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Brain and Behavior > Exam 3 - Pharmacology > Flashcards

Exam 3 - Pharmacology Flashcards

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1
Q

What important factors guide choosing an anti-epileptic drug?

A

Tolerability of adverse effects

Concomitant use of other drugs

Comorbidities

No well-accepted guidelines for choosing among drugs with overlapping indications against seizure types/syndromes

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2
Q

What are the pros and cons of narrow spectrum anti-epileptics?

A

Pro:

-effective in partial seizure

Cons:

  • Less effective in primary generalized tonic-clonic seizures
  • Not useful for myoclonic or absence seizures (can even worsen)
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3
Q

What are the pros of broad spectrum anti-epileptics?

A
  • Effective in partial seizures
  • Effective in generalized seizures (primary or secondary)
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4
Q

What are the narrow spectrum antiepileptics we learned about?

A

Carbamezapine

Phenytoin

Phenobarbital

Gabapentin

Tiagabine

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5
Q

What are the broad spectrum antiepileptics we learned about?

A

Valproate

Topiramate

Lamotrigine

Clonazepam

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6
Q

What sorts of cells can give rise to epilepsy? What sorts of genetic defects can give rise to epilepsy?

A

Densely packed neurons in sheets can lead to synchronized firing through non-synaptic interactions

Channelopathy in voltage gated Na channel > it fails to completely inactivate

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7
Q

What are the 3 major proposed mechanisms of anti-epileptics?

A

Sodium channel block

Ca channel block (T-type and L-type, N type and/or P-type)

GABA enhancement at GABAa channels

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8
Q

Which anti-epileptics inhibit voltage gated Na channels?

A

Carbamazepine

Phenytoin

Valproate

Lamotrigine

Topiramate

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9
Q

What anti-epileptics enhance GABA signalling, and how?

A

Allosteric effect at GABAa receptors

  • Clonazepam, lorazepam (benzodiazepines)
  • Phenobarbital (barbiturate)
  • Topiramate

Increase synaptic levels of GABA

  • Tiagabine: block GABA uptake
  • Gabapentin: may enhance GABA release
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10
Q

What anti-epileptics inhibit T-type Ca channels?

A

Ethosuximide

Valproate (also blocks Na channels)

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11
Q

Phenytoin: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Narrow

Hydantoins (prototype)

Inhibit Na v-gated channels (stabilize inactivated state), preferentially inhibit high-frequency/burst firing

Partial (simple & complex) seizures including secondarily generalized seizures

Primary generalized tonic-clonic seizures

Prevent recurrence of status epilepticus

CYP450 inducer

Plasma concentration NOT proportional to dose (non-linear kinetic); narrow therapeutic window

Hepatic metabolism

Teratogenicity

Hypersensitivity

Cognitive slowing

Increased seizure activity/seizure induction

Gingival hyperplasia

Nystagmus, ataxia, coarsening of facial features

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12
Q

Phenobarbital: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Narrow

Barbiturate

Enhance GABA signalling: allosteric effect at GABAa receptors

Partial (simple and complex) including secondarily generalized seizures (less used)

Primary generalized tonic-clonic seizures (less used)

Status epilepticus if can’t be controlled

CYP450 inducer

Hepatic metabolism and ~25% renal elim

Teratogen

Hypersensitivity

Cognitive slowing

Sedation

Paradoxical excitatory effect in kids

Megaloblastic anemia

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13
Q

Carbamazepine: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Narrow

(Carbamazepine) - no class listed

Inhibit Na channel (stabilize inactivated form, preferentially inhibit high-frequency/burst firing)

Partial (simple and complex) including secondarily generalized seizures

Primary generalized tonic-clonic seizures

Hepatic metabolism

CYP450 inducer

Teratogen

Hypersensitivity

Cognitive slowing

CNS: diplopia, dizziness, drowsiness

GI: nausea and vomiting

Blood: leucopenia, agranulocytosis

Hyponatremia

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14
Q

Ethosuximide: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

(limited to specific applications - not “broad” or “narrow”)

(no class listed)

T-type Ca channel blocker

Absence seizures

Hepatic metabolism

GI: nausea, vomiting, anorexia

CNS: diplopia, dizziness, drowsiness, lethargy, agitation

Hypersensitivity, including Stevens-Johnson syndrome

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15
Q

Valproate: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Broad

(none listed - sodium salt for IV, acid for oral use)

Inhibit Na channel (stabilize inactivated form, preferentially inhibit high-frequency/burst firing)

T-type Ca channel blocker

Partial (simple and complex) including secondarily generalized seizures

Primary generalized tonic-clonic seizures

Status epilepticus if can’t be controlled

Absence seizures

Myoclonic, Atonic

CYP450 inhibitor

Teratogen

Cognitive slowing

GI: nausea, vomiting, anorexia (initial)

CNS: tremor

Thrombocytopenia

Hepatotoxicity (transient LFT changes common; rare fulminant hepatic necrosis)

Weight gain (chronic)

Alopecia

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16
Q

Lorazepam: broad/narrow, class, mechanism(s), used to treat, PK?

A

(limited to specific applications - not “broad” or “narrow”)

Benzodiazepine

Enhance GABA signalling: allosteric effect at GABAa receptors

Used to treat status epilepticus

Hepatic metabolism

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17
Q

Clonazepam: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Broad

Benzodiazepine

Enhance GABA signalling: allosteric effect at GABAa receptors

Absence seizures (less used)

Myoclonic, Atonic (less used)

Hepatic metabolism

CNS: fatigue, sedation, dizziness; in children may get paradoxical excitement (aggression, hyperkinesia)

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18
Q

Gabapentin: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Narrow

(Newer drug)

Increase synaptic levels of GABA: might enhance GABA release

Blockade of amino acid transport

Enhanced conductance through Katp channels

(mechanism uncertain)

Partial (simple and complex) including secondarily generalized seizures

Decrease in bioavailability with increasing dose

Elimination 100% renal

CNS: drowsiness, dizziness, ataxia, fatigue

Weight gain

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19
Q

Lamotrigine: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Broad

(Newer drug)

Inhibit Na channel (stabilize inactivated form, preferentially inhibit high-frequency/burst firing)

N/P-type Ca channel blocker

Partial (simple and complex) including secondarily generalized seizures

Primary generalized tonic-clonic seizures

Absence seizures

Myoclonic, Atonic (off-label)

Hepatic metabolism

CNS: diplopia, sedation

Hypersensitivity – rash, including Stevens-Johnson syndrome

(Relatively few side effects)

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20
Q

Tiagabine: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Narrow

(Newer drug)

Increase synaptic levels of GABA: blocks GABA uptake

Partial (simple and complex) including secondarily generalized seizures

Hepatic metabolism

Dizziness, nervousness, drowsiness, cognitive-confusion (high doses)

Increased seizure activity/seizure induction (in patients without dx seizure disorders)

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21
Q

Topiramate: broad/narrow, class, mechanism(s), used to treat, PK, adverse effects?

A

Broad

(Newer drug)

  • Inhibit Na channel (stabilize inactivated form, preferentially inhibit high-frequency/burst firing)
  • Modulation of AMPA-type glutamate receptors
  • Inhibit carbonic acid anhydrase
  • Enhance GABA signalling: allosteric effect at GABAa receptors

Partial (simple and complex) including secondarily generalized seizures

Primary generalized tonic-clonic seizures

Myoclonic, Atonic (off-label)

Elimination 80% renal

Decreased appetite, weight loss

Renal stones

Cognitive slowing (most common reason for discontinuing)

Acute myopia with secondary angle-closure glaucoma (rare)

Oligohydrosis (sweating deficiency)  fevers, heat stroke (children)

Metabolic acidosis

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22
Q

What is the mechanism of involvement of T-type Ca channels in seizures?

A

T-type Ca channels in the thalamocortical neurons underlie bursting activity & oscillations (sleep spindles 12-14 Hz)

Excessive current through tT-type channel > more intense bursts > absence seizure (slower oscillations, 5Hz)

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23
Q

How is status epilepticus treated?

A

Initial: benzodiazepines (lorazepam), phenytoin (prevent recurrence)

Refractory: if seizures cannot be controlled with ^ drugs

  • Phenobarbitol, valproate
  • If seizures still not controlled after 1 hour, induce general anesthesia
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24
Q

What is induction with respect to drug interactions?

A

Drug A increases the expression of an enzyme so that Drug B is eliminated at a higher rate (e.g. with CYP450 enzymes)

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25
Q

What anti-epileptics are CYP450 inducers?

A

Phenytoin

Carbamazepine:

Phenobarbital

All 3 are substrates for 3A4

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26
Q

How can anti-epileptics cause Stevens-Johnson syndrome?

A

Interaction between lamotrigine and valproate (compete for Phase II enzyme > decreased clearance)

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27
Q

What are some drug interactions among anti-epileptics & what do they cause?

A

Examples:

Carbamazepine + phenytoin

o Decreased carbamazepine levels (increased metabolism)

o Variable changes in phenytoin levels

Valproate + phenobarbital

o Increased phenobarbital levels (metabolism inhibited)

Valproate + lamotrigine

o Increased lamotrigine levels (competition for Phase II

enzyme) > SJS

Valproate + clonazepam

o May precipitate absence status epilepticus (mechanism

unclear)

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28
Q

What are some of the adverse effects of anti-epileptics?

A

Teratogenic

Hypersensitivity (including Stevens-Johnson syndrome)

Cognitive slowing

Sedation (almost all, to some extent)

Increased seizure activity/seizure induction

Suicidal thoughts/behaviors

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29
Q

Cocaine: mechanism, therapeutic, effects, PK, addiction, adverse effects?

A
  • Increase the synaptic levels of dopamine (DA), norepinephrine (NE), and serotonin (5HT).
  • Directly inhibits DAT dopamine reuptake transporter

Stimulation & addiction, due mainly to increased dopamine.

Only FDA-approved use is as a local anesthetic

Vasoconstrictor (increase NE @ synapses, alpha effect dominates)

Systemically: increased HR, BP, contractility (sympathetic effects); but coronary vasoCONSTRICTION

IV > fastest increase in conc, but smoking produces as rapid a high

Elimination: hydrolysis (plasma, hepatic esterases); metabolite benzoylecgonine is detectable in urine 1 wk post-use; ha;f life ~1hr

With repeated exposure, cocaine’s effect on nucleus accumbens is “anticipated”

Increased risk of MI, arrhythmias

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30
Q

Amphetamine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Amphetamines

  • Compete (as a substrate) with DA for uptake by DAT
  • Compete with DA for vesicular monoamine transporter

(VMAT), preventing DA from loading into release vesicles, so DA is released nonvesicularly & new vesicles contain less DA

ADHD, narcolepsy

Elimination: kidney; longer half lives & high than cocaine,

D isomers are more potent for CNS effects, L isomers are more potent at the ANS

Increase BP but can see reflex bradycardia (unlike cocaine)

Crash period after binge use followed by intermediate withdrawal

Increased risk of arrhythmias

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31
Q

Methamphetamine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Amphetamines

Compete (as a substrate) with DA for uptake by DAT

Compete with DA for vesicular monoamine transporter

(VMAT), preventing DA from loading into release vesicles, so DA is released nonvesicularly & new vesicles contain less DA

ADHD, exogenous obesity; narcolepsy (off-label) (D isomer only)

Increase BP but can see reflex bradycardia

Elimination: kidney; longer half lives & high than cocaine,

D isomers are more potent for CNS effects, L isomers are more potent at the ANS

Crash period after binge use followed by intermediate withdrawal

Increased risk of arrhythmias

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32
Q

Methylphenidate: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Amphetamines

Compete (as a substrate) with DA for uptake by DAT

Compete with DA for vesicular monoamine transporter

(VMAT), preventing DA from loading into release vesicles, so DA is released nonvesicularly & new vesicles contain less DA

ADHD, narcolepsy, Depression in medically ill older adults (off-label)

(Increased BP, reflex bradycardia?)

Elimination: kidney; longer half lives & high than cocaine,

D isomers are more potent for CNS effects, L isomers are more potent at the ANS

Crash period after binge use followed by intermediate withdrawal

(Arrhythmias?)

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33
Q

Phentermine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Amphetamines

Compete (as a substrate) with DA for uptake by DAT

Compete with DA for vesicular monoamine transporter

(VMAT), preventing DA from loading into release vesicles, so DA is released nonvesicularly & new vesicles contain less DA

Exogenous obesity

Elimination: kidney; longer half lives & high than cocaine,

D isomers are more potent for CNS effects, L isomers are more potent at the ANS

Crash period after binge use followed by intermediate withdrawal

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34
Q

Modafinil: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

A stimulant, but structurally unrelated to amphetamines

Mechanism not well understood, but produces most of the classic sympathomimetic symptoms

improve wakefulness in narcolepsy, daytime shift disorder, adjunct for the treatment of obstructive sleep apnea; Off-label: for ADHD

Cleared metabolically primarily by CYP3A4

addiction is considered less than with the amphetamines.

Headache, nausea

Hypersensitivity (incl. Stevens-Johnson)

Anxiety, mania, suicidal thoughts possible

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35
Q

Caffeine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Stimulant

Adenosine receptor antagonist

Inhibits phosphodiesterase at higher concentrations

OTC-labeled for increased wakefulness during fatigue

Idiopathic apnea of prematurity

Acute respiratory depression (not 1st line)

Off-label uses include ECT seizure augmentation, spinal

puncture headache

Hepatic metabolism

Tolerance to stimulation develops, withdrawal (fatigue, sedation, H/A, N), but not dependence

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36
Q

Nicotine: class, mechanism, therapeutic, CNS & peripheral effects, addiction, adverse effects?

A

Selective full agonist at all nAChRs

Only approved use is to help curtail tobacco use

Arousal, relaxation (in face of stressful situations), enhanced mood, attention, and reaction time.

Low doses: increased BP, HR, CO, and vasoconstriction

High doses: release of adrenal catecholamines

Extremely high doses: hypotension and slowing of HR.

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37
Q

Synthetic cathinones: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Stimulant drugs (constituent of bath salts)

Mechanism: similar to the amphetamines, including reduced monoamine uptake and increased release

Clinical presentation can differ substantially from amphetamines, due to other constituents in bath salts (hallucinogens and synthetic cannabinoids)

CNS symptoms

i) Agitation, paranoia, hallucinations, psychosis, myoclonus and headaches are the most frequent neurologic symptoms. Synthetic cathinone hallucinations are frequently auditory and tactile in nature and paired with psychoses that can be severe and long lasting.

Peripheral symptoms

i) Most common: hyperthermia, hypertension, tachycardia, hyponatremia, nausea, vomiting, and chest pains.
ii) More serious: liver failure, kidney failure, rhabdomyolysis, and the development of compartment syndrome (swelling in muscular fascia compartments).

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38
Q

Lysergic acid diethylamide (LSD): class, mechanism, therapeutic, effects, PK, addiction, adverse effects?

A

Hallucinogen

5HT2A receptor partial agonists (high density on cortical
pyramidal cells in the prefrontal cortex)

Elimination: hepatic

Hallucinations are primarily visual, Synesthesias, dilation of time

“bad trips” may include depression, anxiety, agitation and paranoia

Peripheral sympathomimetic signs include mydriasis, and increased blood pressure and heart rate

Tolerance can occur with these drugs (and cross tolerance among the members of the 5 HT2A agonist class) but no withdrawal syndrome.

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39
Q

Phencyclidine (PCP, angel dust): class, mechanism, effects, addiction, adverse effects?

A

Hallucinogen

Glutamate receptor (NMDA) non-competitive antagonist

High risk of addiction

CNS effects

o Visual and auditory hallucinations

o Hostile and combative behavior is common, and paranoid

delusions may be present.

o Other symptoms include numbness and insensitivity to pain

Peripheral symptoms:

o Tachycardia, hypertension and sweating

At high toxic doses:

o Anesthesia (PCP is related to the general anesthetic

ketamine), coma with paralytic mydriasis, catatonia

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40
Q

delta-9-tetrahydrocannabinol (THC; marijuana): class, mechanism, effects incl adverse, PK, addiction?

A

Cannabinoid

endogenous agonists at these receptors (CB1 & CB2) are called endocannabinoids.

Elimination: hepatic, 1-1.5 days, mostly bile elimination; metabolites in urine up to a week; highly lipid soluble

Highly variable effects

o A euphoric “mellow” high and giddiness are typical

o Time expansion

o In some cases, anxiety and panic (especially with high doses).

o Cognitive and psychomotor impairments may persist beyond the perceived high.

Tolerance develops, but classical physical dependence

has been difficult to observe.

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41
Q

Dronabinol: class, mechanism, therapeutic?

A

A synthetic cannabinoid (controlled; Schedule III)

CB1 & CB2 agonist

anorexia (“wasting syndrome”), in patients with AIDS, and as an antiemetic for patients ,whose chemotherapy-induced emesis, has not been adequately controlled

o Off-label, it is used for prophylaxis and treatment of post-surgical nausea

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42
Q

3,4-methylenedioxyamphetamine (MDMA; ecstasy): class, mechanism, effects, PK, addiction, adverse effects?

A

Hallucinogen

5HT2A receptor partial agonists (high density on cortical
pyramidal cells in the prefrontal cortex)

Elimination: hepatic

Hallucinations are primarily visual,Synesthesias, dilation of time

Peripheral sympathomimetic signs include mydriasis, and increased blood pressure and heart rate.

“bad trips” may include depression, anxiety, agitation and paranoia

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43
Q

What are the therapeutic indications of stimulants and anorexigenics?

A

o Exogenous obesity

o Attention deficit hyperactivity disorder (ADHD)

o Narcolepsy

o Fatigue, to restore alertness (caffeine, OTC)

o Cessation of tobacco use (nicotine)

o Local anesthesia (cocaine)

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44
Q

What anti-epileptics are most likely to cause teratogenicity?

A

Phenytoin, carbamazepine, phenobarbital, valproate

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45
Q

What anti-epileptics are most likely to cause hypersensitivity (incl. Stevens-Johnson)?

A

Phenytoin, carbamazepine, phenobarbital, ethosuximide,

lamotrigine

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46
Q

What anti-epileptics are most likely to cause cognitive slowing?

A

Topiramate, phenobarbital, carbamazepine, phenytoin,

valproate

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47
Q

What anti-epileptics are most likely to cause sedation?

A

(almost all AEDs to some extent)

Phenobarbital, clonazepam, gabapentin, lamotrigine

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48
Q

What anti-epileptics are most likely to cause increased seizure activity or seizure induction?

A

Phenytoin, tiagabine

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49
Q

What are some other uses of anti-epileptics?

A

Bipolar disorder

o Valproate, carbamazepine, lamotrigine

Neuropathic pain

o Carbamazepine (trigeminal neuralgia)

o Gabapentin (post-herpetic neuralgia)

Migraine (prophylaxis)

o Topiramate, valproate

Alcoholism

o Topiramate (off-label)

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50
Q

What anti-epileptics are used for bipolar disorder?

A

Valproate, carbamazepine, lamotrigine

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51
Q

What anti-epileptics are used for neuropathic pain?

A

Carbamazepine (trigeminal neuralgia)

Gabapentin (post-herpetic neuralgia)

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52
Q

What anti-epileptics are used for migraine prophylaxis?

A

o Topiramate, valproate

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53
Q

What anti-epileptics are used for alcoholism?

A

Topiramate (off-label)

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54
Q

What occurs in Parkinson’s disease, pharmacologically?

A

Substantia nigra degenerates > striatu, deprived of dopaminergic input > direct pathway not stimulated enough, indirect pathway overly stimulated > inhibition of thalamic drive to the cortex

Ach/DA imbalance

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55
Q

What are the 2 main targets of drugs used to treat Parkinson’s?

A

Increase dopaminergic function (increase synthesis, inhibit degradation, directly stimulate receptors)

Inhibit cholinergic function (block muscarinic receptors)

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56
Q

Levodopa: mechanism, use, PK, adverse effects?

A

Prodrug with little or no intrinsic dopaminergic activity - converted to dopamine vy DOPA decarboxylase

Parkinson’s disease, gold standard (when combined w/peripheral DOPA decarboxylase inhibitor)

Peripheral metabolism to dopamine (by dopa decarboxylase) and to 3-OMD (by COMT), therefore needs to be admin w/carbidopa

Absorbed in SI, high protein meal lowers absorp, in brain increases pool of dopamine stored in remaining nigrostriatal terminals

GI: Nausea and vomiting (80% incidence), ulcer

Cardiovascular: Orthostatic hypotension, arrhythmias

CNS: Dyskinesaias, Response fluctuation. due to “on-off” effect (later in Rx), with frequent, abrupt occurrences of immobility or “end-of-dose” or “wearing-off” effect (after months-years Rx)

Euphoria → hallucinations and psychosis

Contraindicated in Psychosis, narrow angle glaucoma, possibly history or suspicion of malignant melanoma

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57
Q

What is the rationale for administering levodopa versus just dopamine?

A

Dopamine cannot get thru BBB to CNS very well

Dopamine can’t be given orally

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58
Q

Why is levadopa administered with carbidopa?

A

Carbidopa is a peripheral inhibitor of DOPA decarboxylase

Reduces systemic conversion to dopamine > more reaches brain, less peripheral effects

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59
Q

What are the uses of direct dopamine agonists in treating Parkinson’s?

A
  • Monotherapy early in disease progression (when mild)
  • Adjunct to L-DOPA + carbidopa (can help w/response fluctuations)
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60
Q

Pramipexole and ropinirole: mechanism, uses, PK, adverse effects?

A

Selective agonists for the D2 group of DA receptors (mainly D2 & D3) over the D1 group (D1 & D5)

Monotherapy for mild Parkinson’s (&neuroprotective effect?)

Adjunct to L-DOPA in Parkinson’s

Pramipexole clearance is primarily renal.

Ropinirole clearance is primarily hepatic, by CYP1A2 (risk of interaction w/ caffeine, warfarin)

Peripheral: anorexia, N&V; bleeding peptic ulcers, other GI effects; orthostatic hypotension

CNS – more frequent and severe than with L DOPA

  • Hallucinations, delusions; pathologic gambling & other compulsive behaviors; hypersexuality
  • Narcolepsy-like sleep attacks/sedation (esp pramipexole)
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61
Q

Carbidopa: mechanism, uses, adverse effects?

A

Blocks DOPA decarboxylase outside of CNS

Combination therapy with L-DOPA in Parkinson’s:

i) Increases the oral bioavailability of L-DOPA
ii) Decreases DA levels in the systemic circulation
iii) Increases the fraction of L-DOPA in the systemic circulation that reaches the CNS

CNS adverse effects of L-DOPA may occur earlier in therapy because the combination permits more rapid escalation of dose.

62
Q

Apomorphine: mechanism, uses, PK, adverse effects?

A

Non-selective DA agonist, with activity at most DA receptors and some noradrenergic alpha-receptors

Parkinson’s (only “off” periods when other drugs ineffective)

s.c. administration only

Rapid elim into urine, unchanged

Potent emetic (vomiting)

CV: angina, orthostatic HTN, syncope

CNS: somnolence, hallucinations, confusion

63
Q

What is the action of MAO-B inhibitors? What are their uses?

A

Reduce the degradation of dopamine by MAO in the brain

MAO-B metabolizes DA, but not NE or 5HT

-Predominant isoform in the striatum

Parksinson’s - adjuncts to L-DOPA

64
Q

What is a major drug interaction of MAO-B inhibitors?

A

DO NOT use with meperidine (opioid analgesic)

Causes serotonin syndrome

• Includes agitation and delirium, potentially progressing to

hyperpyrexic coma and death

Due to MAO-A inhibition (“selective” does not mean specific)

65
Q

Selegiline: mechanism, uses, adverse effects?

A

Increased DA via inhibition of MAO-B (can activate MAO-A @ high doses)

Monotherapy - early Parksinson’s

Adjunct with L-DOPA

Anxiety, insomnia, confusion (via amphetamines; less in transdermal patch/orally disintegrating tablet)

Do not use with meperidine or SSRIs or > serotonin syndrome (excessive serotoninergic activity; can be fatal, MAO-A effect).

Hypertensive crisis due to interaction w/dietary tyramine (MAO-A effect)

66
Q

Rasagline: mechanism, uses, adverse effects?

A

Increased DA via inhibition of MAO-B (more selective than selegiline)

Monotherapy - early Parksinson’s (neuroprotective?)

Adjunct with L-DOPA

No amphetamine metabolites unlike selegiline

67
Q

How do COMT inhibitors treat Parkinson’s?

A

1) COMT in the periphery up-regulates in response to DOPA

decarboxylase inhibition.

  • Limits the effectiveness of carbidopa as an adjunct to L-DOPA
    2) As COMT activity increases, 3-O-methyldopa accumulates.
  • This metabolite competes with L-DOPA for carriers, including those

in blood-brain barrier.

68
Q

Entacapone: mechanism, uses, PK, adverse effects?

A

Inhibits COMT only in the periphery

L-DOPA adjunct for Parkinson’s

Relatively short duration of action

diarrhea (most common)

CNS: similar to L-DOPA + carbidopa

69
Q

Amantadine: mechanism, uses, adverse effects?

A

Anti-viral drug; mechanism uncertain; possible mech:

o Modulation of DA synthesis, release, reuptake

o Anticholinergic property

o Blockade of NMDA-type glutamate receptor

As monotherapy early Parkinson’s

Later as an adjunct to L-DOPA in Parkinson’s

Confusion, agitation, insomnia, hallucinations

Dermatological reactions, including livedo reticularis

70
Q

What can cause drug-induced Parkinsonism?

A

antipsychotic treatment

-older antipsychotics that strongly block D2 receptors

o Treated with antimuscarinic drugs or amantadine.

o Not drugs that enhance dopaminergic function b/c exacerbate psychosis

Poisoning by MPTP

  • Contaminant produced during synthesis of the designer opioid MPPP
  • Metabolized in brain by MAO-B to MPP+, which is neurotoxic to DA neurons
71
Q

What is the rationale behind anticholinergics used to treat Parkinson’s?

A

Cholinergic interneurons of the striatum:

  • Provide excitatory tone to MSNs of the indirect pathway, via muscarinic receptors
  • Serves to reduce thalamic drive to the cortex
  • Act in opposition to the inhibitory effect of DA acting on D2 receptors

When DA input is reduced in PD:

  • Balance between ACh and DA is tipped in favor of ACh
  • Idea is to restore balance
72
Q

Trihexyphenidyl: mechanism, uses, PK, adverse effects?

A

Muscarinic antagonist

Parkinson’s as dopaminergic drug adjunct

Less commonly used nowadays b/c of adverse effects

high ratio of central to peripheral antimuscarinic activity

  • Peripheral antimuscarinic effects
  • CNS antimuscarinic effects include confusion, memory problems, and hallucinations
  • Contraindicated in patients with closed angle glaucoma
73
Q

What are some of the non-motor Sx of Parkinson’s? How are these treated?

A

o Depression

o Dementia

o Loss of executive function

o Sleep disturbances

o Anxiety

o Bladder and bowel disorders, and anosmia

Target specific Sx

o Centrally acting anticholinesterases for dementia

o Antidepressants

o Anxiolytics

74
Q

What is the pathophysiology of Huntington’s disease?

A

Medium spiny neurons and cholinergic interneurons in striatum (not SN like parkinson’s) die off > excessive excitatory drive to the cortex

75
Q

Tetrabenazine: mechanism, uses, adverse effects?

A

Depletes catecholamines from presynaptic fibers (reduced DA in striatum > reduced excitatory thalamocortical drive)

Motor symptoms (only) of Huntington’s

Depression, suicidal ideation, hypotension, sedation, parkinsonism

76
Q

Botulinum toxin: mechanism, uses?

A

Interferes w/release of ACh @ NMJ

Most effective treatment for spasticity (injected)

Induces transient degeneration of motor neuron; symptoms return as new fibrils grow

77
Q

Dantrolene: mechanism, uses?

A

Interferes with Ca release from SR

Used to treat spasticity

Malignant hyperthermia

78
Q

Baclofen: mechanism, uses?

A

GABA-B agonist (acting on CNS)

  • Dampens corticospinal input to motor neurons
  • Directly inhibits motor neurons

Spasticity

79
Q

Tinzanidine: mechanism, uses?

A

Adrenergic alpha-2 agonist

-Inhibit spinal polysynaptic pathways

Spasticity

80
Q

Secobarbital: class, duration of action?

A

Barbiturate

Intermediate

For PK, clinical uses, adverse effects, see cards on barbiturates in general

81
Q

What do anxiolytic, sedative, and hypnotic mean?

A
  • Anxiolytic: reduces anxiety, causes calm
  • Sedative: induces sedation by reducing irritability or excitement; has calming effect
  • Hypnotic: induces sleep or unconsciousness
82
Q

What are the classes of sedative-hypnotics?

A
  • Benzodiazepines
  • Barbiturates
  • Alcohol
  • Non-benzodiazepine sedative-hypnotics
  • Dexmedetomidine
  • Non-benzodiazepine anxiolytics
83
Q

What are the shared clinical effects of sedative-hypnotics?

A
  • Anti-anxiety/Calming effect; rare disinhibition
  • Sedation
  • Anterograde amnesia
  • Sleep promoting
  • Anesthesia
  • Anticonvulsant
  • Muscle relaxation
  • Effects on respiratory and cardiac function (respiratory depression, CV depression due to medullary effects)
84
Q

What is overdose? How does overdose with benzodiazepines compare with barbiturates?

A

Dose-related CNS depression that can be fatal

Benzodiazepines are considered safer because of flatter dose response curve. Overdoses are rarely fatal if discover ingestion early

With barbiturates, however, a dose as low as 10x the hypnotic dose may be fatal if not discovered in time because there is respiratory and cardiovascular depression with severe toxicity.

85
Q

What is the mechanism of action of sedative-hypnotics?

A

Bind to molecular components of the GABA-A receptor in neuronal membranes in the CNS

. GABA appears to interact at two sites between alpha and beta subunits, triggering chloride channel opening

These drugs bind at a single site between alpha and gamma subunits, facilitating the process of chloride ion channel opening

zolpidem, zaleplon, and eszopiclone bind more selectively only with GABAA-receptor isoforms that contain alpha 1 subunits

(Baclofen activates GABA-B)

86
Q

What are the roles of the alpha 1, 2, 3 and 5 subunits of the GABA-A receptor?

A

α1 subunits: mediate sedation, amnesia and ataxic effects

α2 and α3 subunits: mediate anxiolytic and muscle-relaxing effects

α5 subunits: may be responsible for memory impairment

87
Q

What are the withdrawal sx of sedative-hypnotics?

A

anxiety/agitation,

restlessness,

insomnia,

CNS excitability,

tremor,

hyperactive reflexes,

tachycardia,

elevated BP,

seizure,

delirium;

minimal with newer hypnotics

88
Q

What are the ultra-short acting, intermediate acting, and long acting barbiturates?

A

Ultra Short Acting: thiopental (no longer available in US)

Intermediate Acting: Secobarbital, Butalbital

Long Acting: Phenobarbital

89
Q

What are the pharmacokinetics of barbiturates? (absorption/distribution, metabolism, elimination)

A

Absorption and distribution: rapid (lipophilic)

Metabolism: oxidation to form alcohols, acids and ketones; usually slow process; over the long-term, can get enzyme induction

Elimination: Renal; 20-30% of Phenobarbital excreted unchanged

  • Elimination half life: of phenobarbital is 4-5 days
  • Can increase elimination rate of phenobarbital by alkalinization of urine
90
Q

What are barbiturates used for clinically?

A

 Epilepsy (phenobarbital)

 Anesthesia induction (short-acting; sodium thiopental outside of the U.S.)

 Physician-assisted suicide

 Capital punishment by lethal injection (thiopental +pancuronium + KCl)

 “Truth serum”/Amytal interviews (amobarbital; historical)

 Combination headache remedies (butalbital)

 Induction agent for ECT (methohexital)

Not used frequently in current clinical practice

91
Q

What are the adverse effects of barbiturates and what are the effects of mild-moderate and severe toxicity?

A

ADVERSE EFFECTS: Mild sedation, dizziness, impaired coordination

MILD TO MODERATE TOXICITY: Somnolence, slurred speech, nystagmus, confusion, ataxia

SEVERE TOXICITY: coma, hypotension, decreased myocardial contractility, hypothermia, respiratory failure.

 Exam findings: small to midpoint pupils, diminished reflexes

 Death, when it occurs, is usually due to respiratory depression and cardiovascular collapse

92
Q

Why are barbiturates no longer frequently used in clinical practice?

A

 Hangover

 Rapid tolerance to hypnotic effects

 High risk of drug interactions due to induction of CYP450 enzymes

 Absolute contraindication is patient with porphyria

 Ease of suicide/low margin of safety

 Addiction/Physiological Dependence

 No antidote

 Effects on cardiovascular & autonomic functions

93
Q

How do the mechanisms of action of benzodiazepines and barbiturates differ?

A
  • *Benzodiazepines: **
  • potentiate GABAergic inhibition at all levels of the nervous system.
  • do not substitute for GABA but increase efficiency of GABAergic synaptic inhibition and enhance GABA’s effects allosterically w/o directly activating GABA-A receptors or opening chloride channels.
  • enhancement in chloride ion conductance > increase in the frequency of channel-opening events.

Barbiturates:

  • also facilitate the actions of GABA at multiple sites in the central nervous system
  • increase the duration of the GABA-gated chloride channel openings
  • @ high conc may also be GABA-mimetic, directly activating chloride channels
  • less selective in actions: also depress AMPA receptor & non-synaptic membrane effects
94
Q

What are the uses of benzodiazepines in clinical practice?

A

 Panic disorder, Generalized anxiety disorder, Specific Phobia

 Insomnia (short-term, < 2-4 weeks)

 Epilepsy (emergent treatment of status)

 Alcohol or other sedative-hypnotic withdrawal

 Muscle Spasms/relaxation

 Anesthesia (midazolam)

 Acute agitation/psychiatric emergencies

 Parasomnias (clonazepam)

 Catatonia

 Mania

95
Q

What are the pharmacokinetics of benzodiazepines? (absorption/distribution, metabolism, excretion)

A

oral absorption and distribution varies depending on lipophilicity/lipid solublity and other factors

Hepatic metabolism

  • All except lorazepam, oxazepam and temazepam undergo phase I hepatic metabolism (oxidation; CYP3A4) > drug interactions
  • Many phase 1 metabolites are pharmacologically active with long half lives
  • Metabolites of alprazolam are rapidly conjugated to form inactive glucuronides so short half lives
  • In hepatic disease use lorazepam, oxazepam, or temazepam b/c no phase 1 hepatic metabolism

Renal excretion

96
Q

Butalbital: class, duration of action, specific clinical use(s)?

A

Barbiturate

Intermediate

Combination headache rememdies

For PK, clinical uses, adverse effects, see cards on barbiturates in general

97
Q

Midazolam: class, duration of action, specific clinical use, metabolism?

A

Benzodiazepine

Short acting

Anesthesia

Undergoes phase I hepatic metabolism: DON’T use in hepatic disease

For PK, clinical uses, adverse effects, see cards on benzodiazepines in general

98
Q

Alprazolam: class, duration of action, metabolism?

A

Benzodiazepine

Intermediate acting

Undergoes phase I hepatic metabolism: DON’T use in hepatic disease

Short metabolite half life

For PK, clinical uses, adverse effects, see cards on benzodiazepines in general

99
Q

Lorazepam: class, duration of action, specific clinical use(s), metabolism, other effects?

A

Benzodiazepine

Intermediate acting

Alcohol withdrawal if poor hepatic function

Does not undergo phase I hepatic metabolism: can use in hepatic disease

Short half-life (metabolized directly to inactive glucuronides)

Cumulative and residual effects such as excessive drowsiness appear to be less of a problem

For PK, clinical uses, adverse effects, see cards on benzodiazepines in general

100
Q

Clonazepam: class, duration of action, specific clinical use(s), metabolism?

A

Benzodiazepine

Long acting

Parasomnias, seizures (see epilepsy card for more details)

Undergoes phase I hepatic metabolism: DON’T use in hepatic disease

For PK, clinical uses, adverse effects, see cards on benzodiazepines in general

101
Q

Diazepam: class, duration of action, specific clinical uses, metabolism?

A

Benzodiazepine

Long acting

Alcohol withdrawal

Undergoes phase I hepatic metabolism: DON’T use in hepatic disease

For PK, clinical uses, adverse effects, see cards on benzodiazepines in general

102
Q

How does the elimination half life of the parent drug benzodiazepine affect time course of pharmacologic effects?

A

may have little relation to the time course of pharmacologic effects because of the formation of active metabolites.

103
Q

What are the advantages of benzodiazepines?

A

 Rapid onset of action

 Relatively high therapeutic index

 Availability of flumazenil for treatment of overdose

 Low risk of drug interactions based on liver enzyme induction

 Minimal effects on cardiovascular or autonomic functions.

104
Q

What are the adverse effects of benzodiazepines?

A

 Drowsiness

 Falls

 Disinhibition

 Impaired judgment

 Confusion

 Anterograde amnesia

 Impaired motor skills

 Respiratory depression

 Cardiovascular depression

 Misuse/Abuse/Dependence

 Additive CNS depression with ethanol and many other drugs

 Hangover

 Life-threatening withdrawal syndrome

105
Q

What are symptoms of benzodiazepine toxicity/poisoning?

A

 Ataxia

 Slurred Speech

 Somnolence

 Diplopia

 Hallucinations

 Respiratory depression, hypoxemia

 Hypotension

 Aspiration

 Coma

 Death

106
Q

Flumazenil: class, mechanism of action, uses, adverse effects?

A

Synthetic benzodiazepine derivative

Competitive antagonist at benzodiazepine binding site on GABA-A receptor

  • Blocks actions of benzodiazepines and newer hypnotics BUT NOT barbiturates or ethanol
  • Used to reverse CNS depressant effects of benzodiazepine overdose and to hasten recovery after use of these drugs in procedures
  • Reverses sedative effects but less reliably reverses the respiratory depression

agitation, confusion, dizziness, nausea; can get seizures and cardiac arrhythmias if pt has ingested benzo + tricycle antidepressant or if patient benzo dependent

107
Q

What effects should a general anesthetic have?

A

Amnesia

Analgesia (to avoid pain reflexes)

Muscle relaxation

Loss of autonomic responses to noxious stimuli

Loss of consciousness

-Monitored by EEG

108
Q

What are the groups of drugs that can induce anesthesia?

A

Inhalation anesthetics

Intravenous anesthetics

Sedative-hypnotics

-Barbiturates (Thiopental formerly was most widely used induction agent)

Ethanol

-Historical use

109
Q

What is balanced anesthesia?

A

The use of a combination of drugs to produce the effects of an “ideal anesthetic”

Allows for lower doses of the anesthetic, since desirable effects that would be produced only at high anesthetic doses are provided by other drugs (adjuncts).

110
Q

Nitrous oxide: class, induction rate, adverse effects

A

Inhalation anesthetic

Low blood solubility > rapid induction

Replaces nitrogen (displaces)

Molecules of nitrous moves in at a much higher rate than nitrogen moves out; thus in trapped air spaces, pressure increases

Diffusion hypoxia

When nitrous is turned off, it floods the alveoli as it moves out of the body

Oxygen becomes diluted; need to terminate with 100% oxygen, not with room air

-Almost devoid of CV effects

111
Q

Isoflurane: class, induction, adverse

A

Inhalation anesthetic

High blood solubility > slow induction

Lower MAP, SVR, increase HR, lower BP, decrease renal blood flow and GFR

dose-dependent depression of spontaneous respiration.; decrease the normal ventilatory response to CO2

Malignant hyperthermia when used with succinylcholine

112
Q

Desflurane: class, adverse

A

Inhalation anesthetic

lower MAP, SVR, can raise HR, lower BP, decrease renal blood flow and GFR

dose-dependent depression of spontaneous respiration.; decrease the normal ventilatory response to CO2

Malignant hyperthermia when used with succinylcholine

113
Q

What is the hypothesized mechanism of action of inhalation anesthetics?

A

Current thinking is that inhalation anesthetics interact specifically with membrane proteins, including ion channels, to affect synaptic transmission.

Hypothesized mechanisms include:

-Enhancement of inhibitory ligand-gated channels

>GABAA receptors in the brain; glycine receptors in the spinal cord

-Inhibition of excitatory ligand-gated receptor-channels

>AMPA-type and NMDA-type glutamate receptors

>Nicotinic acetylcholine receptors

114
Q

How are inhalation anesthetics dosed?

A

Partial pressures (can be expressed as % of atmospheric pressure)

Vapor pressure = maximum partial pressure that is available for a volatile agent

Give as a multiple of the MAC

115
Q

What is the minimal alveolar concentration (MAC)? How is it determined?

A

Reference dose; essentially a population EC50

Subjects are administered the drug at various partial pressures.

Administration lasts long enough to ensure steady state, so inspired concentration = alveolar concentration

For each subject, the minimum concentration required to suppress movement in response to an incision is determined.

The drug’s MAC is the median value for this minimum concentration.

Expressed as % total pressure

Dose given as multiples of MAC - little individual variation so at 1.2x MAC 99% patients have movement suppressed

116
Q

How are MAC multiples combined with multiple inhalation anesthetics?

A

MAC multiples are additive (1x MAC and 2x MAC agents is 3x MAC combined)

117
Q

What predicts inhalation anesthetic potency? How does it relate to MAC?

A

Lipid solubility

Direct correlation between the drug’s oil:gas partition coefficient and its anesthetic potency

The greater the oil solubility, the lower the MAC

118
Q

What determines the movement of anesthetic btwn compartments?

A

relative partial pressure in each compartment

119
Q

How does the solubility of an inhalation anesthetic affect partial pressure?

A

The more soluble the drug in blood, the more molecules are needed to increase partial pressure.

120
Q

What is the relation between inhalation anesthetic solubility and induction?

A

drugs that are relatively soluble in blood induce more slowly

121
Q

Sevoflurane: class, adverse

A

Inhalation anesthetic

Lower MAP, SVR, CO, lower BP, decrease renal blood flow and GFR

dose-dependent depression of spontaneous respiration.; decrease the normal ventilatory response to CO2

Malignant hyperthermia when used with succinylcholine

122
Q

What is the effect of ventilation on induction rate?

A

Increased ventilation speeds induction

Effect is larger for anesthetics with high blood solubility

123
Q

What affects the rate of recovery from inhalation anesthetics?

A

Just as with induction, recovery is fastest for drugs with relative low blood solubility.

124
Q

What are the MAC multiples for maintenance and induction?

A

Anesthesia is typically maintained at 1.3-1.4 x MAC.

-This narrow range is possible because there is so little inter-patient variabilty in the dose-effect relationship.

If an inhalation anesthetic is used as a sole agent to induce anesthesia, a higher MAC multiple is used.

  • The purpose is to increase partial pressure in the blood more quickly, so it equilibrates with the inspired gas.
  • The MAC multiple for induction is highest for drugs with relatively high blood solubility (3-4 x MAC).
125
Q

What is the second gas effect?

A

Occurs with nitrous oxide

During induction, as nitrous leaves the alveoli, it creates a partial vacuum which passively increases the ventilation rate.

Any other inhalation anesthetic that is co-administered with nitrous will benefit from this increase in delivery by equilibrating more rapidly (the “second gas effect”).

Effect is greatest for drugs with high blood and tissue solubility

126
Q

What drug interactions do inhalation anesthetics have?

A

Inhalation anesthetics have some intrinsic muscle-relaxing activity (a consequence of membrane stabilization).

Lower doses of neuromuscular blockers are required in in the presence of these anesthetics.

127
Q

How are inhalation anesthetics eliminated?

A

The primary route of elimination for most inhalation anesthetics is the lung.

Metabolism is minimal:

  • Desflurane and nitrous – virtually no metabolism
  • Isoflurane < 1%, sevoflurane 5% or less
128
Q

How is malignant hyperthermia from inhalation anesthetics treated?

A

dantrolene

Interferes with the release of calcium from the sarcoplasmic reticulum via the ryanodine receptor.

129
Q

What are the effects of nitrous oxide long term abuse?

A

Bone marrow depression and neuropathy

Due to B12 deficiency, a consequence of oxidation of cobalt in B12

130
Q

Propofol: class, mechanism, uses, systemic (incl adverse) effects, PK,

A

IV anesthetic

Potentiates GABAA currents

Surgical anesthesia within 1 minute

It is the most widely used induction agent, but Not analgesic

Decreases BP more than any other induction agent

Caused by vasodilation

Respiratory depression

Relatively little nausea & vomiting

Is antiemetic at sub-anesthetic doses

Pain on injection (used with local anesthetic)

Rapidly metabolized by glucuronidation (a Phase II reaction)

After a bolus, recovery is manly due to redistribution (next slide)

Rapid phase (a):Distribution to poorly-perfused tissue, including fat

Slow phase (b): Elimination by hepatic metabolism

131
Q

Why does propofol recovery time increases with duration of administration?

A

After a bolus injection, the distribution component is quantitatively more important than elimination.

During infusion, drug accumulates in the poorly perfused tissues.

When the drug is terminated, distribution to poorly perfused tissue is quantitatively less important, and the decline in plasma (and brain) concentration depends more on the slower elimination component.

The context-sensitive half-life is the additional time required for plasma concentration to drop by 50% after an infusion.

132
Q

Etomidate: class, mechanism, effects (incl adverse)

A

IV anesthetic

enhances GABAA signaling

Like propofol, not analgesic

Reduces myocardial O2 consumption

Unlike propofol, minimal decreases in BP, HR, CO

Better for patients at risk of hypotension

Nausea and vomiting

Painful on injection (like propofol); local anesthetic used

133
Q

Ketamine: class, mechanism, effects (incl. adverse), PK, abuse?

A

IV anesthetic

Blocks NMDA receptors

Analgesic even at sub-anesthetic concentrations

Produces a “dissociative anesthesia”

  • Cataleptic state; patient’s eyes remain open; slow nystagmus
  • Unpleasant emergence symptoms (hallucinations)

Increases heart rate and blood pressure

Bronchodilation

No significant respiratory depression

Increases muscle tone

Can be administered i.v., i.m., oral, rectal, epidural

Clearance is predominantly hepatic

Related to phencyclidine (PCP; angel dust)

Also subject to abuse as a hallucinogen (Special K)

134
Q

Zolpidem: class, mechanism, PK, uses, adverse effects

A

Non-Benzodiazepine (Newer) Hypnotics

bind to the benzodiazepine site at the GABA-A receptor more selectively (interact only with GABAA-receptor isoforms w/ alpha 1 subunits)

Rapid absorption and distribution > rapid onset of action

Rapid hepatic metabolism; includes oxidation (CYP3A4); inactive metabolites

Renal excretion

Elimination Half life 1.5-3.5 hrs

Insomnia (Ambien)

Similar to benzodiazepines; most concern: include next-morning impairment and abnormal nocturnal behavior

decreases REM sleep but has minimal effect on slow-wave sleep

135
Q

What are the effects of Benzodiazepines and Barbiturates on sleep?

A

 All induce sleep if high enough doses are given.

 Decrease latency of sleep onset

 Increase duration of stage 2 NREM sleep

 Decrease duration of REM sleep

 Decrease duration of stage 4 NREM slow-wave sleep

136
Q

Buspirone: class, mechanism, pros/cons, uses, PK, adverse effects?

A

Sedative-hypnotic

Mechanism: Partial agonist at brain 5-HT1A receptors

Pro: No rebound anxiety or withdrawal symptoms, minimal abuse liability

Con: Anxiolytic effects may take more than a week to occur

Clinical use: in Generalized Anxiety Disorder

PK: Extensive first-pass metabolism to form several active metabolites; cyp3A4 inhibitors can increase its levels; Elimination half-life is 2–4 hours

Side effects: chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction

137
Q

Dexmedetomidine: class, mechanism, pros/cons, use, admin, adverse effects?

A

Sedative hypnotic

Mechanism: Alpha2 adrenergic receptor agonist; produces sedation by reducing sympathetic activity and the level of arousal

Pros: Sedative, hypnotic, analgesic, sympatholytic & anxiolytic effect without respiratory depression

Cons: expensive; need to use caution in patients with advanced heart block and/o severe ventricular dysfunction

Clinical Use: Sedation in nonintubated patients prior to and during surgical and other procedures and in intubated, vented patients during treatment in ICU

Administration: by continuous infusion, usually for <24 hrs

Adverse Effects: bradycardia, hypotension, sinus arrest

138
Q

What are some ways to ensure safe use of sedative-hypnotics?

A

 Start with a low dose, and maintain at lowest effective dose

 Avoid continued nightly use

 Avoid using for more than 2-4 weeks if possible

 Allow for at least 8 hours of sleep

 Be aware that impairment can be present despite feeling awake

 If can’t fall asleep, use hypnotic with rapid onset of action

 If can’t stay asleep, use hypnotic with slower elimination rate

 If depressed, use antidepressant with sedative properties

 Never mix with alcohol

 Minimize use in: pregnant patients, those with substance use disorders, liver disease, cardiovascular/pulm disease

 Avoid benzodiazepines in patients with sleep apnea

 Use lower doses in elderly patients

 Taper off if patient abuses/misuses

139
Q

Are sedative hypnotics safe to use in pregnancy?

A

 All cross placental barrier

 Controversy of whether benzodiazepines cause cleft palate and long-term neurobehavioral effects

 May cause respiratory depression, lethargy, hypotonia, and withdrawal in newborn

 Detectable in breast milk and may cause sedation in nursing infant

140
Q

What are PK features of ethanol (absorption, peak BAC, distribution, metabolism, excretion

A

 Absorbed rapidly from GI tract.

 Peak blood alcohol concentrations within 30 minutes if fasting.

 Rapid distribution

 Women have higher peak conc.

 Concentration in CNS rises quickly

 Over 90% of alcohol consumed is oxidized in the liver; much of the remainder is excreted through the lungs and in the urine.

 Rate of oxidation follows zero-order kinetics- it is independent of time and concentration of the drug.

 Typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour (about 1 drink)

141
Q

What is the primary pathway of alcohol metabolism?

A

Alcohol dehydrogenase (mainly in liver but small amounts in other organs)

142
Q

What is the secondary pathway of alcohol metabolism?

A

microsomal ethanol-oxidizing system (MEOS) - consists of cytochromes

Induced with chronic alcoholism

143
Q

How is acetaldehyde formed from ethanol metabolized?

A

in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase

144
Q

Disulfiram: mechanism, uses, effects, adverse effects?

A

Inhibits oxidation of acetaldehyde

deter drinking by patients with alcohol dependence

in presence of alcohol, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache (short term)

 Inhibits metabolism of many drugs

 Can cause small increases in liver function tests.

 Poor adherence, weak efficacy

145
Q

What is the mechanism of action of alcohol in the CNS?

A

Ethanol affects a large number of membrane proteins that participate in signaling pathways.

enhances the action of GABA at GABA-A receptors.

inhibits the ability of glutamate to open the cation channel associated with the NMDA subtype of glutamate receptors.

146
Q

What are the acute effects of ethanol on heart, smooth m, and GI?

A

 Heart: Significant depression of myocardial contractility; tachycardia

 Smooth Muscle: Ethanol is a vasodilator; can lead to hypothermia and uterine relaxation

 Gastrointestional: irritation, nausea, vomiting

147
Q

What are the chronic effects of alcohol on liver, GI, cardiovascular, endocrine, immune system?

A

Liver: alcoholic fatty liver disease, hepatitis, cirrhosis, liver failure

GI: chronic pancreatitis, gastritis, injury to small intestine, malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption

CV: Dilated cardiomyopathy and heart failure, arrhythmias, hypertension and coronary artery disease

endo: gynecomastia and testicular atrophy

Immune: immune function in some tissues is inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (eg, liver, pancreas)

148
Q

What are the CNS effects of chronic alcohol use?

A

Tolerance and Dependence:

 Withdrawal: hyperexcitability, seizures, toxic psychosis, and delirium tremens

 Up-regulation of NMDA glutamate receptors and voltage-sensitive Ca2+ channels may underlie the seizures that accompany alcohol withdrawal

 Changes in GABA neurotransmission

 Modulates neural activity in the mesolimbic dopamine reward circuit and increases dopamine release in the nucleus accumbens

Neurotoxicity

 Generalized symmetric peripheral nerve injury

 Cerebellar toxicity: Gait disturbances and ataxia.

 Dementia

Wernicke-Korsakoff syndrome

 Paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death

 Associated with thiamine deficiency

 Most left with a chronic disabling memory disorder known as Korsakoff’s psychosis.

Impaired visual acuity, optic nerve degeneration.

149
Q

What drug interactions does alcohol have?

A

Pharmacokinetic:

o Chronic > hepatic cyt p450 enzymes > enhanced metabolic biotransformation of other drugs.

o Acute > inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow.

Pharmacodynamic Effects:

o Additive CNS depression when alcohol is combined with other CNS depressants, particularly sedative-hypnotics

o Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents.

150
Q

What are the features of alcohol withdrawal?

A
151
Q

Naltrexone: class, use, adverse effects?

A

 Long-acting opioid antagonist

 reduce the rate of relapse to drinking or alcohol dependence and to reduce craving

 Adverse effects: hepatotoxicity

 Avoid combination of naltrexone plus disulfiram

 Do not give to patients on opioids

152
Q

Acamprosate: mechanism, use, PK, adverse effects?

A

 Many molecular effects including actions on multiple neurotransmitter receptors

 Weak NMDA-receptor antagonist and GABA-A-receptor activator.

Adjunctive treatment of alcohol dependence

 1–2 enteric-coated 333 mg tablets three times daily

 Poorly absorbed, food reduces its absorption

 Renal elimination (avoid if severe renal impairment)

 No drug-drug interactions

 Adverse effects: gastrointestinal (nausea, vomiting, diarrhea) and rash

Brain and Behavior (9 decks)

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