Test #2 Flashcards Preview

Toxicology > Test #2 > Flashcards

Flashcards in Test #2 Deck (126):
1

What the body does to the drug

Pharmacokinetics

2

What the drug does to the body

Pharmacodynamics

3

Area of pharmacology concerned w/ unusual response to drugs caused by genetic differences b/w individuals

Pharmacogenetics

4

Repetitive sequence of experimentation & characterization involving biologic assays ranging from the molecular to organism level

Drug screening

5

What is the end result of drug screening process called?

Lead compound (a patentable entity)

6

What is the goal of preclinical studies?

Identifying potential human toxicities & designing mechanism to monitor for these toxicities in clinical trials

7

What are the 3 types of toxic doses?

1. No effect: max dose showing no toxicity
2. Min. lethal dose: min. dose that kills a subject
3. Median lethal dose: kills 1/2 of test subjects

8

What are some limitations of preclinical testing?

1. toxicity testing is time consuming & expensive
2. Large numbers of animal subjects needed
3. Extrapolation of animal data to humans may not be accurate
4. Rare adverse effects are unlikely to be detected

9

What are 5 confounding factors in clinical trials?

1. Most ds's have a variable clinical course
2. Presence of other ds & risk factors
3. Known & unknown ds/risk factors may influence clinical study results
4. Subject & observer bias
5. Study design must account for placebo effect

10

The administrative body charged w/ oversight of the drug evaluation process.

FDA

11

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

Phase I trials

12

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.

Phase II trials

13

These trials try to establish safety & efficacy. These trials are designed to minimize potential confounding factors. Often involve double-blind crossover protocols.

Phase III Trials

14

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

Phase IV trials

15

This Act provided incentives for the investigation & development of drugs for rare ds's

Orphan Drug Act of 1983

16

A reaction to a drug that is harmful or an unintended response. Claimed to be the 4th leading cause of death in the US

Adverse Drug reactions

17

A fundamental principle of pharmcodynamics is that drugs only modify what?

Normal biochemical & physiologic processes; they don't endow new capabilities

18

The pharmacologic effect is mediated through what?

Drug/receptor binding

19

The most biologically important & common receptors are __________ that bind extracellular molecules (ligands) which results in an intracellular change (transduction).

Integral membrane proteins

20

What are the 4 major types of integral membrane proteins?

1. Ligand gated ion channels
2. G-protein coupled receptors
3. Enzyme-linked receptors
4. Intracellular receptors

21

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.

Ligand gated ion channels

22

Voltage gated ion channels in peripheral nerves are receptor sites for what type of drugs?

Local anesthetics

23

Ligand binding to the extracellular receptor site of a G-protein couple receptor leads to what?

Activation of the alpha-subunit of the G-protein, the release of bound GDP, & binding of a GTP

24

Stimulation of G-protein coupled receptors results in responses lasting how long?

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