyperthermia, HTN, etc)
Somatic effects (myoclonus, hyperreflexia, tremor)
```
108
What drugs are assoc. w/ Serotonin Syndrome?
```
Antidepressants
Opioids
CNS stimulants
5-HT agonists
Psychedelics
Herbs
```
109
Type of drug that may be effective in those unresponsive to SSRIs. Have been shown to be effective in treating neuropathic pain (chronic pain) that freq. accompanies depression
Serotonin/NE Re-uptake Inhibitors (SNRIs)
110
These were the first drugs to be consistently effective at relieving depression in large numbers of depressed pts. They block NE & 5-HT re-uptake into the pre-synaptic neuron. Useful in pts not responding to SSRIs & SNRIs
Tricyclic Antidepressants
111
What are the mechanisms of action of TCAs?
- Potent inhibitors of neuronal reuptake of NE & 5-HT into presynaptic nerve terminals. Don't block dopamine reuptake.
- Block serotonergic, alpha-adrenergic, histaminergic, & muscarinic receptors
112
What are the therapeutic uses of TCAs?
Tx severe major depression
| Can be effective in tx of chronic pain
113
Explain the pharmacokinetics of TCAs.
Well absorbed orally & widely distributed d/t their lipophilic nature. Hepatic metabolism involves both the P450 system & glucuronidation w/ urinary excretion of the inactive metabolites
114
What are adverse effects of TCAs?
- Blockade of muscarinic receptors
- Epilepsy can be exacerbated
- Alpha receptor blockade can cause orthostatic hypotension & tachycardia
- Sedation, insomnia
- Can exacerbate manic behavior in bipolars
- Can be lethal at only 5-6x avg daily dose
115
Monoamine Oxidase Inhibitors (MAOIs) are in limited use d/t what?
Dietary restriction required w/ their use
116
What is the mechanism of action of MAOIs?
Form stable complexes w/ the enzyme causing irreversible inactivation resulting in increased stores of monoamines in neurons & diffusion of neurotransmitter into the synaptic cleft
117
What are the therapeutic uses of MAOIs?
- Limited to those not responding to less potentially toxic agents
- May be useful in phobic disorders & atypical depression
118
Explain the pharmacokinetics of MAOIs
Well absorbed orally.
| Regeneration of MOA activity requires up to 4 wks after stopping drug use
119
What are adverse effects of MAOIs?
Side effects caused by excess tyramine which is also found in foods & is normally metabolized by MOA. Leads to HA, tachycardia, HTN, arrhythmias, stroke
120
MAO-A inihibition reduces breakdown of what?
Serotonin
NE
Dopamine
121
MAO-B inhibition reduces breakdown of what?
Mainly dopamine & phenethylamine (no dietary restrictions)
122
Lithium salts can be used as a prophylactic tx for what?
Manic-depressive pts & tx of manic episodes
123
What is the mechanism of action of lithium?
Unknown; inhibits inositol monophosphatase which is thought to interfere w/ the generation/recycling of an intracellular 2nd messenger PIP
124
Explain the pharmacokinetics of lithium
Renally excreted, 80% is reabsorbed in the prox. tubule, caution in decreased renal function & fluid shifts.
125
What are adverse effects of lithium?
- May interfere w/ thyroid function
- Nausea, vomiting, diarrhea, tremor, polydipsia, edema
- NSAIDs may decrease renal clearance by blocking renal PG synthesis
126
What is the only acutely effective tx for depression?
Electroconvulsive therapy
