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Pharm 2- FULL SET

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heroin
Initial use: The first dose of heroin in healthy individuals is often aversive; nausea and emesis are
common. Most persons also experience some pleasurable effects, varying from mild euphoria to the
"rush,"
Tolerance is usually very marked - eventually a big reduction in effect of drug is seen:
• reduced effects of heroin
Characteristics of Opiate Withdrawal in Adults:16-96 hours: mydriasis, anorexia, gooseflesh, restlessness, irritability, tremor, weakness,
depression, nausea, vomiting, intestinal spasms (stomach cramps), diarrhea, muscle and back
pains, muscle spasms, CNS stimulation (ejaculationacid-base balance changes, dehydration, and ketosis
naloxone
facilitates diagnosis of heroine dependence- precipitates withdrawal syndrome

treatment with an opiate antagonist induces a severe but brief period of
withdrawal; i.v. midazolam may be given to induce a heavily sedated state.
methadone
i.v. heroin is replaced by oral methadone (cross-dependence) to
n mood experienced under heroin. Drug dose is then progressively
reduced on a pre-determined regimen (patient will attempt to delay dosage reductions).
Withdrawal is spread over 3-6 weeks, symptoms relatively mild, intense drug craving is reported.
Only approved for in-patient use or in licensed addiction treatment facilities.
-maintenance therapy- Why methadone? Long half-life gives stable levels of drug
clonidine
a centrally acting adrenergic α2-receptor agonist, reduces the
severity of withdrawal symptoms during withdrawal from low to moderate doses of opioids;
reduces the activity of noradrenergic neurons in the locus ceruleus whose firing rate is increased
during opioid withdrawal (these neurons express mu-opioid receptors); clonidine provides useful
but incomplete relief in mildly addicted subjects (probably most street addicts); less effective in
heavily dependent subjects. Side effects are dry mouth and sedation; euphoria is not observed
buprenorphine
a partial opiate agonist, may also assist in detoxification. Patients are
stabilized on buprenorphine which is then progressively withdrawn; withdrawal symptoms
are mild.
cocaine
The reinforcing effects of cocaine result from blockade of the re-uptake of
NE, DA, and serotonin (5HT) after they have been released by noradrenergic, dopaminergic, and
serotonergic nerves.
***increased levels of DA in nuc. accumbens.
There is no
available pharmacological treatment that reduces craving for cocaine and/or amphetamines and
reduces the probability of relapse to chronic use,
amphetamine
Amphetamines are indirectly acting sympathomimetic amines - they release
NE, DA (and 5-HT) from nerve terminals, both in the periphery and in CNS.
methamphetamine
Methamphetamine,
due to its extra methyl group, enters the brain more readily than D-amphetamine, and has a longer
half-life, but the mode of action of the two drugs is identical
MDMA
Drug related to amphetamine
tetrahydrocannabinol (THC)
Pharmacological effects of smoking one marijuana cigarette:
In roughly the following sequence:
• tachycardia -a result of increased sympathetic activity -blocked by propranolol.
• euphoria/"high" (elevation of mood) - usually associated with visual, auditory and
temporal perceptual distortions Frank hallucinations are absent at this dose level.
• relaxation and sedation - this distinguishes THC from LSD-like drugs.
• psychomotor impairment - impaired short term memory; simple motor tasks may be
unaffected, but more complex tasks involving several mental steps (driving, flying, etc.)
are usually performed less efficiently.
• dry mouth, hunger, peripheral vasodilation (e.g., pink conjunctiva), bronchodilation
LSD
HALLUCINOGEN
it is a partial agonist at 5HT2 receptors;
effects reversed by antagonists of 5HT2 receptors and partially by dopamine D2 antagonists.
Marked tolerance can occur; no evidence of physical dependence or compulsive drug use.
• somatic (1-2 hrs) - dizziness, pupil dilatation, weakness, tremor, nausea, paresthesias
• perceptual (2-6 hrs) - blurred vision, difficulty in focusing, altered awareness of shape
and color, micropsia, macropsia, hallucinations
• affective symptoms - elation, euphoria or dysphoria, depression, fear, paranoia, panic
(2-5 hrs); mood swings between these states; after 6 hrs, detachment
mescaline
HALLUCINOGEN
Drug related to LSD
(3,4,5 trimethoxy-ß-
found in peyote cactus, dimethyltryptamine, bufotenin
phenycyclidine (PCP)
Effects include analgesia, amnesia, poor muscle relaxation;
about 40% of patients experience dysphoric reactions, an violent psychotic behaviors.
PCP is a channel blocker at the NMDA receptor, blockingcation flux after NMDA receptor activation - non-competitive NMDA receptor antagonists
-in 2-5 minutes, blank stare, catatonic muscular rigidity, confusion, drowsiness,
hypersalivation,
High doses: stuporous, comatose state for 4-
6 hours; bizarre, unpredictable, aggressive behavior, paranoid psychoses (long duration, some-
times returning long after drug use), convulsive episodes, hypertensive crises
ketamine
drug related to PCP
widely used for animal anesthesia
Effects include analgesia, amnesia, poor muscle relaxation;
about 40% of patients experience dysphoric reactions, an violent psychotic behaviors.
ketamine is a channel blocker at the NMDA receptor, blockingcation flux after NMDA receptor activation - non-competitive NMDA receptor antagonists
-in 2-5 minutes, blank stare, catatonic muscular rigidity, confusion, drowsiness,
hypersalivation,
High doses: stuporous, comatose state for 4-
6 hours; bizarre, unpredictable, aggressive behavior, paranoid psychoses (long duration, some-
times returning long after drug use), convulsive episodes, hypertensive crises
Buprenorphine maintenance
retention rates are higher in
maintenance programs using this opiate partial agonist. Buprenorphine is available in a sublingual
tablet preparation combination with the opiate antagonist, naloxone, which has poor oral
bioavailability. After sublingual administration the naloxone has low bioavailability and
buprenorphine produces mild agonist effects. If the tablet is dissolved and injected i.v., the naloxone
has access to opiate receptors in brain, blocking the agonist effects of buprenorphine
Morphine
the major prototype opiate: given orally (first pass metab.), i.m. duration of action 3-4 hrs
may exert cardeioprotective effect
Codeine
- weaker than morphine; given orally; duration 3-4 hrs. also used as a
cough suppressant.
Heroin
- enters CNS more rapidly than morphine; metabolized to morphine in
liver; effects similar to morphine.
Hydromorphone
- more potent than morphine, otherwise very similar; duration 3-5 hours.
Methadone
- equipotent with morphine; orally active; duration of action 4-6 hours; used as an analgesic
and in treatment of heroin addiction.
Meperidine
- less potent and shorter duration of action than morphine (2-3 hours duration);
effects similar to morphine.
Oxycodone
- weaker drug, like codeine, used orally as analgesic for mild pain; duration of
action 3-4 hours.
Fentanyl
- very potent opiate short duration , approximately 1 hour; used as i.v. anesthetic agent
(similar drugs: sufentanil, alfentanil); also used as an analgesic by continuous transdermal (skin patch)
application.
Loperamide
- highly potent meperidine analog used to control diarrhea; does not enter brain
[rapidly removed by the multi-drug resistance transporter (MDR)] so does not produce analgesia,
respiratory depression; no abuse liability.
Naloxone
- antagonizes actions of all opiates; must be administered parenterally to be
active systemically; used to treat opiate drug overdose; short duration of action, 1-2 hours.
Naltrexone
- longer acting antagonist of opiate drugs; can be administered orally; used in
treatment of opiate addiction and alcoholism
Buprenorphine
- partial agonist at opiate receptors; weak analgesia, euphoria, antagonizes
action of morphine and heroin; used in treatment of opiate and other drug addictions.
Dextromethorphan
- dextroiosmer of an active opiate drug; has little or no effect on opiate
receptors; may act as antagonist on NMDA receptors in medulla; effective cough suppressant;
available in OTC preparations.
for moderate pain, consider combining NSAIDs with _________
codeine
Major cause of death subsequent to opiate OD
respiratory depression
reversed with naloxone
T/F: opiates do not cause diarrhea
TRUE
tranylcypromine
MAOI
imipramine,
TCA
desipramine,,
TCA
amitriptyline,,
TCA
nortriptyline,
TCA
fluoxetine,
SSRI
sertraline,,
SSRI
venlafaxine,,
SNRI
duloxetine,
SNRI
trazodone,
Miscellaneous antidepressant
• weak inhibition of 5-HT and NE reuptake,
• antagonists of post-synaptic 5-HT2A receptors
SE:relatively ***sedating, orthostatic hypotension, nausea, dizziness, few anti-cholinergic side effects
-can be used in combo with SSRI
bupropion,
Miscellaneous antidepressant
Antidepressant efficacy probably due to inhibition of dopamine and NE reuptake - (DAT and
NET),
Side effects: few - dry mouth, nausea; can act as stimulant - agitation, insomnia.
-can be used in combo with SSRI
mirtazapine
Miscellaneous antidepressant
• antagonism of presynaptic α2 adrenergic receptors; this causes increase in noradrenergic (&
serotonergic) transmission
• has little effect on reuptake systems (possibly some NE reuptake block)
• also is antagonist at 5-HT2 and 5-HT3 receptors
Side effects caused by blockade of various other receptors, both in CNS & periphery:
• very potent H1 histamine receptor antagonist (therefore is sedating and can lead to weight
gain and increased appetite)
• less potency at blocking muscarinic and α1 adrenergic receptors
**Sedation
-can be used in combo with SSRI
lithium,
anti-seizure- Bipolar tx
a. interferes with metabolism of inositol phosphates (intracellular "second messengers")
b. inhibits glycogen synthase kinase 3
->Note that lithium is generally not effective alone in abating an acute manic episode
->Lithium has a very narrow therapeutic window. Levels must be monitored
SEs:edema, polydipsia, polyuria, GI irritation
***sodium-depleting diuretics (esp. thiazides; also furosemide, ethacrynic acid); also, ACE
inhibitors, NSAIDs can increase chance of lithium toxicity
valproic acid,
anti-seizure- Bipolar tx
Advantages compared to lithium:
• can increase dose faster, get quicker response
• use to treat acute manic episodes
• wider therapeutic window; better tolerated in many patients
Disadvantages compared to lithium:
• less overall clinical experience
• although efficacy is similar to lithium in mild disease, efficacy in more
severe disease is questionable
carbamazepine,
anti-seizure- Bipolar tx
Advantages compared to lithium:
• can increase dose faster, get quicker response
• use to treat acute manic episodes
• wider therapeutic window; better tolerated in many patients
Disadvantages compared to lithium:
• less overall clinical experience
• although efficacy is similar to lithium in mild disease, efficacy in more
severe disease is questionable
lamotrigine
Bipolar tx
Advantages compared to lithium:
• can increase dose faster, get quicker response
• use to treat acute manic episodes
• wider therapeutic window; better tolerated in many patients
Disadvantages compared to lithium:
• less overall clinical experience
• although efficacy is similar to lithium in mild disease, efficacy in more
severe disease is questionable
D-amphetamine,
ADHD tx
These formulations aim to reduce the abuse potential by achieving
steady blood levels of amphetamine. Adderall® is a cocktail of amphetamine isomers and salts
that have different pharmacokinetics.
Black box warning: increased risk of heart attack, stroke, or sudden death
methylphenidate,
ADHD tx
Methylphenidate inhibits NE, DA, and 5HT uptake like cocaine,
but is less reinforcing. It is administered orally, in a variety of formulations with different
durations of action. The pharmacology of methylphenidate overlaps significantly with that of
amphetamines, and the two drugs have approximately the same efficacy in treating ADHD (70%). The abuse potential of methylphenidate is less than for amphetamines,
atomoxetine
ADHD tx
NE-selective re-uptake inhibitor. Atomoxetine is an FDA-
approved alternative to stimulants, but not all cases respond to this drug. This drug is not
reinforcing, and has a low potential for abuse/addiction; major side effect is drowsiness; other
effects sexual dysfunction, inhib. of CYP2D6, suicidal thoughts in a small percent of patients.
Monamine oxidase inhibitors (MAOIs)
2. MAOIs: neurochemical effects -block oxidative metabolism of biogenic amines by irreversibly inhibiting MAO-A & MAO-B in
nerve terminals
3. MAOIs: general behavioral / clinical effects
- acute (1st several days at least):
• CNS stimulation, agitation, possibly euphoria
- chronic (2-6 weeks):
• improvement of most or all clinical symptoms of depression
• CNS activation remains, may be lessened
5. MAOIs: adverse effects/toxicities
• orthostatic hypotension
• CNS stimulation (insomnia, hypomania, agitation, convulsions, REM suppression)
• GI distress; some weight loss
• some sexual dysfunction
7. MAOIs: Interactions:
Avoid indirectly acting sympathomimetics, including food containing high concentrations of
tyramine (cheese, red wine), amphetamines, bupropion, L-DOPA etc. Can lead to hypertensive
crisis, agitation and seizures.
Should not be taken together with SSRIs as may cause serotonin syndrome
Tricyclic antidepressants (TCAs)
• blockade of neuronal reuptake of NE and/or 5HT, raising synaptic level of these
biogenic amines; this effect correlates with therapeutic effects
TCA side effects often lead to serious problems with patient acceptance & compliance: sedation, seizures, ***orthostatic hypotension, dry mouth, urinary retention,urinary retention, increased appetite, weight gain
low therapeutic index
Because patients taking these drugs may be suicidal, it is critical to dispense in small
amounts
TCAs are highly metabolized by CYP450 enzymes. Their low therapeutic index increases the
probability of adverse drug interactions.
Serotonin-Selective Reuptake Inhibitors (SSRIs)
first-line antidepressant
• selectively block neuronal reuptake of 5-
HT; effect is to raise synaptic levels of 5-
HT
SSRIs are much more specific than tricyclic antidepressants, without significant effect at
neurotransmitter receptors so have less side-effects:
• headache
• GI upset, nausea, weight loss
• ***sexual dysfunction: ↓libido, anorgasmia
High therapeutic index
*** fluoxetine & paroxetine inhibit CYP450 enzymes, and can slow metabolism of various drugs
(most important with drugs with low therapeutic index - TCAs, lithium, warfarin, theophylline).
Best pharmtx for atypical depression
MAOI
Treatment of acute mania
a. antipsychotics
classic treatment: chlorpromazine, haloperidol, related drugs
more recently: olanzapine (Zyprexa®), an atypical antipsychotic with fewer side effects,
quetiapine (Seroquel), risperidone or aripiprazole
b. sedatives
- classic treatment: benzodiazepines; typically, lorazepam, clonazepam or diazepam
c. antiseizure drugs (either alone or in combination with atypical antipsychotic)
- more recently, valproic acid, carbamazepine, lamotrigine
Treatment of bipolar depression
Breakthrough depression may occur despite maintenance treatment. Care must be taken with
antidepressant treatment, not to push patient into mania. Recent trial suggest that addition of
antidepressant to mood stabilizer does not increase efficacy. These combinations have recently
been shown to be efficacious in treating bipolar patients suffering depression
Maintenance therapy with bipolar patients
a. lithium carbonate
b. antiseizure drugs - given alone or with lithium
• valproic acid (also called divalproex sodium) [Depakote®]
• carbamazepine [Tegretol®]
• lamotrigine [Lamictal] (better than lithium at preventing depressive episode).
c. atypical neuroleptic plus lithium or valproic acid - olanzapine, quetiapine or
aripiprazole
Intoxication gradients of Lithium
Acute intoxication - vomiting, profuse diarrhea, coarse tremor, ataxia, seizures and coma

Milder toxicity - look closely for signs:
Nausea, vomiting, diarrhea, abdominal pain, mental confusion, aphasia, ataxia,
motor hyperactivity, bizarre motor movements, hypotension

Treatment of lithium overdose - mainly supportive; osmotic diuretic, dialysis
T/F: NSAIDs can increase chance of lithium toxicity
TRUE
ethanol
One of the most widely used centrally acting drug known to man and a widely used
industrial solvent. Formed in the fermentation of sugars by yeasts; the concentration of ethyeast ferments can rise to about 15%; higher concentrations can be obtained by distillation
Over 90% of ingested ethanol is eliminated by metabolism in the liver
methanol
Methanol is sometimes consumed accidentally, or as a substitute for ethanol, or as a contaminant
in moonshine; effects are qualitatively similar to ethanol, although it is even less potent as a CNS
depressant. Extremely toxic, causes metabolic acidosis, blindness, and death when taken in large
quantities because toxic products are formed. Methanol is metabolized via the same enzymes as
ethanol:
Blindness is a result of the toxicity of formaldehyde
TX: admin of ETOH/fomepizole
ethylene glycol
antifreeze
potent CNS depressant; oxidation product, glycoaldehyde,
is toxic to the kidney, causes renal failure and death from uremia. A secondary product, glycolic
acid, causes metabolic acidosis
TX- fomepizole is also used to delay ethylene glycol metabolism
fomepizole
ADH inhibitor
delay the metabolism of toxic alcohols such as methanol or ethylene glycol that generate severely
toxic metabolites. Since the availability of NAD+ is rate-limiting, metabolism of one alcohol by
ADH can also be inhibited by giving a different alcohol
disulfiram
inhibitor of aldehyde dehydrogenase; leads to accumulation of acetalde-
hyde after ethanol ingestion (or even use of aftershave etc); causes very unpleasant symptoms:
• cutaneous vasodilatation, nausea and vomiting, syncope due to hypotension, overall misery
• hepatitis, with jaundice, fatigue, fever, abdominal pain (in severe cases).
This is an example of aversion therapy - negative reinforcement of undesirable behavior.
Use only with counseling; effectiveness may decline with time (non-compliance with dosing)
naltrexone
an opiate antagonist, reduces reinforcing effects of ethanol; decreased relapse to
alcohol drinking has been demonstrated in double-blind clinical trials of naltrexone in
alcoholics
acamprosate
an analog of GABA, thought to impair NMDA receptor function - reduces
neuronal hyperexcitability during abstinence; reduces craving, voluntary alcohol intake and
relapse, effectiveness comparable to naltrexone in clinical trials; combined treatment may be
better.
Primary metabolizers of ETOH
alcohol dehydrogenase (ADH) +
aldehyde dehydrogenase
Rate of Metabolism: ETOH
Maximum rate of ethanol oxidation by alcohol dehydrogenase is limited
by the availability of NAD+. Oxidation exhibits zero-order kinetics since reaction proceeds at maximum rate when blood alcohol levels are in excess of about 0.1 mg/ml. A constant amount of
ethanol is eliminated per unit time (rather than a constant fraction); t1/2 (half-time) increases with
dose. Average metabolic rate in adults is approx. 7 grams/hour and nothing can effectively increase
this rate (acutely); a single shot (1.5 oz of 80 proof alcohol; approx 14 g ethanol) requires about 2
hours plus to be cleared.
Effects of EOTH on Liver
Ethanol is a weak drug; many grams must be taken to induce an effect; this places a heavy
burden on the elimination system. A large fraction of available NAD+ in liver is consumed in the
metabolism of ethanol by ADH, and then in the metabolism of acetaldehyde by aldehyde
dehydrogenase - this results in an altered redox potential from the increased NADH:NAD+ ratio.
Effects of reduced NAD+: fatty acid synthesis increased, fatty acid oxidation decreased; plasma free
fatty acid levels increased; triglycerides accumulate in the liver; all at low, non-intoxicating doses
ETOH- ____________ of a glutamate (NMDA)-activated cation current, reducing synaptic transmission at some synapses
inhibition
ETOH- ____________ of GABA-mediated increase in Cl- conductance through action at an allosteric site in
the GABA-receptor-Cl- channel complex;
potentiation
SXS of withdrawal from ETOH (signs of dependence)
• tremors (often severe), hyper-reflexia, sweating, muscle cramps, vomiting
• visual hallucinations, delirium tremens or DTs (about day 3-4)
• hyperthermia, cardiovascular collapse
• generalized tonic-clonic seizures
albuterol,
BRONCHODILATOR
β-adrenergic agonists
tx sxs of asthma, not underlying condition
inhaled or oral, short acting β2
agonists (SABA); these are used for rapid relief—not for long-term prophylaxis; albuterol is
the primary medication for exercise-induced asthma
β adrenergic receptor agonists stimulate adenylyl cyclase → increased cAMP in airway
tissues and, therefore, relaxation of smooth muscle
tiotropium,
BRONCHODILATOR
muscarinic antagonists
tx sxs of asthma, not underlying condition
valuable for patients intolerant of inhaled β agonists
• block action of acetylcholine released from parasympathetic (vagal) neurons in bronchi by
competitively binding muscarinic receptors on the bronchial smooth muscle cells
theophylline,
BRONCHODILATOR
methylxanthines
tx sxs of asthma, not underlying condition
• most importantly antagonism of adenosine receptors
• inhibition of phosphodiesterases - elevation of cAMP (at high concentrations)
fluticasone,
ANTI-INFLAMMATORY AGENT
corticosteroids
Drugs that treat underlying cause of asthma- inhaled
FIRST LINE FOR LONG-TERM CONTROL
2. Mechanism of Action
• act through soluble nuclear glucocorticoid receptors to regulate gene expression
• inhibit eosinophil-induced inflammation of airway mucosa—mechanism unknown
• inhibit cytokine production
• inhibit activity of Phospholipase A2 and thereby inhibit release of arachidonic acid from cell
membranes - decrease prostaglandin and leukotriene synthesis
montelukast,
ANTI-INFLAMMATORY AGENT
leukotriene pathway modifiers
Drugs that treat underlying cause of asthma
2. Mechanism of action:
• leukotrienes are made by a variety of inflammatory cells in airways (e.g. eosinophils, mast
cells, macrophages, and basophils)
• LTB4 is a neutrophil chemo-attractant; LTC4 and LTD4 → bronchoconstriction, increased
bronchial reactivity, mucosal edema, and mucus hypersecretion
• leukotriene synthesis requires 5-lipoxygenase activit
cromolyn,
ANTI-INFLAMMATORY AGENT
release inhibitors
Drugs that treat underlying cause of asthma
Mechanism of Action
• inhibit delayed chloride channels in cell membrane - reduced accumulation of antigen-
induced intracellular calcium in sensitized mast cells
• reduce mast cell degranulation (i.e., release of histamine/autacoids) (mast cell stabilizer)
• inhibit release of inflammatory mediators from several cell types
• block activating effects of chemotactic peptides - reduction in burden of infiltrating cells
• inhibit IgE production by B lymphocytes
omalizumab
ANTI-INFLAMMATORY AGENT
anti-IgE therapy
Drugs that treat underlying cause of asthma
Blocks IgE-dependent mast cell
activation by removing unbound circulating IgE, preventing its interaction with mast cell surface
receptor. Administered iv or by subcutaneous injection every 2-4 weeks
Adverse Effects/Toxicity of ANTI-INFLAMMATORY AGENT
corticosteroids
Inhaled:
minimal (low oral bioavailability!)
• cataracts
• decreased bone density (fractures)
• oral candidiasis (less with ciclesonide
since it is activated only in the lung)

Oral:
• severe weight gain
• bone loss
• iatrogenic Cushing's syndrome
• adrenal suppression
L-dopa®
L-dopa, the direct precursor of
dopamine, does permeate the striatal tissue where it is taken up by the few remaining dopaminergic
neurons via dopamine transporters (DAT) and is decarboxylated to dopamine.
Large doses of L-dopa are required because more than 95% of the ingested L-dopa is
decarboxylated to dopamine in the peripheral tissues
The drug must be increased very gradually to minimize the many side effects and toxicity of the
large doses of L-dopa required for the desired therapeutic efficacy. L-dopa is effective in reducing
bradykinesia and rigidity, but is less effective in reducing tremor. All symptoms improve over a
period of weeks to months.
carbidopa,
co-administration of a
decarboxylase inhibitor (such as carbidopa) that does not enter the brain, allows lower doses of L-
dopa to be given, since a higher percentage of the administered dose of L-dopa is unmodified and
can enter the brain. Therapeutic effectiveness can be achieved with 75% less L-dopa when it is
combined with carbidopa.
Sinemet®,
Carbidopa is widely used in the US in a fixed combination with L-dopa at a ratio of 1 part
carbidopa to 10 parts L-dopa. This combination is known as Sinemet® and is presently the most
widely used medication in the treatment of Parkinson's disease. A controlled-release formulation,
Sinemet CR-Du Pont, is also available for treatment of Parkinson's disease.
bromocriptine,
DOPAMINE AGONISTS
ergot derivative with dopaminergic agonist properties, is used to treat
Parkinson's disease.
The combination of bromocriptine with L-dopa (and carbidopa)
substantially reduces the incidence of the 'on-off' phenomenon
ropinirole,
DOPAMINE AGONISTS dopaminergic agonists
(non-ergots)
pramipexole,
DOPAMINE AGONISTS dopaminergic agonists
(non-ergots)
rotigotine,
DOPAMINE AGONISTS a transdermal dopamine agonist, was introduced for treatment of PD
amantadine,
Initially introduced as an antiviral drug, amantadine was serendipitously found to improve the
symptoms of Parkinson's disease. The drug is believed to act as a dopamine-releasing agent (by
displacing dopamine from nerve terminals). Although the side effects are mild, amantadine is not as
effective as L-dopa; it is more effective than antimuscarinics alone. It is sometimes used in the
initial treatment of Parkinson's disease.
rasagiline,
COMBINATION OF L-DOPA WITH RASAGILINE - A SELECTIVE MAO B
INHIBITOR
MAO B predominates in the
brain, and is specifically inhibited by the MAO B inhibitor, rasagiline. Rasagiline decreases
dopamine breakdown in the brain but does not cause catecholamine build-up in the peripheral
tissues. Therefore, rasagiline does not cause hypertensive crisis. Rasagiline was approved for the
treatment of PD in 2006.
selegiline,
COMBINATION OF L-DOPA WITH RASAGILINE - A SELECTIVE MAO B
INHIBITOR
Selegiline is an older MAO B inhibitor that is still used
propranolol,
TX cardiac SE of L-dopa
• cardiac arrhythmias due to dopamine stimulation of beta receptors on the heart.
Arrhythmias are more likely to occur in patients with coronary artery disease, and can
be controlled by the administration of the beta blocker, propranolol.
benztropine,
CENTRALLY ACTING ANTIMUSCARINIC AGENTS
For more than a century prior to the introduction of L-dopa, anticholinergic drugs were the drugs
of choice in the treatment of Parkinson's disease because they reduced tremor. It is thought that
their therapeutic efficacy results from their blockage of muscarinic receptors within the striatum.
Use of anticholinergic drugs has greatly diminished, but they are still quite useful in combination
with L-dopa.
Side effects include dry mouth, blurred vision, and occasionally, urinary retention
trihexyphenidyl,
CENTRALLY ACTING ANTIMUSCARINIC AGENTS
For more than a century prior to the introduction of L-dopa, anticholinergic drugs were the drugs
of choice in the treatment of Parkinson's disease because they reduced tremor. It is thought that
their therapeutic efficacy results from their blockage of muscarinic receptors within the striatum.
Use of anticholinergic drugs has greatly diminished, but they are still quite useful in combination
with L-dopa.
Side effects include dry mouth, blurred vision, and occasionally, urinary retention
entacapone
COMT INHIBITORS
catechol O-methyltransferase inhibitors. These COMT inhibitors
prevent the breakdown of L-dopa by COMT primarily in peripheral tissues. Therefore, less L-dopa
needs to be administered and the "off" time is decreased.
donepezil,
acetylcholinesterase inhibitor
currently
available to treat Alzheimer's disease
CNS-selective.
Adverse effects: Most common side effects are nausea, vomiting, diarrhea, abdominal pain, and
anorexia
rivastigmine,
acetylcholinesterase inhibitor
currently
available to treat Alzheimer's disease
CNS-selective.
Adverse effects: Most common side effects are nausea, vomiting, diarrhea, abdominal pain, and
anorexia
galantamime,
acetylcholinesterase inhibitor
currently
available to treat Alzheimer's disease
CNS-selective.
Adverse effects: Most common side effects are nausea, vomiting, diarrhea, abdominal pain, and
anorexia
memantine
an NMDA receptor antagonist, may have neuroprotective properties and therefore
may slow the progression of the disease. Memantine has been used in Germany since 1982; it was
approved for use in the US in the fall of 2003
RECOMMENDATIONS
FOR SELECTING DRUGS FOR THE TREATMENT OF PARKINSON'S DISEASE:
1. In early stages, start patients off with dopamine AGONISTS such as pramipexole or ropinirole
or transdermal rotigotine. These drugs are less likely to cause motor problems seen with L- dopa and may be neuroprotective.
2. When dopamine agonists no longer provide enough symptomatic relief, add L-dopa and carbidopa. L-dopa is the most effective drug for the treatment of Parkinson's disease.
3. COMT inhibitors, such as entacapone, can be used with L-dopa to prolong the effectiveness of
L-dopa and to reduce 'wearing off' periods.
4. The addition of an 'atypical antipsychotic' (such as risperidone, olanzapine, or quetiapine) will
help control hallucinations caused by L-dopa without worsening parkinsonian symptoms.
5. Rasagiline may delay the onset of symptoms in newly diagnosed patients, but it is still unknown if rasagiline is neuroprotective.
In general, increasing the hydrophobicity __________ the anesthetic potency and duration of action,
but toxic side effects also are increased
increases
Local anesthetics
• selectively block the transient rise in sodium permeability that is responsible for conduction
in excitable membranes.
• progressively: 1) increase the threshold and decrease the rate of rise and amplitude of the
action potential; and 2) decrease the conduction velocity and finally block action potential
generation and nerve conduction.
• do not significantly alter the resting membrane potential, except at high concentrations,
which affect K+ channels.
• binding site is located in the intracellular region of the Na+ channel pore.
• degree of block is voltage and frequency dependent. This is because the charged form gains
access to the binding site in the channel pore only in the open state and local anesthetics bind
more tightly and stabilize the inactivated state of the Na+ channel.
T/F • do not significantly alter the resting membrane potential, except at high concentrations,
which affect K+ channels.
TRUE
T/F Cocaine
itself produces vasoconstriction
TRUE
Local Anesthetics- Metabolism:
• Ester-type local anesthetics (e.g. procaine) are hydrolyzed very rapidly by plasma
cholinesterase (pseudocholinesterase).
****Exception: Cocaine is metabolized in liver and plasma and
partially excreted unchanged in urine.
• Amide-type local anesthetics (e.g. lidocaine) are metabolized by liver microsomal CyP450.
Local Anesthetics- Cardio effect:
Local anesthetics decrease myocardial electrical excitability and conduction rate
and decrease blood pressure via reduced myocardial contraction strength and arteriolar dilation. This
occurs because of direct effects on myocardium and smooth muscle and indirect effects via actions
on autonomic neurons.
***Exception: Cocaine increases heart rate and blood pressure due to its
intrinsic sympathomimetic and vasoconstrictor properties. Cocaine is the
only local anesthetic that inhibits catecholamine uptake.
***
T/F Cocaine also produces mood and behavioral alterations
TRUE
Cocaine
When abused, cocaine is snorted, smoked, injected or ingested
orally. Cocaine will block re-uptake of NE, DA, and serotonin (5HT), but the reinforcing effects of
cocaine are due to increased activation of mesolimbic pathways by DA. Chronic cocaine users
become sensitized to the pleasurable effects of cocaine, but repeated acute use produces tolerance,
leading to increased doses to achieve the high. Chronic use of high doses may result in cardiac
damage (enlarged heart), paranoia and psychotic behavior. Chronic intranasal use can result in
damage to the nasal septum from repeated local vasoconstriction. Withdrawal is associated with
ahedonia (and associated craving for more cocaine), along with increased appetite, lethargy, and
chronic depression. Despite the acute aphrodisiac qualities of cocaine, sexual dysfunction is
common among heavy users
**oral ingestion route increases risk of OD
Desirable properties of local anesthetics:
1. Short time of onset
2. Appropriate duration of action
3. Fairly quick recovery
4. Non-irritating to tissue
5. Produces no permanent damage to nervous tissue
6. Low systemic toxicity (i.e., high therapeutic index)
cocaine
ESTER
Nerve conduction blockade
Vasoconstriction due to inhibition of NE uptake
Toxicity & abuse potential due to inhibition of catecholamine (particularly dopamine) uptake
Primary clinical use is topical anesthesia in upper respiratory tract
procaine
ESTER
Prototype ester local anesthetic
Low potency, short duration
Decreased use; used for infiltration anesthesia &
occasionally diagnostic nerve blocks
Hydrolyzed to Psulfonamides
local anesthetic suitable for injection
benzocaine
ESTER
Topical use only, often directly to wounds / ulcers
Widely used in OTC topical preparations
Long duration due to low solubility in water
local anethetic suitable for mucous membranes and skin
lidocaine
AMIDE
Greater potency, longer duration than procaine
Still one of the most widely used local anesthetics -
can be used for most clinical applications where
intermediate duration local anesthetic is needed
Also used as an antiarrythmic agent
local anethetic suitable for mucous membranes and skin and injection
bupivacaine
AMIDE
Greater potency, longer duration than lidocaine
More cardiotoxic than lidocaine
**most lipophilic- can cause CV depression before convulsion
proparacaine
local anesthetic suitable for opthalmological use
Tetrodotoxin
TTX; from puffer fish, some poisonous newts and frogs
reversibly block sodium permeability, but the binding site
is the outer mouth of the Na+ channel pore and thus is not use-dependent. Both toxins are extremely
potent and can cause fatal poisoning in humans.
saxitoxin
from
dinoflagellates that cause "red tide"
reversibly block sodium permeability, but the binding site
is the outer mouth of the Na+ channel pore and thus is not use-dependent. Both toxins are extremely
potent and can cause fatal poisoning in humans
Nonselective COX inhibitors
Asprin
Indomethacin
ibuprofen
naproxen
phenylbutazone
acetaminophen
COX-2 Selective inhibitor
Celecoxib
methotrexate (MTX)
DMARD
most widely used DMARD to date;
mg given as a single weekly oral dose may produce an anti-inflammatory
effect within 4 to 6 weeks (side effects: anorexia, vomiting, abdominal cramps, increased hepatic
enzyme activity, immuno-suppresion leading to infections, bone marrow suppression, lympho- mas); combinations of MTX with cyclosporine or infliximab are more effective that MTX alone
leflunomide
DMARDs often given together with MTX
taken orally; active metabolite is an immunosuppressant, inhibits dyhydroorotate
dehydrogenase (important in lymphocyte proliferation); slows joint destruction
etanercept
DMARDs often given together with MTX
a TNF-α antagonist - a dimeric protein composed of the TNF-α binding domains of
p75 TNF receptor coupled to Fc fragments of immunoglobulin; binds to TNF-α, preventing it
from stimulating TNF-α receptors. Given by s.c. injection twice weeklyinflammation evident in 2 weeks to 3 months. Can be given with MTX.
infliximab
DMARDs often given together with MTX
TNF-α chimeric monoclonal antibody (human Fc region of IgG + Fab sequences of
mouse anti-TNF-α antibody); binds to free TNF-α; reduces joint swelling and damage. Given i.v. Adalimumab is a humanized version of infliximab
abatacept
DMARDs often given together with MTX
selectively modulates a co-stimulatory signal required for full T-cell activation.
Reduces production of TNF-α. Recombinant chimera of CTLA-4 extracellular domain fused to
the Fc portion of human IgG1
rituximab
DMARDs often given together with MTX
chimeric mouse/human anti-CD20 monoclonal antibody that causes depletion of
CD20 positive B lymphocytes. FDA approved for RA. May be useful in TNF-α inhibitor resistant
RA.
anakinra
DMARDs often given together with MTX
naturally occuring IL-1 receptor antagonist- competitively inhibits pro-inflammatory
actions of IL-1. Should not be given together with TNF-α antagonists, as increases risk of adverse
effects.
Asprin
an irreversible non-selective inhibitor of COX enzymes; it acetylates the enzyme. New enzyme synthesis required for recovery of COX activity
Indications for NSAIDs
Treatment of mild-to-moderate pain
Treatment of primary dysmenorrhea
Treatment of inflammatory conditions
The irreversible inhibition of COX induced by aspirin, specifically, has 2 important uses:
• Aspirin in low dose (~80 mg) has been shown to reduce the incideninfarction by 32% in men, and of ischemic stroke in women by 24%
Patent ductus arteriosus:
Bartter's syndrom
Schizophrenia tx
it has been proposed that the antipsychotics may exert their beneficial actions in schizophrenia by
blocking dopamine receptors in mesolimbic areas of the brain, such as the nucleus accumbens
Typical antipsychotics
chlorpromazine
haloperidol.
Nonneurological SEs of typical antipsychotics (chlorpromazin, haloperidol)
Orthostatic Hypotension
Altered sexual fx
Increased Prolactin secretion (hyperprolactinemia, gynecomastia)
Weight gain
Sedation
Seizures
Anticholinergic effects- nasal congestion, dry mouth
Phototoxicity
neurological (extrapyramidal) SEs of typical antipsychotics (chlorpromazin, haloperidol)
Parkinsonism syndrome- akinesia, rigidity- controlled with anticholingergic (benztropine, trihexphenidyl)
Dystonia- spastic movements- tx with antichol benztropine or antihist diphenhydramine
Akathisia- restlessness- tx with antichol benztropine
Tardive dyskinesia- involuntary facial movements- NO TX
Atypical antipsychotics
Risperidone, clozapine, olanzapine, quetiapine, and ziprasidone
In addition to blocking D2-type dopamine receptors,
these compounds also block serotonin 5HT2A receptors.
Aatypical' antipsychotics cause
more severe weight gain than the older antipsychotic
Risperidone
Atypical antipsychotics
causes some elevation of prolactin, and, at higher concentrations, causes
extrapyramidal side effects
Clozapine
Atypical antipsychotics
does not cause prolactin elevation and causes only very mild extrapyramidal side
effects. Tardive dyskinesia has never developed in patients treated with clozapine. However,
clozapine is associated with the development of ***agranulocytosis, a potentially fatal blood
dyscrasia in which the number of white cells plummets. The potential development of
agranulocytosis limits its use. Patients treated with clozapine must have white cell counts done
every week
Olanzapine
structurally similar to clozapine and binds to many of the same receptors, including
the 5HT2A and the D4, although it also binds with a moderately high affinity to the D2 dopamine
receptor. Olanzapine is at least as effective as risperidone in relieving symptoms, has a lower
incidence of extrapyramidal effects, and is less likely to elevate serum prolactin concentrations.
Neither tardive dyskinesia nor hematologic abnormalities (such as agranulocytosis) have been
attributable to olanzapine.
improve cognitive function of schizophrenic patients
clozapine & olanzapine
Quetiapine and ziprasidone
atypical antipsychotic
greater affinity for
5HT2A serotonin receptors than for D2 dopamine receptors. They also antagonize H1 histamine
receptors (causing some sedation) and 1 adrenergic receptors (causing some hypotension). High
doses of quetiapine or ziprasidone cause less hyperprolactinemia and fewer extrapyramidal
symptoms than high doses of risperidone or olanzapin
Dopaminergic pathway
dopamine containing neurons project from the Ventral Tegmental Area (VTA) to the mesolimbic system (Nuc. Accumb, olfactory bulb, PFC, amygdala, and cortical regions)
Aripiprazole
DOPAMINE SYSTEM STABILIZER
a partial agonist at D2 dopamine and
5HT1A serotonin receptors & an antagonist at 5HT2A receptors. It seems to be as good as atypical
antipsychotics and may be safer. It causes little or no sedation, extrapyramidal side effects,
hyperprolactinemia, or hypotension.
Prostaglandin analogues
aloprostadil, misoprostol, iloprost
cGMP phosphodiesterase inhibitor
cGMP phosphodiesterase inhibitor: sildenafil
anti histamine - 1st generation:
diphenhydramine, dimenhydrinate, meclizine, promethazine
anti histamine - 2nd generation
loratadine, fexofenadine
antimigraine drugs
sumatriptan, ergotamine, dihydroergotamine
NITRIC OXIDE
• is a gas.
• diffuses through membranes to act on surrounding cells.
• has a very short half life- usually a few seconds.
• is inactivated by interaction with O2 and converted to nitrite or nitrate.
• interacts with other radicals, thiols, or metals to exert many of its effects.
• activates guanylate cyclase through binding to iron in heme group.
• increases levels of cGMP, may activate cGMP-dependent protein kinase, relaxing smooth
muscle.
• causes vasodilation.
Inhalation of NO is used to produce selective pulmonary vasodilation and to improve
oxygenation in persistent pulmonary hypertension of the newborn and in adult respiratory
distress syndrome.
Neuronal NO
• NO may couple brain activity to cerebral blood flow.
• Glutamate-induced increases in NO, mediated by Ca2+ entry through NMDA receptors, may be
involved in diverse processes ranging from excitotoxic cell death to memory (LTP).
• In the peripheral autonomic nervous system, it is one of the neurotransmitters in nonadrenergic,
noncholinergic neurotransmission (NANC) in the GI, urogenital, and vascular systems.
• In the GI tract as a regulator of sphincter contraction, and intestinal motility. Children with
pyloric stenosis have been shown to have deficient NOS myenteric nerves at the pylorus.
• In the urogenital system NO is thought to be the major neurotransmitter in penile erection.
Lack of NO may account for some forms of erectile dysfunction, and this may be another
potential therapeutic avenue.
• NO may play a role in the etiology of migraine (see below).
Endothelial NO
NO plays a major role in vascular function and it is probable that alterations in NO synthesis will
contribute to vascular disease.

NO acts
• as a vasodilator and mediator of the vasodilatory effects of acetylcholine, substance P,
bradykinin, ATP, histamine and other signaling molecules.
• to prevent platelet adherence and aggregation and neutrophil aggregation.
• to prevent smooth muscle proliferation.
Inducible NO
Inducible NOS expression is part of an adaptive response during inflammation or injury. NO kills
the foreign body, probably through the formation of damaging radicals and peroxynitrite ions.
These large amounts of NO can be detrimental in septic shock.
Prostaglandins
• are eicosanoids from the fatty acid arachidonic acid.
• are not stored but are synthesized in response to diverse stimuli.
• are released in bursts into the extracellular space.
• act through specific G protein linked cell surface receptors (EP1-4).
• generally act locally.
• circulate at low levels in the normal state.
• are targets for pharmaceutical intervention, either by inhibition of their synthesis (see anti-
inflammatory lecture) or by using stable analogues to enhance/mimic their effects.
Reproductive system - Prostaglandins
• cause contraction of uterine smooth muscle.
• are used in conjunction with anti-progestins to prematurely terminate pregnancy.
• are used to induce cervical ripening to aid labor (at full term the myometrium is very sensitive to
prostaglandins).
• are responsible for menstrual cramps - NSAID are useful in alleviating these symptoms
sildenafil
PHARMACOLOGICAL TREATMENT OF ERECTILE DYSFUNCTION
oral sildenafil (Viagra®) specific cGMP phospho-diesterase
inhibitor
Increases cGMP
Adverse Effects: Sildenafil is absolutely contraindicated in all patients taking nitrate drugs, as a
profound systemic vasodilatory effect may result from the two classes of drug acting synergistically. Also there may be slight visual impairment due to partial inhibition of cGMP phosphodiesterase type
Bradykinin
• acts locally.
• has a very short half life (approx 15 secs) -synthesis and degradation are tightly controlled.
• produces pain through actions on sensory neurons.
• produces marked vasodilation (10 times more potent than histamine).
• increases vascular permeability and leads to hypotension.
• induces synthesis of prostaglandins of E series (through activation of phospholipase A2).
• stimulates the production of other autocoids, such as histamine and serotonin.
• acts through B1 or B2 receptor - B2 receptor is constitutively expressed, and activation leads to
release of NO and consequent vasodilation, hypotension, microvascular permeability,
and sensory nerve stimulation. B1 receptor is up-regulated during inflammation and plays a
major role in the chronic inflammatory response.
Histamine
vasodilation (H1: endothelial cells; H2: vascular smooth muscle)
increased capillary permeability
decrease in systemic blood pressure (major effect of histamine in
body)
increased cardiac contractility and increased pacemaker rate (H2)
together with other mediators: effects of anaphylaxis
First generation antihistamines
small molecules which cross blood brain barrier
cross react with other receptors
available "over the counter"
major side effect is sedation
dimenhydrinate
diphenhydramine
meclizine
promethazine
Second generation antihistamines
larger lipophobic molecules which do not readily cross the blood brain barrier
more specific for H1 receptors
available by prescription only (except loratadine and cetirizine)
non-sedating
loratadine
fexofenadine
Sleep induction- antihist
diphenhydramine & doxylamine
Vertigo/motion sickness- antihist
meclizine, promethazine, and dimenhydrinate
sumatriptan
Triptans
• 5-HT1 agonist - thought to activate the inhibitory 5-HT1D receptors on trigeminal sensory
neurons innervating the cerebral vasculature and prevent nociceptive impulses
• specific agonist, little cross reactivity with other non-5-HT receptors, reducing side effects.
• constrictor effect on coronary vessels - contraindicated with angina or ischemic heart
disease.
• contraindicated for those taking MAO inhibitors. (MAO necessary for breakdown of
sumatriptan, hence MAO inhibitors may cause build up of sumatriptan levels.)
• prototype of a class of "triptans" - Others include zolmitriptan, naratriptan, rizitriptan,
frovatriptan & eletriptan
bismuth subsalicylate
Colloidal bismuth compounds
(such as bismuth subsalicylate -
Pepto-Bismol®) bind to the ulcer
site, and bind bile acids. Bismuth
subsalicylate stimulates prostag-
landin and alkali secretion.
cimetidine
H2-RECEPTOR ANTAGONISTS (H2RA)
As structural analogs of histamine, these drugs competi-
tively and selectively inhibit histamine binding to H2 receptors on gastric parietal cells.
They can reduce basal, food stimu- lated, and nocturnal gastric acid secretion by up to 90%
PHARMACOKIN: Rapidly and well absorbed (peak plasma concentration in 1-2 hrs) - mainly
excreted unmetabolized in the urine. Few significant side effects permit them to be adminis-
tered at relatively high doses 1x or 2x daily to compensate for their short (2-3 hour) half-life.
DRUG INTERX: cimetidine (but not other H2 blockers) inhibits multiple cytochrome P450
isoforms and prolongs the half-life of many drugs including phenobarbital, theophylline, diaze- pam, etc.
ranitidine
H2-RECEPTOR ANTAGONISTS (H2RA)
As structural analogs of histamine, these drugs competi-
tively and selectively inhibit histamine binding to H2 receptors on gastric parietal cells.
They can reduce basal, food stimu- lated, and nocturnal gastric acid secretion by up to 90%
PHARMACOKIN: Rapidly and well absorbed (peak plasma concentration in 1-2 hrs) - mainly
excreted unmetabolized in the urine. Few significant side effects permit them to be adminis-
tered at relatively high doses 1x or 2x daily to compensate for their short (2-3 hour) half-life.
DRUG INTERX: cimetidine (but not other H2 blockers) inhibits multiple cytochrome P450
isoforms and prolongs the half-life of many drugs including phenobarbital, theophylline, diaze- pam, etc.
omeprazole
PROTON PUMP INHIBITORS (inhibitors of the H+, K+- ATPase)
These drugs covalently bind to and irreversibly in-
hibit the proton pump of the gastric parietal cells, causing more than 90% inhibition of gas-
tric acid secretion. At neutral pH, they are inactive prodrugs that become activated at low
pH
Prodrug from a capsule that dissolves in the duodenum is absorbed rapidly
an increase in hip fractures
All PPIs inhibit
CYP2C19, but only omeprazole inhibition is sufficient to significantly reduce the activity of
clopidogrel.
rabeprazole
PROTON PUMP INHIBITORS (inhibitors of the H+, K+- ATPase)
These drugs covalently bind to and irreversibly in-
hibit the proton pump of the gastric parietal cells, causing more than 90% inhibition of gas-
tric acid secretion. At neutral pH, they are inactive prodrugs that become activated at low
pH
Prodrug from a capsule that dissolves in the duodenum is absorbed rapidly
an increase in hip fractures
All PPIs inhibit
CYP2C19, but only omeprazole inhibition is sufficient to significantly reduce the activity of
clopidogrel.
misoprostol
PROSTAGLANDIN
prostaglandin E1 analog that inhibits gastric
acid secretion from parietal cells, and stimulates mucin secretion by superficial epithelial cells. It
is used exclusively to prevent NSAID-induced ulcers. Side effects include diarrhea; it is a poten-
tial abortifacient and SHOULD NOT be used in pregnant women or in women when conception
is a possibility
Metoclopramide
PROKINETIC AGENT
A benzamide derivative that
acts as 5-HT3 receptor anta-
gonist, and as a 5-HT4 re-
ceptor agonist stimulating
acetylcholine release from
myenteric neurons, thus in-
creasing cholinergic input.
It also acts as a D2 dopa-
mine receptor antagonist.
These effects result in: i)
raising lower esophageal
sphincter pressure; ii) in-
creasing the rate of gastric
emptying; and iii) decreas-
ing small bowel transit time
droperidol
droperidol (a butyrophenone) D2 antagonist effective for prophylaxis of postopera-
tive nausea and vomiting; side effects include hypotension, drowsiness, dysphoria,
and potentially fatal cardiac arrhythmias
ondansetron
5-HT3 receptor antagonist
act solely on 5-HT3 receptors (central and peripheral); there are none of the extra-
pyramidal side effects associated with the use of D2 antagonists.
- are particularly effective in suppressing emesis in patients receiving radiation therapy
or cisplatin cancer chemotherapy, and in suppressing postoperative nausea and vo-
miting. Ondansetron is also useful to treat vomiting in children with viral illnesses.
- are often used in combination with corticosteroids
- generally elicit only mild side effects such as headache, constipation, diarrhea, or diz-
ziness
granisetron,
5-HT3 receptor antagonist
act solely on 5-HT3 receptors (central and peripheral); there are none of the extra-
pyramidal side effects associated with the use of D2 antagonists.
- are particularly effective in suppressing emesis in patients receiving radiation therapy
or cisplatin cancer chemotherapy, and in suppressing postoperative nausea and vo-
miting. Ondansetron is also useful to treat vomiting in children with viral illnesses.
- are often used in combination with corticosteroids
- generally elicit only mild side effects such as headache, constipation, diarrhea, or diz-
ziness
aprepitant
Neurokinin-1 (Substance P) receptor antagonist that
acts directly on NK1 receptors in the CTZ to inhibit chemotherapy-induced, and postopera-
tive nausea and vomiting; used is combination with other antiemetics
meclizine,
H1 antihistamines
particularly effective in combating the
nausea and vomiting associated with motion sickness; optimal results are obtained if ad-
ministered approximately 1 hr prior to travel. H1 blockers are drugs of choice for treat-
ment of motion sickness in children
dimenhydrinate
H1 antihistamines
particularly effective in combating the
nausea and vomiting associated with motion sickness; optimal results are obtained if ad-
ministered approximately 1 hr prior to travel. H1 blockers are drugs of choice for treat-
ment of motion sickness in children
nabilone
Cannabinoid acting at central CB1 receptors to treat chemotherapy-
induced nausea and vomiting unresponsive to other agents
sulfasalazine,
AGENTS FOR TREATING INFLAMMATORY BOWEL DISEASE
inhibition of production of arachidonic acid metabolites in the colon, and
are useful for treatment ulcerative colitis and Crohn's disease; side effects are relatively minor
mesalamine,
AGENTS FOR TREATING INFLAMMATORY BOWEL DISEASE
inhibition of production of arachidonic acid metabolites in the colon, and
are useful for treatment ulcerative colitis and Crohn's disease; side effects are relatively minor
loperamide
ANTIDIARRHEAL AGENT
inhibiting opioid-sensitive, acetylcholine release in the
enteric nervous system. Their activity is primarily mediated by peripheral μ receptors
• loperamide (Imodium
®) is also a piperidine opioid. However, its penetration of the CNS is
relatively poor, decreasing the likelihood of abuse
bismuth subsalicylate
antidiarrheal properties due to its antimicrobial activity, its
ability to bind enterotoxins, and its inhibitory effect on prostaglandin and water secretion
from the intestinal epithelium. Bismuth subsalicylate binds hydrogen sulfide that can help
reduce the odor of embarrassing flatulence
tegaserod
LAXATIVES AND STOOL SOFTENERS
5-HT4 agonist for treatment of IBS (constipation-predominant) in women and
idiopathic chronic constipation in men and women; major side effects are diarrhea, flatu-
lence, and cholecystitis. Serious risk of myocardial infarction and stroke - can only be ob-
tained for a limited group of patients and even then, only with great difficulty
lubiprostone
LAXATIVES AND STOOL SOFTENERS
a bicyclic fatty acid metabolite of PGE1 that opens the ClC-2 chloride chan-
nel, located in the apical intestinal membrane, increasing intestinal water secretion; used to
treat chronic idiopathic constipation, and IBS (constipation-predominant); side effects in-
clude delayed gastric emptying
alvimopan
peripheral antagonist of μ-opioid receptors (does not cross the blood-
brain barrier; approved ONLY for postoperative ileus, following partial large or
small bowel resection surgery with primary anastomosis
sodium phosphate/sodium biphosphate
Osmotically active agents - act to promote water retention in the distal ileum and colon; gen-
erally act within 0.5 - 3 hr
**oral preparations not to be used for colo-
noscopy preparation in patients with impaired renal function or who are taking diuret-
ics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers; acute
phosphate nephropathy
polyethylene glycol
Osmotically active agents - act to promote water retention in the distal ileum and colon; gen-
erally act within 0.5 - 3 hr
bisacodyl
Stimulant laxatives - promote accumulation of water and electolytes in the lumen and stimu-
late motility
senna
Stimulant laxatives - promote accumulation of water and electolytes in the lumen and stimu-
late motility
Purpose of Anesthetics
The primary purpose of general anesthesia is to prevent the perception of pain and to induce loss of consciousness during surgical procedures in order to reduce stress and distress to the patient; other objectives are to improve postoperative outcomes and to maintain homeostasis. Additionally, the anesthesiologist must ensure that the deleterious effects of anesthetics are minimized
General Anesthesia
A controlled reversible state of analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation
Balanced Anesthesia
Use of several drugs (e.g. short-acting barbiturates, inhalational agents, and/or opioids) to achieve a state of general anesthesia.
Minimum Alveolar Concentration (MAC):
The steady-state minimum alveolar concentration
(%) of an inhalational agent required for immobility of 50% of subjects exposed to a noxious stimulus (e.g. surgical incision). Despite wide variation in chemical structure, MAC provides a means to compare the potency of the various inhalational agents and serves as a guide to determining dose. It is similar to an ED50 value for an intravenous agent
2 types of general anesthetics
A. Inhalational Anesthetics: Drugs administered as gases, usually via a face mask or endotracheal tube. Agents currently in use in developed countries include halothane, isoflurane, enflurane, desflurane, and sevoflurane. Nitrous oxide (N2O) is an incomplete (also relatively impotent) anesthetic that exists as a gas at ambient temperature and pressure. It is often used to augment the potent inhalational anesthetics and/or intravenous agents.

B. Intravenous Anesthetics: Drugs administered into the circulation via an IV. These agents are usually incomplete anesthetics and are given in combination with other agents to achieve the state of general anesthesia. They include:
1. sedative-hypnotics (barbiturates, etomidate, propofol, benzodiazepines)
2. opioids
3. dissociative anesthetics (ketamine)
4 stages of anesthesia
1. Stage of Analgesia: Analgesia without amnesia, impaired judgment, vertigo/ataxia,
increased respiration, blood pressure, heart rate.
2. Stage of Excitement: Delirious, excited, amnestic. Irregular respirations, struggling,
retching and vomiting.
3. Stage of Surgical Anesthesia: Recurrence of regular respiration to cessation of spontaneous
respiration. Loss of corneal, swallowing, and eyelid reflexes. Skeletal muscle
relaxation, decreased blood pressure. Four planes of surgical anesthesia have been described based on pupillary changes, ocular movement, and eye reflexes.
4. Stage of Medullary Depression: Begins with cessation of spontaneous respiration. Includes severe depression of vasomotor center in the medulla as well as the respiratory center. Without circulatory and respiratory support, death rapidly ensues.
Pharmacokinetics of inhaled anesthetics
Inhaled anesthetics exert their effects by achieving an optimal steady state concentration (partial pressure) of a particular agent in the brain. The rate at which a given partial
pressure of inhalational agent in the brain is achieved depends on multiple factors, which influence the movement of the gas from the anesthesia machine to the brain. These factors include: solubility (blood:gas and blood:brain partition coefficients), inspired anesthetic concentration, pulmonary ventilation, arteriovenous concentration gradients, and pulmonary and cerebral blood flow.
True/False: The speed of induction of anesthesia by an inhalational agent can be increased by increasing the inspired concentration of the agent (FI), according
to Fick's law of diffusion
True
True/False: Increasing ventilation brings more of the inhalation anesthetic agent to the alveoli more quickly and generally increases the speed of induction
True
True/False: Patients with low cardiac output have a relatively quick induction of
anesthesia, since the rate of rise of arterial tension of the agent is increased
True
Dose Response of an inhaled anesthetic
The dose of an inhaled anesthetic can be given in multiples of its MAC value. The MAC value
of an anesthetic represents one point on its dose response curve. Certain parameters (extremes of age, concomitant drug administration, temperature, certain disease states, etc.) can have the effect of either increasing or decreasing MAC [necessitating the use of higher or lower concentrations (doses)]; other factors (height, sex, weight) have no effect on MAC value
Halothane (inhalational anesthetic)
halogenated hydrocarbon, most widely used inhaled agent in the world.

Pro: cheap (old), patients tolerate mask inductions.

Con: relatively high solubility, prominent myocardial depression (decreased
contractility) and sensitization of the the myocardium to catecholamine induced arrythmias.
Isoflurane (inhalational anesthetic)
halogenated ether, most widely used inhaled agent in modern countries.

Pro: relatively cheap (off patent), minor myocardial depression and sensitization,
relatively low solubility. Increases CBF less than other inhalational agents.

Con: airway irritation, mainly decreases mean arterial pressure by vasodilitation. Increases heart rate
Desflurane
halogenated ether

Pro: low solubility, fast onset/ elimination/ response to changes in concentration
otherwise much like isoflurane.

Con: expensive, requires special expensive vaporizer, airway irritation, decreases mean arterial pressureby vasodilitation. Increases heart rate.
Sevoflurane
halogenated ether

Pro: low solubility (fast on and off/fast changes in anesthetic depth), well tolerated by patients for mask inductions. No change in heart rate.

Con: expensive, risk of fluoride toxicity if low carrier gas flows are used (difficult to conserve drug/cost), decreases MAP by vasodilatation and decreasing cardiac output.
Nitrous Oxide
non-halogenated gas

Pro: minimal myocardial or vascular effects, low solubility (fast on/off), good adjunct allowing lower concentrations of potent agents and/or less IV drug to be used. NMDA receptor antagonist may enhance analgesia

Con: not potent, i.e., MAC > 100% so requires high concentrations. Rapidly moves into Nitrous containing spaces and causes distention. Increased ICP and increased cerebral blood flow.
IV anesthetic: barbiturates
Cause profound CNS depression via enhancement of GABAA actions. Thiopental,
ultra-short acting, is the most common agent used for induction of General Anesthesia (GA). Rapid crossing of the blood-brain barrier permits hypnosis within 1-2 circulation times. Duration of effect based on T1/2 alpha (redistribution half-life), so effect very short-lived at clinically useful doses.
IV anesthetic: Etomidate
Induction of GA (profound CNS depression) via enhancement of GABAA actions. A carboxylated imidazole anesthesia induction agent with minimal cardiovascular and respiratory effects, rapid onset, and recovery. Usefulness somewhat limited by potential for adrenocortical suppression. Associated with myoclonic movements and post operative nausea and vomiting.
IV anesthetic: Propofol
Sedation or induction of GA profound CNS depression via enhancement of GABAA
actions. A phenol derivative intravenous anesthetic with physiologic effects similar to barbiturates, with a slightly more rapid recovery. Propofol is a profound respiratory depressant and causes significant decrease in mean arterial pressure secondary to a decrease in systemic vascular resistance. Useful for continuous infusion because of its rapid clearance and extrahepatic sites of metabolism. Propofol has gained great popularity because of its amnestic and anti-emetic effects as well as for its
usefulness in total intravenous anesthesia (TIVA). Careful titration of intravenous infusions of this drug make it useful for sedation in regional/local anesthetic cases and prolonged sedation in the critical care setting as well.
True/False: Neither barbiturates, etomidate nor propofol have any analgesic properties.
True
Opioids:
Action at central and peripheral mu, kappa, and delta receptors. Mainstay of our analgesic drugs used in clinical settings. Large doses of
these drugs can provide the basis for a very hemodynamically stable anesthetic (minimal circulatory deterioration) in even the most critically ill patients.
IV anesthetics: Benzodiazepines
GABAA receptor mediated inhibitory neurotransmission. Are used primarily
for their anxiolytic/amnestic effects and, as such, are frequently given pre-operatively or for intraoperative sedation. Midazolam is the most commonly used intravenous benzodiazepine because it is water-soluble and has a relatively short half-life.
Midazolam
most commonly used IV benzodiazepine used for anesthesia
Ketamine:
Inhibitor of the excitatory neurotransmitter, glutamic acid, at the N-Methyl-DAspartate
(NMDA) receptor. A phencyclidine derivative which produces a state of dissociative
anesthesia characterized by catatonia, amnesia, and analgesia. It can be used for sedation as well as general anesthesia. Ketamine produces cardiovascular stimulation. The cardiovascular stimulation is secondary to indirect sympathomimetic activity. It decreases the re-uptake of catecholamines. If no catecholamines are available ketamine is a myocardial depressant. Ketamine also increases cerebral
metabolic rate, and increases cerebral blood flow. Ketamine causes minimal respiratory depression.
What is a phencyclidine derivative that produces a state of dissociative
anesthesia characterized by catatonia, amnesia, and analgesia?
Ketamine

It can be used for sedation as well as general anesthesia
SYNAPTIC TRANSMISSION
- Classical neurotransmitters are synthesized in nerve terminals and stored in vesicles
• Action potentials propagate down the axon &
depolarize the nerve terminal
• Terminal depolarization causes Ca2+ influx
• Ca2+ influx leads to vesicle fusion and
neurotransmitter release into the synaptic cleft
• Released neurotransmitter binds to its
receptors, which mediate the response
• Neurotransmitter is cleared from the synaptic
cleft by diffusion, re-uptake, metabolism and /
or degradation
• Synaptic vesicle lipids & proteins are endocytosed and recycled
Glutamate
Most excitatory synapses in the CNS are glutamatergic.
• Glutamate is synthesized from glutamine in nerve terminal mitochondria.
• Glutamate transporters clear glutamate from the synapse.
• Ionotropic receptors - mediate EPSPs
- AMPA receptors: most permeable to Na+ & K+
- Kainate receptors: permeable to Na+ & K+
- NMDA receptors: permeable to Na+, K+ & Ca2+; requires binding of glutamate & glycine as well as
membrane depolarization to relieve voltage dependant Mg2+ block
GABA
Most inhibitory synapses in the CNS are GABAergic.
• GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD).
• GABA transporters clear GABA from the synapse.
• GABA is catabolized to glutamine by GABAtransaminase (GABA-T) in mitochondria.
ACETYLCHOLINE
Acetylcholine acts as a primary neurotransmitter in the autonomic nervous system and
neuromuscular junction (covered extensively in Block 1), but also acts as a neurotransmitter in
the CNS.
• Cholinergic systems have been implicated in Alzheimer's, Huntington's and Parkinson's
diseases as well as the normal sleep-wake cycle, pain perception and hallucinations.
• Ionotropic receptors (nicotinic receptors; nAChRN), - mediate EPSPs - permeable to cations
• Metabotropic receptors (muscarinic receptors; M)
- M1, M3 increase IP3 / Ca2+; M2, M4 decrease cAMP
Serotonin
Serotonin (5-HT) is synthesized from tryptophan.
• 5-HT is catabolized by monoamine oxidase
(MAO).
• 5-HT transporters (SERT) clear 5-HT from the
synapse.

Serotonin has been implicated in depression,
anxiety, stress, schizophrenia, hallucinations,
obsessive compulsive disorder, substance abuse
and migraine as well as sleep, temperature and
neuroendocrine control.
Sedative or anxiolytic agents
reduce anxiety and exert a relaxing / calming effect
Hypnotic agents
produce drowsiness and facilitate the onset and maintenance of sleep. Usually decrease time to sleep onset, decrease number of awakenings and increase total sleep time
Medication / substance-related anxiety
can occur during use of certain drugs, including caffeine, hallucinogens, stimulants, anti-depressants, steroids, sympathomimetics and during alcohol/sedative withdrawal. Alterations in dosing regimens or medication choices may relieve anxiety
Disease-related anxiety
such as anxiety associated with gastric ulcer, myocardial infarction etc. Treat the medical condition. Short-term use of sedative-hypnotic may be appropriate
Situational anxiety
such as anxiety associated with death of a family member, surgery, etc. Situational anxiety is generally limited by the duration of the event. But, short-term use of sedative hypnotic may be appropriate.
Chronic anxiety
should be investigated thoroughly and carefully diagnosed. Some chronic anxiety syndromes, such as generalized anxiety disorder, panic disorder, etc, respond well to a combination
of psychotherapy and sedative-hypnotic treatment. However, chronic anxiety may be a symptom of another psychiatric illness or depressive disorder, which may require an alternative treatment plan.
Sleep apnea
characterized by episodes of decreased or complete cessation of breathing during
sleep and can be caused by central or obstructive mechanisms. Hypnotics should not be prescribed
for sleep apnea because they can decrease the arousal response to hypoxia and may exacerbate
obstructive sleep apnea by reducing airway muscle tone
What should NOT be prescribed for sleep apnea?
Hypnotics should not be prescribed for sleep apnea because they can decrease the arousal response to hypoxia and may exacerbate
obstructive sleep apnea by reducing airway muscle tone
Circadian rhythm disturbances
can occur with air travel over time zones, shift work etc. and alter the natural tendency to sleep 7-8 hours. Hypnotics can help reset the body's internal clock
Disease-related insomnia
can occur in patients with psychiatric or medical illnesses, such as depression, anxiety, psychosis, chronic heart failure, pain, etc. Treatment of the medical condition will often relieve the insomnia.
Medication / substance-related insomnia
can occur during use of many commonly used drugs, ncluding, alcohol, SSRIs, anti-Parkinson's drugs, methylxanthines, diuretics, etc. Alterations in dosing regimens or medication choices may relieve sleep disruption.
Transient insomnia
can occur for a variety of reasons including stress, lifestyle changes, etc. Hypnotic use is generally limited to 1-3 days, but not more than 2-3 wks. Patients treated > 2 wks with hypnotics that have significant withdrawal effects (barbiturates, benzodiazepines) should be
gradually tapered off the hypnotic. Abrupt termination may precipitate severe withdrawal reactions
BARBITURATES: MoA
Increase GABAA receptor-mediated inhibition by binding to the barbiturate site on the GABAA receptor, allosterically enhancing the binding of GABA and increasing the duration of GABA-induced Cl- channel openings
• At higher doses, also directly activate GABAA receptors, inhibit AMPA receptor function
and inhibit nAChR at autonomic ganglia and muscle
• General CNS depressants, which produce a dose-dependent continuum of:
sedation» sleep» anesthesia» coma» death

Death results from depression of respiration and cardiovascular function
Why might death occur from barbiturates
Death results from depression of respiration and cardiovascular function
Problems with barbiturates:
1. Low therapeutic index, overdose can be fatal
2. Do not induce physiological sleep
3. Significant drug interactions
4. Abuse and addiction (in recent years - has limited the use of barbiturates as hypnotics)
5. After effects - residual CNS depression
6. Tolerance
7. Withdrawal - 1-2 nights rebound insomnia through life-threatening
How would you avoid barbiturate w/drawal sx?
To avoid withdrawal symptoms maintain on phenobarbital and taper off slowly
What are uses of barbiturates?
1. Long acting: Daytime sedative, antiseizure agent, phenobarbital (Luminal etc); t1/2 = 80-120 hr (also used for hypnosedative withdrawal)
2. Intermediate acting: Hypnotic, preoperative sedative, emergency management of seizures
pentobarbital (Nembutal); t1/2 = 15-50 hr
3. Short acting: Induction or maintenance of anesthesia
thiopental (Pentothal); t1/2 = 8-10 hr
Are barbiturates currently used?
Barbiturates are not currently recommended as anxiolytics, but are still used as hypnotics and antiseizure agents in limited settings (due to potential lethality; consider that it is part of the chemical cocktail used in lethal injections)
Barbiturate Poisoning (SX):
Moderate: (or early) intoxication resembles alcohol intoxication

Severe: coma, hypothermia (depression of thermoregulatory center), hypotension (depression of vasomotor centers in medulla),
bradyapnea (depression of neurogenic respiratory drive); hypoxia & respiratory acidosis,
possible early tachycardia (hypoxia) then bradycardia (sympathetic ganglia depression)
hypoxia can cause shock, which results in further hypotension; rapid, weak & thready pulse; cold, sweaty cyanotic skin; and renal failure
Most deaths related to barbiturates occur because of...?
Most deaths occur due to cardiovascular collapse, respiratory complications and renal failure due to shock
Tx for barbiturate poisoning
Remove drug - vomiting, gastric lavage, activated charcoal, if < 24hr after ingestion
- hydration, urine alkalinization, diuretics

Treat for shock including - artificial respiration
- cardiovascular support
- metabolic corrections
What should never be given for barbiturate poisoning?
CNS stimulants
What largely replaced barbiturates and
older agents as sedative-hypnotics and why?
BENZODIAZEPINEs because they have a higher therapeutic index, lower toxicity when overdosed,
fewer alterations on physiological sleep patterns and decreased potential for tolerance and abuse
BENZODIAZEPINE: MoA
• Increase GABAA receptor-mediated inhibition by binding to the benzodiazepine site on the
GABAA receptor, allosterically enhancing the binding of GABA and increasing the frequency of GABA-induced Cl- channel openings.
• No effect on GABAA receptor function in absence of GABA
• Are NOT general CNS depressants, produce a dose-dependent continuum of sedation »sleep
Clinical use: alprazolam (xanax)
anx
Clinical use: chlordiazepoxide
Anxiety, alcohol withdrawal, preanesthetic medication
Clinical use: clonazepam (Klonopin)
Seizures, mania, movement disorders
Clinical use: diazepam (valium)
Anxiety, status epilepticus,muscle relaxation,
preanesthetic medication
Clinical use: flurazepam (Dalmane)
Insomnia
Clinical use: lorazepam (Ativan)
Anxiety, status epilepticus, preanesthetic medication
Clinical use: midazolam (Versed)
Preanesthetic and intraoperative medication
Clinical use: temazapam (Restoril)
Insomnia
Adverse effects of Benzodiazepine
Alters normal sleep patterns

Impaired mental and motor function, ataxia, residual daytime sedation, anterograde amnesia, additive with other CNS depressants (i.e. ethanol)

Abrupt withdrawal after chronic use can cause anxiety, nausea, seizures

Tolerance, Abuse [i.e. flunitrazepam (Rohypnol) as a date rape drug]
Benzodiazepine: Metabolism
For most benzodiazepines, distribution first to high perfusion regions (brain), followed by distribution to lower perfusion regions (muscle and fat)

KEY POINT: Many benzodiazepines are metabolized in the liver to active metabolites; activity of metabolites may outlast that of the parent compound (ex: diazepam!)

Drug interactions with CYP450 3A4 inhibitors
Non-benzodiazepines: (also known as the z-drugs)
zolpidem
zaleplon
eszopiclone
Clinical uses: eszopiclone
(Lunesta): Increases sleep duration (~8hr duration)
Approved for long-term use (up to 6 mos)

Pre-marketing studies show low potential for tolerance, dependence or abuse
Clinical uses: zolpidem (Ambien)
Increases sleep duration (~8hr duration)

Approved for short-term use (up to 10 days)

Withdrawal may cause anxiety, tremor, agitation, rebound insomnia and seizures

Some cases of habituation and abuse have been reported
Clinical uses: zaleplon (Sonata):
Decreases latency to sleep (~4hr duration of action)

Approved for short-term use (up to 10 days)

Long term use may increase risk of addiction
Adverse effects of z-drugs:
Headaches, additive with other CNS depressants

Morning sedation with late night use of zolpidem, eszopiclone

May be habit-forming following chronic use

Reports on sleep-walking or -eating with zolpidem
Antagonist for benzodiazepine
Flumazenil (Romazicon) is a competitive antagonist at the benzodiazepine site. Rapid onset, but SHORT half-life.

Adverse effects: Agitation, confusion, dizziness, nausea

Use: Decrease recovery time from benzo-diazepine receptor modulators
Melatonin
serotonin derivative synthesized and secreted by the pineal gland. Synthesis is controlled by light. Melatonin lightens skin pigment, suppresses ovarian function and is thought to play a role in biological rhythms. Synthetic melatonin has
been sold for years as a dietary supplement to promote sleep or reduce jet lag, but data from clinical trials are inconclusive
Ramelteon (Rozeram)
a MT1 / MT2 (melatonin) receptor agonist. MT1 and MT2 receptors are localized in the suprachiasmatic nucleus (SCN). Activation of MT1 is thought to regulate sleepiness; MT2 to regulate circadian rhythm

Use: Hypnotic (promotes falling asleep, no effect on sleep maintenance)

Metabolism: Liver CYP450
Advantages of Ramelteon
Does not promote sleep through general CNS depression (MT1/MT2 receptors in SCN; GABA receptors throughout the brain)

No apparent motor or cognitive impairment

Little change in sleep patterns

Not a controlled substance, no apparent abuse potential

Approved for long-term use
Adverse effects of Ramelteon
Increased serum prolactin (32% of pt in one 6 month study), which if chronic could lead to hypogonadism, infertility, decreased libido, osteoporosis

Decreased testosterone levels
SEROTONERGIC AGENTS
Uses: 1. Anxiety
2. Depression
3. Numerous psychiatric disorders

Advantages: Safer, less psychomotor impairment and less abuse potential than benzo-diazepines

Disadvantages: SSRIs: slow onset, substantial population of non-responders to anxiolytic
effects, sexual dysfunction, sleep disturbances
OTC sleep aids:
ANTIHISTAMINES Doxylamine (Unisom, others) and diphenhydramine (Nytol, Benadryl, others) are approved as sleep-aids

ALCOHOL is widely used as a hypnotic. However, it causes initial CNS depression followed by rebound excitation, which disrupts sleep.

Melatonin

Valerian is a dietary supplement derived from the roots, rhizomes and stems of the Valerian (Valeriana officinalis) plant
MODAFINIL (Provigil®)
modafinil is a **stimulant**, not a sedative / hypnotic / depressant

Mechanism of action: inhibition of NE and DA uptake

Uses: Modafinil is approved for the treatment of narcolepsy and excessive sleepiness due to
obstructive sleep apnea/hypopnea syndrome or shift-work sleep disorder.

Modafinil is also used by the military to maintain soldier alertness during long missions, and has partly replaced amphetamine for this purpose.
Adverse effects of modafinil
Adverse effects: Modafinil has a low potential for abuse; it does not activate the mesolimbic reward
system, and users experience neither a high, nor a "crash" afterwards. The most common side effect is headache
SPASMOLYTICS
subclass of muscle relaxants are used in symptomatic treatment of skeletal muscle
spasms resulting from multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord
transection, cerebral palsy, stroke or local muscle trauma. Except for the benzodiazepines,
spasmolytics are not approved for muscu-loskeletal problems
tizanidine:
Mechanism of action: Central α2 adrenergic receptor agonist. Increases pre and postsynaptic inhibition of motor neurons

Adverse effects: Drowsiness, hypotension, dry mouth, and weakness
dantrolene:
Mechanism of action: Decreases Ca2+ release from sarcoplasmic reticulum, thereby inhibiting excitation-contraction coupling. Direct action on skeletal muscle

Adverse effects: General muscle weakness (therefore contraindicated in ALS), Sedation, Rare but serious hepatotoxicity
baclofen:
Mechanism of action: GABAB receptor agonist
Reduces transmitter release by increasing K+
permeability and inhibiting Ca2+ influx into
nerve terminals

Adverse effects: Drowsiness and increased risk of seizures; Intrathecal administration can cause CNS depression; Less sedation than benzodiazepines.
diazepam
benzodiazepines used for spasticity and musculoskeletal problems
List spasmolytics
baclofen, tizanidine, dantrolene, diazepam, clonazepam
List drugs used for treating narcolepsy
γ-hydroxybutyrate (GHB) / sodium oxybate, modafinil
List MELATONIN RECEPTOR AGONISTS
melatonin, ramelteon
List examples of barbiturates
phenobarbital, pentobarbital, thiopental
Seizure:
Transient episode of brain dysfunction resulting from rhythmic, synchronous neuronal firing
DIAGNOSIS and TREATMENT (of most common seizure types)
Etiologic Diagnosis: Identification of seizure cause - if possible, treat the cause

Seizure Diagnosis: Identification of seizure type(s) - treat the seizure type(s)
PARTIAL SEIZURES
Localized onset
3 types: simple, complex, and partial seizure secondarily generalized.

Drug of choice used for tx: carbamazepine, phenytoin, oxcarbazepine, lamotrigine, valproate, topiramate
Characteristics of simple vs complex partial seizure
Simple: Preservation of consciousness,
sensory "auras" or limited unilateral motor convulsions. Duration: ~20-60s

Complex: Impaired consciousness; automatisms common; post-ictal confusion and/or lethargy. Most common refractory seizure type in adults. Duration: ~30s-2min
GENERALIZED SEIZURES
No localized onset
2 types: tonic-clonic (grand mal) and absence (petit mal)
Drugs of choice for treating grand mal seizures
valproate
phenytoin
carbamazepine
Drugs of choice for treating petite mal seizures
ethosuximide
valproate
Characteristics of grand mal seizure
Loss of consciousness; major convulsions; tonic spasm of body musculature followed by
synchronous clonic jerking; prolonged post-ictal stupor. Other seizure types can progress
secondarily to grand mal seizures. Duration: ~1-2min
BASIC MECHANISMS OF ACTION OF ANTISEIZURE DRUGS
Decrease spread of seizure discharge AND Increase seizure threshold by acting to decrease excitation, enhance inhibition, and modify neuronal excitability by altering activity of ion channels that mediate neuronal firing/rhythmicity
PHENYTOIN
Tx: Partial & Generalized Tonic-Clonic Seizures

Mechanism of action: Inhibits Na+ channels

Adverse effects: Gingival hyperplasia; hirsutism; coarsened facial features; endocrine abnormalities; teratogenicity; rarely - systemic lupus & hepatic necrosis

Lab tests: Monitor therapeutic drug levels; can interfere with thyroid function tests
CARBAMAZEPINE
Tx: Partial & Generalized Tonic-Clonic Seizures

Mechanism of action: Inhibits Na+ channels, decreases synaptic transmission
Metabolism: Significant induction of its own hepatic metabolism
Adverse effects: Liver damage; mild, persistent leukopenia common - rarely aplastic anemia &
agranulocytosis; hyponatremia; teratogenicity; osteoporosis
Lab tests: Liver function test required by the FDA; monitor therapeutic drug levels,
hematology, renal function & serum Na+
OXCARBAZEPINE
Tx: Partial & Generalized Tonic-Clonic Seizures

Mechanism of action: Inhibits Na+ & high voltage activated Ca2+ channels; enhances K+ currents

Adverse effects: Hyponatremia, Stevens Johnson syndrome, toxic epidermal necrolysis,
multi-organ hypersensitivity reactions; less adverse effects than carbamazepine
GABAPENTIN (Neurontin)
Tx: partial and grand mal seizures

Mechanism of action: Decreases Ca2+ influx in nerve terminals via binding to auxillary α2δ subunit of voltage-gated Ca2+ channel; increases presynaptic release of GABA
Drug Used Only for Absence Seizures
ETHOSUXIMIDE
ETHOSUXIMIDE
Mechanism of action: Inhibits T-type Ca2+ channels

Adverse effects: Blood dyscrasias; skin reactions; Parkinson-like symptoms; photophobia
Drugs Used for a Variety of Seizure Types
VALPROIC ACID / SODIUM VALPROATE (Depakote)

LAMOTRIGINE

TOPIRAMATE
VALPROIC ACID / SODIUM VALPROATE
Mechanism of action: Inhibits Na+ channels, T-type Ca2+ channels & GABA transaminase (GABA-T); stimulates GABA synthetic enzyme, glutamic acid decarboxylase (GAD)

Pharmacokinetics: Highly bound to plasma proteins

Adverse effects: Idiosyncratic hepatotoxicity (most fatalities in 1st 6 months of therapy; risk
greatest in patients <2yo on multiple meds.); pancreatitis; teratogenicity; idiosyncratic thrombocytopenia; hyperammonemia; osteoporosis

Lab tests: Liver function test required by the FDA
LAMOTRIGINE
Mechanism of action: Inhibits Na+ channels, inhibits glutamate release

Clinical use: Lennox-Gastaut syndrome is the only indication for patients <16 yrs of age

Adverse effects: Stevens-Johnson syndrome (0.3% adults, 1% children); arthritis; hypersensitivity reactions; multiorgan failure; intravascular coagulation
TOPIRAMATE
Mechanism of action: Inhibits Na+ channels, enhances GABA transmission, activates a
hyperpolarizing K+ channel, acts as AMPA/ KA receptor antagonist, carbonic anhydrase inhibitor

Adverse effects: Metabolic acidosis; severe myopia & secondary glaucoma; hypohidrosis &
hyperthermia; renal calculi; weight loss; language dysfunction
STATUS EPILEPTICUS (seizure type)
• Continuous, prolonged seizure (>5-10 min)
or multiple seizures in rapid succession
• Most common is generalized tonic-clonic
status epilepticus, which is a lifethreatening
emergency
• Also requires cardiovascular, respiratory
and metabolic management
INFANTILE SPASMS
• Epileptic syndrome characterized most
often by myoclonic spasms
• 1st attack before 1 yo in 90% of patients
• Refractory to usual antiseizure drugs
FEBRILE SEIZURES
• NOT a form of epilepsy
• Seizures brought on by fever in infants and
small children
Drugs of choice for status epilepticus
iv lorazepam
iv or rectal diazepam
iv fosphenytoin
Drugs of choice for infantile seizures
corticotropin (ACTH)
prednisone
Issues Associated With Antiseizure Therapy
• Some antiseizure drugs require gradual titration to therapeutic levels
• Many antiseizure drugs have a low therapeutic index
• Adverse effects common during initiation of therapy
• Multi-drug therapy requires knowledge of mechanism of action, drug interactions and major
adverse effects to maximize odds of seizure control and minimize adverse effects
• Loss of seizure control may be due to development of tolerance to the antiseizure drug (i.e. phenobarbital), drug interactions or progression of the underlying seizure disorder
• Seizure exacerbation during antiseizure drug therapy can occur from direct effects of the
antiseizure drug [i.e. use of wrong drug, homeostatic plasticity, antiseizure drug overdose
(phenytoin, carbamazepine, lamotrigine)] or indirect effects.
1. A 55-year-old man takes aspirin by mouth for a headache. In which region of the
gastrointestinal tract is the local pH MOST LIKELY to facilitate the absorption of aspirin, a
weak acid.
A. buccal cavity
B. esophagus
C. stomach
D. ileum
E. colon
C. stomach
2. Which of the following statements CORRECTLY describes factors influencing passage of
drugs across the blood-brain-barrier into or out of the central nervous system (CNS)?
A. Transport into or out of the CNS is always faster for large proteins than for small
bioactive peptides.
B. For the majority of drugs, metabolism by hepatic CYP450 enzymes generates active
metabolites that more readily cross into the CNS than the parent molecule.
C. All drug transporters controlling the passage of drugs across the blood brain barrier are
members of the SLC (solute-linked carrier) family of transporters.
D. There are many pores in the endothelial cell lining of blood vessels throughout the
CNS that permit entry of psychoactive drugs directly without transfer across a lipid
membrane.
E. Members of the ABC (ATP binding cassette) family of transporters participate in
the removal of selected drugs from the CNS.
E. Members of the ABC (ATP binding cassette) family of transporters participate in
the removal of selected drugs from the CNS.
3. In the elderly, the rate of elimination of a drug may be calculated by an empirical formula that
employs which of the following factors?
A. heptane-water partition coefficient and drug molecular weight
B. age and serum creatinine concentration
C. ideal body weight and urinary creatinine concentration
D. age and urinary creatinine concentration
E. heptane-water partition coefficient and serum creatinine concentration
B. age and serum creatinine concentration
4. Which of the following statements CORRECTLY describes the properties of CYP3A4 (the
enzyme, cytochrome P450 type 3A4)?
A. It is a zinc-containing flavoprotein.
B. The rate-limiting step in the reaction cycle for this enzyme is the binding of the parent
drug to the reduced form of the enzyme.
C. Metabolism of drugs by this enzyme requires the availability of NADPH and
molecular oxygen.
D. Metabolism of drugs by this enzyme requires the availability of coenzyme A and
UDP-glucuronide.
E. Fewer drug entities are subject to metabolism by CYP3A4 than by CYP2E1.
C. Metabolism of drugs by this enzyme requires the availability of NADPH and
molecular oxygen.
5. You are treating a 38-year-old male patient with HIV with the protease inhibitor saquinavir.
With a standard dose of this drug his viral load is only slightly reduced. You decide to add
another drug to his treatment regimen. Which of the following therapeutic strategies is
MOST LIKELY to be of immediate benefit to the patient?
A. rifampin, since this drug will be effective as a prophylactic against a possible future
tubercular infection
B. risperidone, since this drug will be an effective inhibitor of AIDS dementia if the
infection progresses
C. retinoic acid, since this drug will decrease expression of drug transporters in the
kidney, raising the blood concentration of saquinavir.
D. ritonavir, since this drug will competitively inhibit the metabolism of saquinavir,
raising its blood concentration to a more effective level
E. chloramphenicol, since this will add an effective treatment for opportunistic bacterial
infections
D. ritonavir, since this drug will competitively inhibit the metabolism of saquinavir,
raising its blood concentration to a more effective level
6. A 48-year-old woman is started on a course of irinotecan for the treatment of metastatic
colorectal cancer. After three weeks she develops severe neutropenia. This effect is MOST
PROBABLY attributable to her relatively slow metabolism of this drug because she carries a
mutation in a gene coding for
A. pseudocholinesterase.
B. catechol-O-methyltransferase.
C. glucuronyl transferase.
D. N-acetyltransferase.
E. thiopurine methyltransferase.
C. glucuronyl transferase.
7. A 25-year-old male is admitted to the emergency room with severe vomiting. He reports
consuming an unknown number of extended-release Tylenol tablets about 4 hours earlier.
In taking a history, you elicit that he is a habitual consumer of alcoholic beverages. Which
of the following is the MOST APPROPRIATE pharmacologic treatment for this patient?
A. pharmacologic induction of CYP2E1 activity to accelerate acetaminophen
metabolism
B. administration of an exogenous source of glutathione or related sulfhydryl-
containing agent to facilitate the inactivation of a toxic acetaminophen
metabolite
C. administration of an exogenous source of UDP-glucuronide to facilitate the
inactivation of a toxic acetaminophen metabolite
D. administration of bicarbonate anion to accelerate the elimination of salicylate
E. increased levels of NADPH in the liver by dietary modification to increase
cytochrome reductase activity
B. administration of an exogenous source of glutathione or related sulfhydryl-
containing agent to facilitate the inactivation of a toxic acetaminophen
metabolite
9. A patient recovering from abdominal surgery has prolonged gastric atony, abdominal
distention and urinary retention. Which of the following would be the MOST
APPROPRIATE therapy?
A. bethanechol
B. oxybutynin
C. acetylcholine
D. nicotine
E. prazosin
A. bethanechol
10. Which of the following is a critical feature of the processes by which a drug-metabolizing
enzyme is induced following exposure to a xenobiotic agent?
A. increased stability of the mRNA coding for the enzyme, increasing enzyme
translation
B. increased phosphorylation of the enzyme, increasing its catalytic activity
C. increased expression of drug transporters, permitting greater access of the drug
substrate to the enzyme
D. binding of a nuclear receptor complex to the enzyme, increasing its stability
E. binding of a nuclear receptor complex to the gene coding for the enzyme,
increasing its rate of transcription
E. binding of a nuclear receptor complex to the gene coding for the enzyme,
increasing its rate of transcription
11. Which of the following is MOST LIKELY to reverse an episode of psychosis caused by
exposure to BZ, an incapacitating drug developed as a chemical warfare agent?
A. galantamine
B. edrophonium
C. atropine
D. diazepam
E. 2-PAM
A. galantamine
12. To facilitate an intubation, you inject a 35-year-old man (with no previous history of medical
problems) with a standard dose of succinylcholine. He develops abnormally prolonged
apnea. This is MOST LIKELY due to a deficiency in
A. CYP3A4.
B. plasma cholinesterase.
C. acetylcholinesterase.
D. neuropathy target esterase.
E. muscarinc acetylcholine receptors.
B. plasma cholinesterase.
13. A migrant worker slips and falls into a vat of pesticide. He is brought to the emergency room
with pinpoint pupils, muscle weakness, and bronchial congestion. You identify the pesticide
as parathion and give him atropine, then 2-PAM. One hour later, he has a seizure. What
would be the MOST APPROPRIATE drug to administer now?
A. rivastigmine
B. physostigmine
C. pyridostigmine
D. diazepam
E. pilocarpine
D. diazepam
14. The intermediate formed by pyridostigmine and acetylcholinesterase
A. contains a phosphorylated serine at the active site.
B. lasts for minutes and is susceptible to ageing.
C. lasts for seconds and undergoes spontaneous hydrolysis.
D. lasts for hours and is susceptible to ageing.
E. lasts for hours and undergoes spontaneous hydrolysis.
E. lasts for hours and undergoes spontaneous hydrolysis.
15. A 32-year-old male was administered a neuromuscular blocker during a minor surgical
procedure. At the end of the procedure, transdermal nerve stimulation using the "train-of-
four" stimulus paradigm elicited four muscle twitches that were similarly reduced in
amplitude (i.e. no fade) compared to stimulation conducted just prior to administration of the
neuromuscular blocking agent. Immediate administration of neostigmine to this patient will
A. enhance the Phase I neuromuscular blockade caused by succinylcholine.
B. reverse the Phase I neuromuscular blockade caused by succinylcholine.
C. enhance the Phase II neuromuscular blockade caused by succinylcholine.
D. reverse the Phase I neuromuscular blockade caused by d-tubocurarine.
E. enhance the Phase II neuromuscular blockade caused by d-tubocurarine.
A. enhance the Phase I neuromuscular blockade caused by succinylcholine.
16. Local administration of botulinum toxin A to treat blepharospasm must be repeated every 3-6
months because
A. the biologic half-life (t1/2) of botulinum toxin A is 3-6 months.
B. the muscle cells are regenerated.
C. the muscle is reinnervated by the motor neuron.
D. acetylcholinesterases must be resynthesized.
E. the botulinum toxin A - nAChR complex is subject to ageing
C. the muscle is reinnervated by the motor neuron.
19. You are monitoring a 70 kg patient who is receiving a daily oral dose of 70 mg of
cyclosporine to suppress renal transplant rejection. The laboratory reports that the steady
state serum concentration of cyclosporine in your patient is 800 ng/ml. The t1/2 of
cyclosporine is approximately 14 hr, and the volume of distribution is 4 L/kg. The clearance
(CL) of the drug is:
A. 0.2 L hr-1
B. 1.4 L hr-1
C. 2.0 L hr-1
D. 14 L hr-1
E. 60 L hr-1
D. 14 L hr-1
23. Your patient is admitted to the Emergency Room with a blood pressure reading of 225/150
mm Hg. You decide to administer a D1 dopamine agonist by intravenous infusion to lower
his blood pressure and increase blood flow to his kidneys. The drug you should infuse is
A. carvedilol.
B. fenoldopam.
C. albuterol.
D. phenylephrine.
E. prazosin.
B. fenoldopam.
24. A 25-year-old female is experiencing paroxysmal supraventricular tachycardia. Other than
having a rapid heart rate, she is in excellent health. You decide to administer a compound
that will raise her blood pressure and elicit a reflex vagal discharge. The compound that you
SHOULD administer is
A. amphetamine.
B. guanethidine.
C. dobutamine.
D. pheoxybenzamine.
E. phenylephrine.
E. phenylephrine.
25. A 40-year-old male subject is overweight, hypertensive and has a persistent cough. He has
been smoking a pack of cigarettes a day for about 10 years. Which drug treatment is MOST
LIKELY to be effective in reducing his smoking habit?
A. hexamethonium
B. pyridostigmine
C. carbachol
D. alcohol (half a pint of bourbon a day)
E. varenicline
E. varenicline
27. A 28-year-old woman has asthma that has been difficult to manage. Her physician has
decided to prescribe a fast-acting medication to use for exacerbations. Which of the
following would BEST provide fast relief from an acute asthma exacerbation?
A. a mast cell stabilizer
B. an inhaled corticosteroid
C. an oral corticosteroid
D. a leukotriene receptor antagonist
E. an inhaled Beta 2 adrenergic receptor agonist
E. an inhaled Beta 2 adrenergic receptor agonist
28. Which of the following asthma medications is a muscarinic receptor antagonist?
A. albuterol
B. montelukast
C. omalizumab
D. tiotropium
E. cromolyn
D. tiotropium
29. You have been prescribing amphetamines to a 30-year-old female who has narcolepsy. You
decide to change her therapy to modafinil. Which of the following is MOST LIKELY to be
caused by the change in medication?
A. increased risk of addiction
B. more cardiovascular side effects
C. decreased efficacy of an oral contraceptive
D. increased depression when the drug wears off
E. greater disturbances in nocturnal sleep
C. decreased efficacy of an oral contraceptive
30. BOTH cocaine and amphetamine
A. have a similar duration of action.
B. stimulate the mesolimbic dopamine pathway.
C. are inactivated by pseudocholinesterase.
D. block monoamine reuptake.
E. inhibit monoamine oxidase.
B. stimulate the mesolimbic dopamine pathway.
31. Vasoconstrictors are often included in preparations of local anesthetics to
A. increase local anesthetic solubility.
B. decrease local anesthetic duration of action.
C. increase local anesthetic absorption.
D. decrease local anesthetic efficacy.
E. decrease local anesthetic absorption.
E. decrease local anesthetic absorption.
32. A 33-year-old Navy veteran with paraplegia was unable to sleep after his release from
rehabilitation. His sedative-hypnotic medication was changed and he was sent home with a
single medication to better control his insomnia. He now reports muscle spasms in his legs and pronounced anxiety, but no problems sleeping. What is the MOST LIKELY identity of
his CURRENT hypnotic agent?
A. zolpidem
B. diazepam
C. baclofen
D. alprazolam
E. thiopental
A. zolpidem
33. A 5-year-old boy describes "times when everything goes black". When he "comes back" he
"feels good". His parents estimate that the duration of the two episodes they witnessed were about 30 seconds. They also noted that both of his eyelids twitched during each episode.
Which of the following CORRECTLY pairs the type of seizures he is experiencing with a
DRUG OF CHOICE for treatment?
A. simple partial - carbamazepine
B. complex partial - lamotrigine
C. absence - valproate
D. complex partial - ethosuximide
E. absence - phenytoin
C. absence - valproate
34. Which of the following statements regarding the differential block of nerve conduction by
local anesthetics is generally TRUE?
A. Nerves with longer critical lengths are blocked before those with shorter critical
lengths.
B. Myelinated axons are blocked before unmyelinated axons.
C. Sensations of temperature are lost before those of deep pressure.
D. Motor neurons fire more rapidly than sensory neurons.
E. Nerves in the inner part of a bundle are infiltrated before those in the outer regions.
C. Sensations of temperature are lost before those of deep pressure.
35. Which of the following CORRECTLY pairs an antiseizure drug with one of its MAJOR
mechanisms of action?
A. valproate - inhibition of GABA transaminase
B. valproate - inhibition of glutamic acid decarboxylase
C. gabapentin - positive modulation of the NMDA receptor
D. oxcarbazepine - inhibition of the GABAA receptor
E. phenytoin - positive modulation of glutamatergic transmission
A. valproate - inhibition of GABA transaminase
36. Which of the following drugs is MOST LIKELY to INDUCE hepatic CYP450s?
A. gabapentin
B. phenobarbital
C. valproate
D. ethosuximide
E. procaine
B. phenobarbital
37. A 45-year-old female was administered midazolam as part of the total intravenous anesthesia
required for a minor surgical procedure. The BEST drug to reverse the effects of midazolam
at the end of the procedure is
A. neostigmine.
B. atropine.
C. flunitrazepam.
D. naloxone.
E. flumazenil.
E. flumazenil.
38. Your 35-year-old bipolar patient has been on lithium maintenance therapy for the past 2
years, which has successfully prevented recurrence of manic or depressive symptoms. He
now presents with tremor, diarrhea, excessive thirst and confusion. You ask him about other
medications he has been taking recently and discover that he has taken ibuprofen for a week for a sprained ankle, and fexofenadine for the past two weeks for allergic rhinitis. His new symptoms are MOST LIKELY caused by
A. increased serum lithium levels caused by concurrent fexofenadine administration.
B. increased serum lithium levels caused by concurrent ibuprofen administration.
C. breakthrough depression as ibuprofen reduced serum lithium levels.
D. breakthrough mania as fexofenadine reduced serum lithium levels.
E. increased serum lithium levels caused by inhibition of CYP2D6.
B. increased serum lithium levels caused by concurrent ibuprofen administration.
39. Which of the following antidepressants has a unique mechanism of action that involves
inhibition of both the dopamine transporter and the norepinephrine transporter, but NOT the
serotonin transporter?
A. fluoxetine
B. amitriptyline
C. venlafaxine
D. bupropion
E. selegiline
D. bupropion
40. Ms. H, a 24-year-old army veteran, presents with abnormally depressed mood, inability to
get out of bed each morning, and decreased ability to concentrate and accomplish anything.
You take a detailed medical history and discover that a year earlier she reported having spent
a week barely sleeping, partying, having a number of sexual encounters and writing the majority of a novel she had been working on. Then this mood wore off and she returned to
her more normal stable behavior. She requests to start taking medication. The MOST
APPROPRIATE drug for her now would be
A. imipramine.
B. tranylcypromine.
C. lamotrigine.
D. amitriptyline.
E. haloperidol.
C. lamotrigine.
41. Which of the following pairings is CORRECT?
A. anakinra - soluble TNF- receptor
B. abatacept - anti interleukin-1 monoclonal antibody
C. etanercept - soluble interleukin-1 receptor
D. leflunomide - dihydrofolate reductase inhibitor
E. infliximab - anti TNF-alpha monoclonal antibody
E. infliximab - anti TNF-alpha monoclonal antibody
42. Celecoxib but NOT ibuprofen
A. selectively inhibits cyclooxygenase-1.
B. selectively inhibits cyclooxygenase-2.
C. inhibits cyclooxygenase-1 and cyclooxygenase-2.
D. inhibits cyclooxygenase-2 and 5-lipoxygenase.
E. inhibits cyclooxygenase-1 and phospholipase A.
B. selectively inhibits cyclooxygenase-2.
43. You are treating a 40-year-old female for unipolar depression. She is insistent that she does
not want to take medication that will make her sleepy. The MOST APPROPRIATE
medication for her is
A. amitriptyline.
B. mirtazapine.
C. trazadone.
D. sertraline.
E. olanzapine.
D. sertraline.
44. A 22-year-old male incurred a compound fracture of his tibia while improperly sliding into
second base during a baseball game. After surgically setting the bone, you prescribe a
transdermal preparation of an opiate to provide your patient with continuous relief from pain.
Which TRANSDERMAL OPIATE do you prescribe?
A. morphine
B. oxycodone
C. fentanyl
D. loperamide
E. dextromethorphan
C. fentanyl
45. Morphine diminishes pain in part by
A. inhibiting prostaglandin synthesis in injured tissue.
B. inhibiting histamine release from mast cells in injured tissue.
C. stimulating GABA release in the periaqueductal gray region of the brain.
D. inhibiting substance P release from A-delta pain neurons in the dorsal horn region of
the spinal cord.
E. stimulating noradrenergic neurons in the locus ceruleus.
D. inhibiting substance P release from A-delta pain neurons in the dorsal horn region of
the spinal cord.
46. ET, a 28-year-old man is admitted to the Emergency Room after taking a drug that has
caused severe anxiety, agitation, confusion and paranoia. Physical examination reveals that
he is hypertensive, has marked muscular rigidity, has reduced sensitivity to painful stimuli,
and is sweating and salivating excessively. Which of the following drugs is the MOST
LIKELY culprit?
A. lysergic acid diethylamide
B. phencyclidine
C. phenylephrine
D. heroin
E. modafinil
B. phencyclidine
47. Alcohol
A. inhibits a glutamate-activated NMDA receptor regulated cation current.
B. inhibits a GABA-mediated chloride current by competing for GABA binding sites.
C. directly opens potassium channels.
D. directly inhibits adenylyl cyclase activity.
E. activates a phosphodiesterase.
A. inhibits a glutamate-activated NMDA receptor regulated cation current.
48. Which of the following BEST describes the changes in the blood concentration of 9-
tetrahydrocannabinol after it reaches a peak following the smoking of a single marijuana
cigarette?
A. linear zero-order redistribution and elimination
B. initial slow decline associated with redistribution, followed by a much more rapid
decline reflecting metabolism and elimination
C. initial slow decline associated with metabolism and elimination, followed by a more
rapid decline reflecting redistribution of metabolites
D. initial rapid decline associated with elimination, followed by a much slower decline
reflecting redistribution and metabolism
E. initial rapid decline associated with redistribution, followed by a much slower
decline reflecting metabolism and elimination
E. initial rapid decline associated with redistribution, followed by a much slower
decline reflecting metabolism and elimination
49. HF, a 56-year-old male, has a history of consuming at least a bottle of red wine a day over a
period of 15 years or more. To which of the following chronic effects is he at significantly
HIGHER RISK?
A. constipation
B. hypotension
C. increased hepatic lipid peroxidation
D. elevation of hepatic glutathione
E. long-term inhibition of CYP2E1
C. increased hepatic lipid peroxidation
50. Diagnosis of an opioid-dependent state can be achieved by
A. monitoring saliva for the presence of oxycodone.
B. identifying morphine in a urine sample.
C. induction of constipation after a subcutaneous injection of naloxone.
D. induction of miosis after an oral dose of naloxone.
E. induction of gooseflesh and mydriasis after a subcutaneous injection of
naloxone.
E. induction of gooseflesh and mydriasis after a subcutaneous injection of
naloxone.
51. MQ, a 28-year-old woman, has been using moderate doses of heroin by intravenous injection
once or twice daily for a period of about 2 months. If she stops taking the drug, she
experiences muscle spasms, intestinal cramps and nausea and vomiting. Which of the
following drugs might reasonably be used to partially relieve her withdrawal symptoms?
A. propanolol
B. prazosin
C. phenylephrine
D. ephedrine
E. clonidine
E. clonidine
52. Which combination of drugs is MOST APPROPRIATE for the treatment of a 53-year-old
man with peptic ulcers caused by H. pylori?
A. amoxicillin + bismuth subsalicylate + alosetron
B. esomeprazole + metronidazole + tetracycline + bismuth subsalicylate
C. omeprazole + metoclopramide + bismuth subsalicylate
D. ranitidine + metronidazole + amoxicillin + ondansetron
E. ranitidine + loperamide + bismuth subsalicylate
B. esomeprazole + metronidazole + tetracycline + bismuth subsalicylate
53. An upper gastrointestinal endoscopic examination of a 40-year-old woman with a history of
gastrointestinal esophageal reflux disease (GERD) reveals areas of erosion in the lower esophagus. You prescribe the proton pump inhibitor esomeprazole to treat her condition,
with instructions to take it twice a day, 30 minutes before breakfast and 30 minutes before
dinner. Which of the following BEST EXPLAINS the reason for this approach?
A. Esomeprazole has a low affinity for the H+, K+ - ATPase and therefore needs to be
administered immediately prior to eating.
B. Esomeprazole must be absorbed into the circulation, taken up by the parietal
cells of the stomach, transported into the acidic caniculi, activated, and must
irreversibly bind to the H+, K+ - ATPase.
C. Esomeprazole dissolves slowly in the acidic environment of the stomach before
irreversibly binding to the H+, K+ - ATPase.
D. Esomeprazole must be activated by CYP2C19 before the product is taken up by the
parietal cells of the stomach, a process that takes approximately 30 minutes.
E. Esomeprazole has a very long elimination half-life and therefore needs to be
administered only twice a day.
B. Esomeprazole must be absorbed into the circulation, taken up by the parietal
cells of the stomach, transported into the acidic caniculi, activated, and must
irreversibly bind to the H+, K+ - ATPase.
54. The speed of induction of an inhalational anesthetic is INCREASED by
A. decreasing pulmonary blood flow.
B. decreasing the inspired concentration of the anesthetic agent.
C. increasing cardiac output.
D. decreasing ventilation.
A. decreasing pulmonary blood flow.
55. Malignant hyperthermia is caused by
A. administration of nitrous oxide.
B. increased mobilization of intracellular calcium.
C. increased levels of cAMP.
D. activation of 2-adrenergic receptors.
E. administration of local anesthetics.
B. increased mobilization of intracellular calcium.
56. The PRIMARY mechanism of action of ketamine's sedative effect is
A. activation of sodium channels.
B. inhibition of GABAB receptors.
C. activation of GABAB receptors.
D. inhibition of acetylcholinesterase.
E. blockade of a NMDA receptor-regulated cation current.
E. blockade of a NMDA receptor-regulated cation current.
lack of analgesic response to codeine
D. CYP2D6
improved therapeutic response to omeprazole monotherapy for H. pylori infection
CYP2C19
. a complexing agent that might be appropriate for elemental mercury poisoning but not for
poisoning by methyl-mercury
dimercaprol
62. contracts bronchioles, lowers blood pressure, potentiated by cholinesterase inhibitors
acetylcholine
A 20-year-old female with amyotrophic lateral sclerosis has been taking a single agent to
relieve her muscle spasms. Her latest follow-up exam revealed hypotension, dry mouth and
drowsiness
tizanidine
A 7-year-old boy has been taking an antiseizure medication. His current laboratory results are
indicative of impaired liver function and leukopenia. Baseline tests were within normal
limits
carbamazepine
. Drug that increases cGMP concentration in smooth muscle cells leading to smooth muscle
relaxation.
A. sildenafil
70. Drug that is efficacious for migraine prophylaxis.
B. amitriptyline
1. Which of the following statements accurately describes a PRIMARY mechanism of
antiseizure drug action?

A. Carbamazepine activates NMDA receptors.
B. Valproate activates Na+ channels.
C. Ethosuximide activates Ca2+ channels.
D. Phenobarbital inhibits GABAA receptors.
E. Lamotrigine inhibits Na+ channels.
E. Lamotrigine inhibits Na channels.
2. One of the PRIMARY reasons that barbiturates have a lower therapeutic index than
benzodiazepines is that

A. barbiturates directly activate muscarinic acetylcholine receptors at low
concentrations.
B. benzodiazepines directly activate muscarinic acetylcholine receptors at low
concentrations.
C. barbiturates directly activate GABAA receptors at high concentrations.
D. benzodiazepines directly activate GABAA receptors at high concentrations.
E. barbiturates directly activate AMPA receptors at high concentrations.
C. barbiturates directly activate GABAA receptors at high concentrations.
3. Different monotherapies have failed to control your patient's complex partial seizures. You
decide to treat this patient with phenytoin and a second, concurrent anti-seizure medication.
What is the MOST APPROPRIATE choice of additional therapy if your goals are to
MAXIMIZE control of your patient's seizures and MINIMIZE an overlap in mechanism of
action and the possibility of drug interactions with phenytoin?

A. gabapentin
B. ethosuximide
C. carbamazepine
D. valproate
E. chlorpromazine
A. gabapentin
4. A 55-year-old Army general began experiencing difficulty sleeping 3 months ago after her
daughter was deployed to Iraq. You decide to prescribe a hypnotic to be taken every night.
What is the MOST APPROPRIATE choice of drug?

A. thiopental
B. baclofen
C. flumazenil
D. eszopiclone
E. vigabatrin
D. eszopiclone
5. You diagnose a pediatric patient with attention deficit hyperactivity disorder (ADHD), but his
mother does not want him treated with a stimulant. Which of the following is a NON-
STIMULANT agent useful for treating ADHD?

A. fluoxetine
B. methylphenidate
C. amphetamine
D. phencyclidine
E. atomoxetine
E. atomoxetine
. A drug smuggler caught crossing the border swallowed his stash of cocaine to avoid its
confiscation by the border patrol. An hour later, he began having seizures and was rushed to
the emergency room. He died before the doctors could see him. The MOST PROBABLE
cause of death was

A. stimulant withdrawal.
B. cardiopulmonary failure.
C. over-stimulation of the nucleus accumbens.
D. CNS depression due to over-activation of GABA receptors.
E. depletion of dopamine.
B. cardiopulmonary failure.
7. Which immunosuppressive drug is CORRECTLY paired with its mechanism of action?
A. daclizumab - binding to 4 1-integrin
B. infliximab - binding to TNF alpha
C. leflunomide - inhibition of gluconeogenesis
D. sirolimus - inhibition of calcineurin
E. tacrolimus - inhibition of FKBP-12
B. infliximab - binding to TNF alpha
8. A 39-year-old "celebrity" was found unconscious in her hotel room. The media reported that,
upon arrival at the scene, paramedics tried to resuscitate her using a variety of techniques
including intravenous administration of naloxone. The media subsequently reported that all
of the following medications were found in the "celebrity's" hotel room. Which class of
medications is MOST LIKELY to have caused the paramedics to use naloxone in their
attempts at resuscitation?

A. benzodiazepines
B. stimulants
C. antibiotics
D. opiates
E. cold medications
D. opiates
9. A 23-year-old female with severe respiratory depression from an apparent heroin overdose is
taken to an emergency room. When asked about the needle tracks on her arms, she admits to
intravenous self-administration of heroin at least twice daily for about 12 months. She has
previously experienced severe withdrawal symptoms when attempting to voluntarily reduce
her heroin usage. After recovery she is referred to a drug addiction treatment clinic for
follow-up. Which of the following treatments would be MOST LIKELY to result in
detoxification from heroin within 4 to 6 weeks, with the patient experiencing the lowest
severity (peak intensity) of withdrawal symptoms?

A. substitution of daily oral methadone for the daily intravenous heroin, followed
by a scheduled reduction of the methadone dose to zero over 3 to 6 weeks
B. administration of a single dose of naltrexone, followed by complete removal of all
opiate drugs
C. substitution of daily oral meperidine for the daily intravenous heroin, followed by a
scheduled reduction of the meperidine dose to zero over 3 to 6 weeks
D. administration of a single dose of disulfiram, followed by complete removal of all
opiate drugs
E. substitution of daily oral fentanyl for the daily intravenous heroin, followed by a
scheduled reduction of the fentanyl dose to zero over 3 to 6 weeks
A. substitution of daily oral methadone for the daily intravenous heroin, followed
by a scheduled reduction of the methadone dose to zero over 3 to 6 weeks
10. The 23-year-old female in the previous question is successfully detoxified. She is offered
maintenance therapy consisting of a sublingual preparation containing buprenorphine and
naloxone combined in one tablet. Naloxone is included in this preparation to

A. facilitate the absorption of buprenorphine and delay its elimination by inhibition of
CYP450 enzymes.
B. reduce the sublingual absorption of buprenorphine and delay its elimination by
induction of CYP450 enzymes.
C. potentiate the buprenorphine "high" following sublingual or intravenous
administration.
D. antagonize the buprenorphine "high" if the tablet were dissolved and self-
administered intravenously, while leaving unaffected the effects of
buprenorphine after sublingual administration because of the poor absorption
and low bioavailability of naloxone.
E. potentiate the buprenorphine "high" if the tablet were dissolved and self-administered
intravenously, while leaving unaffected the mild effects of buprenorphine after
sublingual administration because of the poor bioavailability of naloxone.
D. antagonize the buprenorphine "high" if the tablet were dissolved and self-
administered intravenously, while leaving unaffected the effects of
buprenorphine after sublingual administration because of the poor absorption
and low bioavailability of naloxone.
11. Which of the following describes a LIKELY mechanism for the acute actions of ethanol in
inducing BOTH intoxication and ataxia?

A. potentiation of GABAA receptor-mediated chloride conductances in brain
B. induction of CYP2E1 in liver
C. blockade of endogenous adensosine at adenosine receptors in brain
D. inhibition of monoamine oxidase B in brain
E. potentiation of NMDA receptor-mediated cation conductances in brain
A. potentiation of GABAA receptor-mediated chloride conductances in brain
12. A 47-year-old man who has recently received a kidney transplant begins to experience renal
failure. Biopsy reveals that this is a toxic reaction to one of the immunosuppressive drugs
he is taking to prevent organ rejection. The drug MOST LIKELY to be responsible for the
renal toxicity is
A. azathioprine.
B. cyclosporine.
C. daclizumab.
D. mycophenolate mofetil.
E. sirolimus.
B. cyclosporine.
13. A 32-year-old depressed female has failed to respond to 3 different antidepressant drugs.
You decide to prescribe the monoamine oxidase (MAO) inhibitor, tranylcypromine. Which
of the following should she AVOID while taking tranylcypromine?

A. drinking grapefruit juice
B. exercising too vigorously
C. drinking beer or wine
D. taking vitamin C
E. traveling on an airplane
C.drinking beer or wine
14. Non-steroidal anti-inflammatory drugs can effectively treat all of the following EXCEPT

A. patent ductus arteriosus.
B. primary dysmenorrhea.
C. rheumatoid arthritis.
D. gout.
E. gastric ulcers.
E. gastric ulcers.
15. A 40-year-old male who is suffering from major depressive disorder reports feeling very
irritable and being unable to sleep well or focus on his work. Three weeks after starting
treatment with fluoxetine, his symptoms start to improve. The MOST LIKELY effect of
fluoxetine on the monoamine transporters is

A. inhibition of the norepinephrine and dopamine transporters, but not the serotonin
transporter.
B. inhibition of the norepinephrine and serotonin transporters, but not the dopamine
transporter.
C. inhibition of the dopamine transporter, but not the norepinephrine or serotonin
transporters.
D. inhibition of the serotonin transporter, but not the norepinephrine or dopamine
transporters.
E. inhibition of the serotonin and dopamine transporters, but not the norepinephrine
transporter.
D. inhibition of the serotonin transporter, but not the norepinephrine or dopamine
transporters.
16. Montelukast is efficacious in treating asthma because it is a

A. 2 adrenergic receptor antagonist.
B. 2 adrenergic receptor agonist.
C. muscarinic acetylcholine receptor antagonist.
D. glucocorticoid receptor agonist.
E. leukotriene CysLT1 receptor antagonist.
E. leukotriene CysLT1 receptor antagonist.
17. A 58-year-old man with chronic obstructive pulmonary disease (COPD) remains
symptomatic despite taking an inhaled sympathomimetic drug for 2 weeks. Which drug
should you ADD to his therapy to BEST relieve his symptoms?

A. ipratropium
B. albuterol
C. salmeterol
D. omalizumab
E. montelukast
A. ipratropium
18. Sildenafil enhances the activity of an endogenous vasodilator by
A. increasing IP3 levels.
B. increasing cAMP levels.
C. increasing cGMP levels.
D. activating the RAS-MAPK cascade.
E. increasing phospholipase C activity.
C. increasing cGMP levels.
19. A 24-year-old male experiencing his first episode of acute mania has been hospitalized
against his will. Upon arrival, he was violent and had to be forcibly restrained. His wife
reported that he has not slept for more than an hour per night for the past week, has stood in
their yard and yelled obscenities at the neighbors, and has given away their new car to a
transient at a bus stop because "the guy looked cold". The BEST INITIAL course of action
is to
A. place him in a padded cell and let him "cool off" on his own.
B. administer low dose lithium and closely monitor his serum lithium levels.
C. administer haloperidol, then gradually add lithium and closely monitor his
serum lithium levels.
D. administer fluoxetine, lamotrigine and lithium, and closely monitor his serum lithium
levels.
E. begin intense psychotherapy and then administer lamotrigine for long term
maintenance.
C. administer haloperidol, then gradually add lithium and closely monitor his
serum lithium levels.
20. H1 receptors can DIRECTLY mediate all of the following actions of histamine EXCEPT
A. vasodilation.
B. increased force of cardiac muscle contraction.
C. bronchoconstriction.
D. stimulation of sensory nerve endings.
E. increased permeability of post-capillary venules.
B.increased force of cardiac muscle contraction.
21. A 55-year-old female with terminal cancer has been referred to you at the pain clinic. She
has been taking aspirin and codeine for pain, but this combination is clearly no longer
effective. What is the MOST APPROPRIATE drug regimen to alleviate her pain?

A. Switch her NSAID from aspirin to ibuprofen (because ibuprofen is more potent), and
double her dose of codeine.
B. Prescribe sublingual naloxone tablets and instruct her to take as many as needed to
alleviate the pain.
C. Inject increasing doses of heroin to determine the dose required to alleviate the pain.
Then give her an adequate supply of heroin and instruct her to inject the appropriate
dose of heroin every 2-3 hours.
D. Determine the dose of an opiate agonist (e.g. morphine) required to alleviate the
pain. Then prescribe the appropriate dose of the same opiate in both a slow-
release formulation to persistently suppress her pain and a short-acting
formulation to suppress any breakthrough pain.
E. Prescribe the potent opiate, loperamide, because recent clinical studies have shown
that loperimide is superior to morphine in relieving pain due to cancer.
D. Determine the dose of an opiate agonist (e.g. morphine) required to alleviate the
pain. Then prescribe the appropriate dose of the same opiate in both a slow-
release formulation to persistently suppress her pain and a short-acting
formulation to suppress any breakthrough pain.
22. The administration of an opiate agonist would likely cause all of the following EXCEPT
A. nausea.
B. respiratory depression.
C. diarrhea.
D. analgesia.
E. miosis.
C. diarrhea.
23. Which of the following drugs used to control gastric acidity or treat gastric ulcers is
CORRECTLY matched with its mechanism of action?
A. bismuth subsalicylate - activation of H1 receptors
B. calcium carbonate - activation of calmodulin
C. misoprostol - irreversible inhibition of H+, K+-ATPase
D. omeprazole - reversible inhibition of H+, K+-ATPase
E. ranitidine - reversible antagonism of H2 receptors
E. ranitidine - reversible antagonism of H2 receptors
24. Which of the following are endogenous brain lipids that are not stored in synaptic vesicles,
are rapidly synthesized following neuronal depolarization and Ca2+ influx, can act as
retrograde transmitters and whose receptors are activated by 1- 9-tetrahydrocannabinol
(THC)?
A. amino acids
B. endocannabinoids
C. catecholamines
D. purines
E. neuropeptides
B. endocannabinoids
26. During a routine OB/GYN exam, your 28-year-old female patient complains of decreased
libido and inability to conceive. A battery of blood tests reveals increased serum prolactin
and decreased testosterone levels. Upon follow-up, you discover that for the last 9 months
your patient has been taking a hypnotic prescribed by her primary care physician. Which hypnotic is MOST LIKELY to have caused the adverse effect?
ramelteon
27. A 22-year-old male has been taking an antiseizure medication for 9 months. For the last 7 months he has been out of the country on a humanitarian mission in Africa without access to
a physician or modern health care facilities. He presents with moderate gingival hyperplasia
and hirsutism, which cannot be attributed to any of the conditions he encountered in Africa.
Which antiseizure drug is MOST LIKELY to have caused the adverse effects?
phenytoin
28. A 14-year-old male with cerebral palsy presents with a history of excessive daytime
drowsiness and the recent occurrence of a single seizure. Upon further questioning, his
mother reports that he has been taking a single daily medication for the last year to reduce
his muscle spasms and anxiety, but abruptly stopped taking his medication 2 days ago due to
long-standing complaints of impaired mental function. Which drug is MOST LIKELY to
have caused the adverse effect?
diazepam
29. an agent that induces disorienting hallucinations and dry mouth
scopolamine
30. an agent that induces disorienting hallucinations, hypersalivation and analgesia
E. phencyclidine
31. A 28-year-old schizophrenic male, who has been treated with an antipsychotic for the last 8 years, has developed tardive dyskinesia. Upon physical examination, you note that he also
has gynecomastia. Which of the above drugs is MOST LIKELY to be responsible for the
development of these side effects?
haloperidol
32. You decide to switch the medication of the schizophrenic patient described in the previous
question to a drug that acts as a partial agonist at D2 dopamine receptors and an antagonist at
5HT2A receptors. Which of the above drugs is MOST APPROPRIATE?
aripiprazole
33. Which of these drugs would be MOST EFFECTIVE in treating ulcerative colitis?
mesalamine
34. Which of these drugs would be MOST SUITABLE for treatment of a patient receiving
chemotherapy and radiation therapy for the treatment of Hodgkin's lymphoma, who is
experiencing severe nausea and vomiting?
granisetron
Which of these drugs would be MOST APPROPRIATE for the treatment of an episode of
acute diarrhea?
loperamide
36. A 62-year-old male with a noticeable slouch shuffles into your neurology office. Upon
examination, you note that he displays very slow movement (bradykinesia) and a pill-rolling
tremor in both hands. When you try to straighten his arm, you notice that there is 'cogwheel
resistance' to the passive movement of his arm. You decide to start him on l-dopa therapy.
The l-dopa is effective in relieving the symptoms of his disease, but he now complains of
nausea after taking his medication and pronounced dizziness when he gets out of bed in the
morning. What drug would you add to his regimen to prevent (or greatly reduce) his
peripheral side effects and to increase l-dopa levels in his brain?
carbidopa
37. Three years later, the patient in the previous question now complains of abnormal
involuntary movements (dyskinesias). Recently he has begun to notice that one minute his
medication is working very effectively and then the next minute, all the symptoms of his
disease abruptly return. You decide that he is experiencing the 'on-off' phenomenon.
Which of the above drugs would you add to his regimen to alleviate his recent symptoms
and maintain higher levels of l-dopa in the brain by inhibiting the enzyme, catechol-O-
methyltransferase (COMT)?
entacopone
38. a drug that is CONTRAINDICATED in a patient taking sodium nitroprusside
sildenafil
39. a drug that acts as an antagonist at the H1 histamine receptor, but does not readily cross the
blood brain barrier
fexofenadine
. an antidepressant with a reduced incidence of sexual side effects relative to other
antidepressants
bupropion
1. ______________________________ is a direct-acting spasmolytic agent that decreases Ca2+
release from the sarcoplasmic reticulum of the muscle. It is also used to treat malignant
hypothermia, but is contraindicated for use in patients with amyotropic lateral sclerosis
(ALS).
dantrolene
2. Many drugs of abuse act either directly or indirectly to increase activity of dopaminergic
neurons in the ventral tegmental area (VTA), which innervate the ______________________.
nucleus accumbens
3. As the chain length of alcohols from methanol (CH3OH) to butanol (C4H9OH) is increased,
the concentration of the alcohol in brain required to induce intoxication is
______________________________.
reduced
4. In a patient with renal failure, who is anemic, the colony stimulating factor,
______________________________, can be used to stimulate red blood cell production.
epoetin alfa
5. ______________________________ would reverse the psychosis caused by an overdose of
amphetamines.
haloperidol or D2 receptor antagonist
6. Monoamine oxidase (MAO) inhibitors should not be prescribed together with specific
serotonin reuptake inhibitors because of the potential for the development of
______________________________ syndrome.
serotonin
7. Both histamine and bradykinin cause vasodilation through activation of the enzyme,
______________________________, in endothelial cells.
nitric oxide synthase
8. Salmeterol, which is used to treat asthma, is a long-duration, _________________________
receptor agonist that has increased efficacy when combined with fluticasone, which acts at
the ______________________________ receptor.
beta 2 adrenergic,
glucocorticoid
9. Name an antipsychotic drug that blocks D4 dopamine receptors and 5HT2A serotonin
receptors, is very effective in treating schizophrenics who do not respond to other
antipsychotic medications, and may cause agranulocytosis.
______________________________
clozapine
10. Rivastigmine is used to treat Alzheimer's disease because it inhibits the enzyme,
______________________________.
acetylcholinesterase
1. A 76-year-old male with a 12 year history of idiopathic Parkinson's disease has been taking
levodopa and pramipexole for the past several years with relatively good control of his motor
symptoms, primarily tremor and rigidity. However, he recently began to experience disturbing
visual hallucinations, confusion, and paranoid delusions. Which of the following
antipsychotics SHOULD NOT be used to alleviate these psychotic manifestations?
A. risperidone
B. haloperidol
C. olanzapine
D. quetiapine
E. ziprasidone
B. haloperidol
2. A 60-year-old female has been recently diagnosed with Parkinson's disease. Levodopa has
been effective in relieving her rigidity and akinesia, but she is now experiencing severe emesis
and orthostatic hypotension. What drug, acting only in peripheral tissues, would be the
MOST APPROPRIATE addition to her therapy to decrease these side effects of levodopa?
A. rasagiline
B. pramipexole
C. entacapone
D. benztropine
E. carbidopa
carbidopa
3. Which of the following is an approved pharmacologic treatment to reduce craving for alcohol
that is CORRECTLY paired with its presumed mechanism of action?
A. acamprosate - inhibition of alcohol dehydrogenase
B. methadone - potentiation of GABA at GABAB receptors
C. naltrexone - blockade of opioid receptors
D. N-acetylcysteine - inhibition of aldehyde dehydrogenase
E. disulfiram - inhibition of dopamine re-uptake in CNS
C. naltrexone - blockade of opioid receptors
4. Which of the following asthma medications is inhaled to control inflammation?
A. albuterol
B. cocaine
C. omalizumab
D. fluticasone
E. tiotropium
D. fluticasone
5. Naloxone is combined with buprenorphine in the proprietary drug therapy for opiate
dependency, Suboxone®, because
A. the combination of the two drugs allows the manufacturer to charge a higher price.
B. if the medicine is taken sublingually (as advised by the package insert instructions),
naloxone potentiates the reinforcing properties of buprenorphine.
C. if the medicine is taken sublingually (as advised by the package insert instructions),
naloxone blocks the reinforcing properties of buprenorphine.
D. if the medicine is taken intravenously (against the package insert instructions),
naloxone potentiates the reinforcing properties of buprenorphine.
E. if the medicine is taken intravenously (against the package insert instructions),
naloxone blocks the reinforcing properties of buprenorphine.
E. if the medicine is taken intravenously (against the package insert instructions),
naloxone blocks the reinforcing properties of buprenorphine.
6. An 18-year-old male has asthma that has been difficult to manage. His physician has decided
to prescribe a fast-acting medication to use for exacerbations. Combined with albuterol,
which of the following would BEST provide fast relief from an acute asthma exacerbation?
A. oral corticosteroid
B. inhaled corticosteroid
C. nebulized anticholinergic agent
D. leukotriene receptor antagonist
E. mast cell stabilizer
C. nebulized anticholinergic agent
7. Which of the following causes a decrease in mean arterial pressure (MAP) via prominent
myocardial depression?
A. propofol
B. thiopental
C. etomidate
D. isoflurane
E. halothane
E. halothane
8. Which of the following CORRECTLY pairs a sedative-hypnotic with one of its PRIMARY
indications?
A. midazolam - mania
B. zolpidem - seizures
C. alprazolam - anxiety
D. ramelteon - muscle spasms
E. modafinil - insomnia
C. alprazolam - anxiety
9. A 19-year-old Operation Iraqi Freedom soldier sustains an intra-abdominal wound that is
hemorrhaging severely. Although he is being rapidly resuscitated with blood via two large
bore peripheral intravenous lines, his blood pressure is still very low (80/40 mm Hg). A surgeon asks you to induce general anesthesia so that she can repair a lacerated artery. With
which agent would you induce anesthesia because of its ability to indirectly support blood
pressure via the decreased re-uptake of catecholamines?
A. propofol
B. midazolam
C. thiopental
D. ketamine
E. fentanyl
D. ketamine
10. You also administer the intravenous skeletal muscle relaxant succinylcholine to the above soldier to induce paralysis and facilitate placement of a breathing tube. After placement of
the endotracheal tube, you initiate mechanical ventilation and administer oxygen and
isoflurane via the breathing circuit. Despite your best efforts to hyperventilate the patient,
instead of achieving the expected skeletal muscle relaxation, you notice increased muscle
tone, an exaggerated rise in blood pressure and heart rate, as well as marked carbon dioxide
production. Treatment of this situation would NOT include
A. administration of dantrolene.
B. administration of more succinylcholine.
C. administration of a continuous propofol infusion.
D. turning off the isoflurane.
E. delivery of 100% oxygen.
B. administration of more succinylcholine.
11. Your patient is a 1-year-old female with a history of myoclonic spasms, which began at 2 months-of-age. What is a DRUG OF CHOICE to treat this patient's infantile spasms?
A. carbamazepine
B. ethosuximide
C. phenytoin
D. prednisone
E. felbamate
D. prednisone
12. Your patient is a 13-year-old female. Her mother describes 3 separate short episodes of unresponsiveness, which were associated with finger tapping in the patient's left hand. The patient describes the episodes as "blacking out, then 'waking up' feeling exhausted and
confused". Which of the following CORRECTLY pairs her seizure type with a DRUG OF
CHOICE for treatment?
A. absence - phenytoin
B. absence - ethosuximide
C. complex partial - felbamate
D. complex partial - valproate
E. complex partial - ethosuximide
D. complex partial - valproate
13. Treatment with a single drug failed to control a patient's complex partial seizures. You
decide to treat this patient with two anti-seizure drugs simultaneously. Your patient's current
antiseizure medication is lamotrigine. What is the MOST APPROPRIATE choice of
adjunct therapy if your goals are to MAXIMIZE control of your patient's seizures and
MINIMIZE the possibility of drug interactions and an overlap in mechanism of action?
A. phenytoin
B. gabapentin
C. valproate
D. ethosuximide
E. carbamazepine
B. gabapentin
14. A liver function test is REQUIRED in patients taking
A. carbamazepine.
B. gabapentin.
C. topiramate.
D. ethosuximide.
E. midazolam.
A. carbamazepine.
15. At high concentrations, which of the following directly activates GABAA receptors and
inhibits BOTH AMPA receptors and nicotinic acetylcholine receptors?
A. dantrolene
B. zolpidem
C. flurazepam
D. pentobarbital
E. baclofen
D. pentobarbital
16. Flumazenil will MOST EFFECTIVELY inhibit the actions of
A. chlorpromazine.
B. -hydroxybutyrate.
C. tizanidine.
D. thiopental.
E. chlordiazepoxide.
E. chlordiazepoxide.
17. Your 32-year-old female patient presents with infertility and a long history of insomnia,
which has been well controlled for the last 6 months with a prescription hypnotic. Lab results reveal increased serum prolactin and decreased serum testosterone levels. Which of
the following is MOST LIKELY to cause these adverse effects?
A. ramelteon
B. clonazepam
C. phenobarbital
D. dantrolene
E. modafinil
A. ramelteon
18. Which of the following statements regarding local anesthetics is TRUE?
A. Local anesthetics selectively enhance the transient rise in Na+ permeability that is
responsible for conduction in excitable membranes.
B. Local anesthetics progressively decrease the threshold and increase the rate of rise
and amplitude of the action potential.
C. At clinically useful concentrations, local anesthetics significantly alter the resting
membrane potential by preferentially blocking K+ channels.
D. The receptor site for local anesthetics is located in the extracellular region of the Na+
channel pore.
E. The degree of block by local anesthetics is voltage and frequency dependent.
E. The degree of block by local anesthetics is voltage and frequency dependent.
19. A 29-year-old male is admitted to the emergency room because of lacerations in his nose and
forehead from being hit with a snowball containing a large chunk of ice. He states that he is allergic to ester-type local anesthetics. The MOST APPROPRIATE choice of local
anesthetic to inject prior to suturing is
A. cocaine.
B. procaine.
C. tetracaine.
D. benzocaine.
E. lidocaine.
E. lidocaine.
20. You prescribe duloxetine to a 25-year-old man who is suffering from major depressive
disorder. He is very irritable and reports an inability to sleep well or focus on his work. Three
weeks after taking duloxetine, his symptoms start to improve. Duloxetine is MOST
LIKELY inhibiting
A. the norepinephrine and dopamine transporters but not the serotonin transporter.
B. the norepinephrine and serotonin transporters but not the dopamine transporter.
C. the dopamine transporter but not the norepinephrine or serotonin transporters.
D. the serotonin transporter but not the norepinephrine or dopamine transporters.
E. the serotonin and dopamine transporters but not the norepinephrine transporter.
B. the norepinephrine and serotonin transporters but not the dopamine transporter.
21. Which of the following is the BEST treatment for bipolar depression?
A. lamotrigine
B. atomoxetine
C. quetiapine and mirtazapine
D. amitriptyline
E. phenelzine
A. lamotrigine
22. Which of the following CORRECTLY pairs an antidepressant drug with its MAJOR
mechanism of action?
A. fluoxetine - inhibition of monoamine oxidase
B. bupropion - inhibition of dopamine and norepinephrine transport
C. trazadone - inhibition of dopamine transport
D. tranylcypromine - antagonism of 5-HT2 serotonin receptors
E. imipramine - antagonism of D dopamine receptors
B. bupropion - inhibition of dopamine and norepinephrine transport
23. A 24-year-old woman comes to your office with mild depression and a history of at least one
episode of hypomania. She was previously treated for depression but is not currently taking
any medication. You prescribe lithium for her depression and maintenance of her bipolar
disorder. A MAJOR side-effect of lithium treatment is
A. constipation.
B. lacrimation.
C. dry mouth.
D. weight loss.
E. polyuria.
E. polyuria.
24. A migraine attack will MOST LIKELY be aborted by treatment with specific
A. D2 dopamine receptor antagonists.
B. 5-HT2 serotonin receptor antagonists.
C. M3 muscarinic receptor agonists.
D. 5-HT1 serotonin receptor antagonists.
E. 5-HT1 serotonin receptor agonists.
E. 5-HT1 serotonin receptor agonists.
25. A 60-year-old woman is suffering from stiffness in her wrists and knees, that is particularly
painful after exercise. Her joints are swollen and a blood test reveals that she is positive for
rheumatoid factor. You decide to prescribe a disease modifying anti-rheumatic drug.
However, you notice from her medical history that she has a latent TB infection. What is the
BEST drug to treat her rheumatoid arthritis?
A. acetaminophen
B. methotrexate
C. etanercept
D. ibuprofen
E. infliximab
B. methotrexate
26. A 21-year-old truck driver has developed allergic rhinitis. Which of the following is the
BEST treatment to relieve her symptoms while driving?
A. aspirin
B. diphenhydramine
C. fexofenadine
D. verapamil
E. meclizine
C. fexofenadine
27. Sildenafil enhances the activity of an endogenous vasodilator by
A. increasing IP3 levels.
B. activating protein kinase A.
C. inhibiting cGMP phosphodiesterase.
D. inhibiting cAMP formation.
E. inhibiting phospholipase C.
C. inhibiting cGMP phosphodiesterase.
28. Aspirin is a(n)
A. reversible inhibitor of cyclooxygenase 2 only.
B. reversible inhibitor of cyclooxygenase 1 only.
C. irreversible inhibitor of both cyclooxygenase 1 and 2.
D. irreversible inhibitor of cyclooxygenase 2 only.
reversible inhibitor of both cyclooxygenase 1 and 2.
C. irreversible inhibitor of both cyclooxygenase 1 and 2.
29. Which of the following drugs used to control gastric acidity or treat gastric ulcers is
CORRECTLY matched with its major mechanism of action?
A. bismuth subsalicylate - decreases gastric emptying time
B. calcium carbonate - decreases gastric pH
C. misoprostol - binds bile acids
D. rabeprazole - reversibly inhibits H+, K+-ATPase
E. ranitidine - reversibly antagonizes histamine binding to H2
histamine receptors
E. ranitidine - reversibly antagonizes histamine binding to H2
histamine receptors
30. A 63-year-old man with Type II diabetes develops significant gastroparesis. Which of the following agents would be MOST EFFECTIVE in increasing gastric motility and relieving
his symptoms, but has serious potential side effects including tardive dyskinesia?
A. lubiprostone
B. metoclopramide
C. metronidazole
D. misoprostol
E. sulfasalazine
B. metoclopramide
31. Your new patient is a 22-year-old female who has recently moved to your region of the
country. She was diagnosed with schizophrenia about a year ago and was prescribed a low
dose of an antipsychotic by her previous family doctor. You notice that she shuffles when
she walks. You also discover that she is lactating even though she has not recently given birth. Which antipsychotic medication did her previous family doctor MOST LIKELY
prescribe?
haloperidol
32. You decide to change the medication of the patient in the previous question to an
antipsychotic that is a partial agonist at D2 dopamine receptors and an antagonist at 5-HT2A
serotonin receptors. Which drug have you chosen for this patient?
aripiprazole
33. Timothy Trotts is a second year law student who gets nervous during exams and occasionally
develops diarrhea. He is currently preparing for his board exam and asks you to recommend
a drug to prevent or terminate his diarrhea. Which drug would be MOST APPROPRIATE
for you to recommend?
loperamide
34. Willamena Whiner is a 40-year-old female who sprained her wrist playing golf. She tells her doctor that she has been taking aspirin for the pain, but her wrist still hurts. Her doctor
prescribes a mild opiate that she is to use in combination with the aspirin. Now, she returns to her doctor claiming that the prescribed opiate is completely ineffective. In a follow-up
test, it is discovered that she is deficient in active CYP2D6. Which opiate had her doctor
MOST LIKELY prescribed that was ineffective in this patient?
codeine
35. acts at kappa opioid receptors to induce brief hallucinatory episodes
E. salvinorin A
36. causes dry mouth, memory loss, confusion, and delirium in elderly subjects
D. scopolamine
37. causes hypersalivation, violent psychotic behavior, and catatonic muscular rigidity
C. PCP (phencyclidine)
38. acts at 5-HT2 serotonin receptors to induce long-lasting hallucinations
B. LSD (lysergic acid diethylamide)
39. A 63-year-old man with inoperable bladder cancer who is receiving chemotherapy that
includes cisplatin experiences significant chemotherapy-induced nausea and vomiting.
Which of the above is a 5-HT3 serotonin receptor antagonist that could be used to control
these side effects?
D. ondansetron
40. A 53-year-old woman is diagnosed with diarrhea-predominant irritable bowel syndrome.
Which of the above would be MOST EFFECTIVE in treating her?
A. alosetron
Purpose of Anesthetics
The primary purpose of general anesthesia is to prevent the perception of pain and to induce loss of consciousness during surgical procedures in order to reduce stress and distress to the patient; other objectives are to improve postoperative outcomes and to maintain homeostasis. Additionally, the anesthesiologist must ensure that the deleterious effects of anesthetics are minimized
General Anesthesia
A controlled reversible state of analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation
Balanced Anesthesia
Use of several drugs (e.g. short-acting barbiturates, inhalational agents, and/or opioids) to achieve a state of general anesthesia.
Minimum Alveolar Concentration (MAC):
The steady-state minimum alveolar concentration
(%) of an inhalational agent required for immobility of 50% of subjects exposed to a noxious stimulus (e.g. surgical incision). Despite wide variation in chemical structure, MAC provides a means to compare the potency of the various inhalational agents and serves as a guide to determining dose. It is similar to an ED50 value for an intravenous agent
2 types of general anesthetics
A. Inhalational Anesthetics: Drugs administered as gases, usually via a face mask or endotracheal tube. Agents currently in use in developed countries include halothane, isoflurane, enflurane, desflurane, and sevoflurane. Nitrous oxide (N2O) is an incomplete (also relatively impotent) anesthetic that exists as a gas at ambient temperature and pressure. It is often used to augment the potent inhalational anesthetics and/or intravenous agents.

B. Intravenous Anesthetics: Drugs administered into the circulation via an IV. These agents are usually incomplete anesthetics and are given in combination with other agents to achieve the state of general anesthesia. They include:
1. sedative-hypnotics (barbiturates, etomidate, propofol, benzodiazepines)
2. opioids
3. dissociative anesthetics (ketamine)
4 stages of anesthesia
1. Stage of Analgesia: Analgesia without amnesia, impaired judgment, vertigo/ataxia,
increased respiration, blood pressure, heart rate.
2. Stage of Excitement: Delirious, excited, amnestic. Irregular respirations, struggling,
retching and vomiting.
3. Stage of Surgical Anesthesia: Recurrence of regular respiration to cessation of spontaneous
respiration. Loss of corneal, swallowing, and eyelid reflexes. Skeletal muscle
relaxation, decreased blood pressure. Four planes of surgical anesthesia have been described based on pupillary changes, ocular movement, and eye reflexes.
4. Stage of Medullary Depression: Begins with cessation of spontaneous respiration. Includes severe depression of vasomotor center in the medulla as well as the respiratory center. Without circulatory and respiratory support, death rapidly ensues.
Pharmacokinetics of inhaled anesthetics
Inhaled anesthetics exert their effects by achieving an optimal steady state concentration (partial pressure) of a particular agent in the brain. The rate at which a given partial
pressure of inhalational agent in the brain is achieved depends on multiple factors, which influence the movement of the gas from the anesthesia machine to the brain. These factors include: solubility (blood:gas and blood:brain partition coefficients), inspired anesthetic concentration, pulmonary ventilation, arteriovenous concentration gradients, and pulmonary and cerebral blood flow.
True/False: The speed of induction of anesthesia by an inhalational agent can be increased by increasing the inspired concentration of the agent (FI), according
to Fick's law of diffusion
True
True/False: Increasing ventilation brings more of the inhalation anesthetic agent to the alveoli more quickly and generally increases the speed of induction
True
True/False: Patients with low cardiac output have a relatively quick induction of
anesthesia, since the rate of rise of arterial tension of the agent is increased
True
Dose Response of an inhaled anesthetic
The dose of an inhaled anesthetic can be given in multiples of its MAC value. The MAC value
of an anesthetic represents one point on its dose response curve. Certain parameters (extremes of age, concomitant drug administration, temperature, certain disease states, etc.) can have the effect of either increasing or decreasing MAC [necessitating the use of higher or lower concentrations (doses)]; other factors (height, sex, weight) have no effect on MAC value
Halothane (inhalational anesthetic)
halogenated hydrocarbon, most widely used inhaled agent in the world.

Pro: cheap (old), patients tolerate mask inductions.

Con: relatively high solubility, prominent myocardial depression (decreased
contractility) and sensitization of the the myocardium to catecholamine induced arrythmias.
Isoflurane (inhalational anesthetic)
halogenated ether, most widely used inhaled agent in modern countries.

Pro: relatively cheap (off patent), minor myocardial depression and sensitization,
relatively low solubility. Increases CBF less than other inhalational agents.

Con: airway irritation, mainly decreases mean arterial pressure by vasodilitation. Increases heart rate
Desflurane
halogenated ether

Pro: low solubility, fast onset/ elimination/ response to changes in concentration
otherwise much like isoflurane.

Con: expensive, requires special expensive vaporizer, airway irritation, decreases mean arterial pressureby vasodilitation. Increases heart rate.
Sevoflurane
halogenated ether

Pro: low solubility (fast on and off/fast changes in anesthetic depth), well tolerated by patients for mask inductions. No change in heart rate.

Con: expensive, risk of fluoride toxicity if low carrier gas flows are used (difficult to conserve drug/cost), decreases MAP by vasodilatation and decreasing cardiac output.
Nitrous Oxide
non-halogenated gas

Pro: minimal myocardial or vascular effects, low solubility (fast on/off), good adjunct allowing lower concentrations of potent agents and/or less IV drug to be used. NMDA receptor antagonist may enhance analgesia

Con: not potent, i.e., MAC > 100% so requires high concentrations. Rapidly moves into Nitrous containing spaces and causes distention. Increased ICP and increased cerebral blood flow.
IV anesthetic: barbiturates
Cause profound CNS depression via enhancement of GABAA actions. Thiopental,
ultra-short acting, is the most common agent used for induction of General Anesthesia (GA). Rapid crossing of the blood-brain barrier permits hypnosis within 1-2 circulation times. Duration of effect based on T1/2 alpha (redistribution half-life), so effect very short-lived at clinically useful doses.
IV anesthetic: Etomidate
Induction of GA (profound CNS depression) via enhancement of GABAA actions. A carboxylated imidazole anesthesia induction agent with minimal cardiovascular and respiratory effects, rapid onset, and recovery. Usefulness somewhat limited by potential for adrenocortical suppression. Associated with myoclonic movements and post operative nausea and vomiting.
IV anesthetic: Propofol
Sedation or induction of GA profound CNS depression via enhancement of GABAA
actions. A phenol derivative intravenous anesthetic with physiologic effects similar to barbiturates, with a slightly more rapid recovery. Propofol is a profound respiratory depressant and causes significant decrease in mean arterial pressure secondary to a decrease in systemic vascular resistance. Useful for continuous infusion because of its rapid clearance and extrahepatic sites of metabolism. Propofol has gained great popularity because of its amnestic and anti-emetic effects as well as for its
usefulness in total intravenous anesthesia (TIVA). Careful titration of intravenous infusions of this drug make it useful for sedation in regional/local anesthetic cases and prolonged sedation in the critical care setting as well.
True/False: Neither barbiturates, etomidate nor propofol have any analgesic properties.
True
Opioids:
Action at central and peripheral mu, kappa, and delta receptors. Mainstay of our analgesic drugs used in clinical settings. Large doses of
these drugs can provide the basis for a very hemodynamically stable anesthetic (minimal circulatory deterioration) in even the most critically ill patients.
IV anesthetics: Benzodiazepines
GABAA receptor mediated inhibitory neurotransmission. Are used primarily
for their anxiolytic/amnestic effects and, as such, are frequently given pre-operatively or for intraoperative sedation. Midazolam is the most commonly used intravenous benzodiazepine because it is water-soluble and has a relatively short half-life.
Midazolam
most commonly used IV benzodiazepine used for anesthesia
Ketamine:
Inhibitor of the excitatory neurotransmitter, glutamic acid, at the N-Methyl-DAspartate
(NMDA) receptor. A phencyclidine derivative which produces a state of dissociative
anesthesia characterized by catatonia, amnesia, and analgesia. It can be used for sedation as well as general anesthesia. Ketamine produces cardiovascular stimulation. The cardiovascular stimulation is secondary to indirect sympathomimetic activity. It decreases the re-uptake of catecholamines. If no catecholamines are available ketamine is a myocardial depressant. Ketamine also increases cerebral
metabolic rate, and increases cerebral blood flow. Ketamine causes minimal respiratory depression.
What is a phencyclidine derivative that produces a state of dissociative
anesthesia characterized by catatonia, amnesia, and analgesia?
Ketamine

It can be used for sedation as well as general anesthesia