Exam 3 - Pharmacology Flashcards
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
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)
3
Q
What are the pros of broad spectrum anti-epileptics?
A
- Effective in partial seizures
- Effective in generalized seizures (primary or secondary)
4
Q
What are the narrow spectrum antiepileptics we learned about?
A
Carbamezapine
Phenytoin
Phenobarbital
Gabapentin
Tiagabine
5
Q
What are the broad spectrum antiepileptics we learned about?
A
Valproate
Topiramate
Lamotrigine
Clonazepam
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
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
8
Q
Which anti-epileptics inhibit voltage gated Na channels?
A
Carbamazepine
Phenytoin
Valproate
Lamotrigine
Topiramate
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
10
Q
What anti-epileptics inhibit T-type Ca channels?
A
Ethosuximide
Valproate (also blocks Na channels)
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
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
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
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
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
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
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)
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
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)
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)
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
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)
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
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)
25
What anti-epileptics are CYP450 inducers?
Phenytoin
Carbamazepine:
Phenobarbital
All 3 are substrates for 3A4
26
How can anti-epileptics cause Stevens-Johnson syndrome?
Interaction between lamotrigine and valproate (compete for Phase II enzyme \> decreased clearance)
27
What are some drug interactions among anti-epileptics & what do they cause?
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)
28
What are some of the adverse effects of anti-epileptics?
Teratogenic
Hypersensitivity (including Stevens-Johnson syndrome)
Cognitive slowing
Sedation (almost all, to some extent)
Increased seizure activity/seizure induction
Suicidal thoughts/behaviors
29
Cocaine: mechanism, therapeutic, effects, PK, addiction, adverse effects?
- 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
30
Amphetamine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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
31
Methamphetamine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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
32
Methylphenidate: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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?)
33
Phentermine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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
34
Modafinil: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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
35
Caffeine: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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
36
Nicotine: class, mechanism, therapeutic, CNS & peripheral effects, addiction, adverse effects?
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.
37
Synthetic cathinones: class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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).
38
Lysergic acid diethylamide (LSD): class, mechanism, therapeutic, effects, PK, addiction, adverse effects?
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.
39
Phencyclidine (PCP, angel dust): class, mechanism, effects, addiction, adverse effects?
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
40
delta-9-tetrahydrocannabinol (THC; marijuana): class, mechanism, effects incl adverse, PK, addiction?
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.
41
Dronabinol: class, mechanism, therapeutic?
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
42
3,4-methylenedioxyamphetamine (MDMA; ecstasy): class, mechanism, effects, PK, addiction, adverse effects?
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
43
What are the therapeutic indications of stimulants and anorexigenics?
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)
44
What anti-epileptics are most likely to cause teratogenicity?
Phenytoin, carbamazepine, phenobarbital, valproate
45
What anti-epileptics are most likely to cause hypersensitivity (incl. Stevens-Johnson)?
Phenytoin, carbamazepine, phenobarbital, ethosuximide,
lamotrigine
46
What anti-epileptics are most likely to cause cognitive slowing?
Topiramate, phenobarbital, carbamazepine, phenytoin,
valproate
47
What anti-epileptics are most likely to cause sedation?
(almost all AEDs to some extent)
Phenobarbital, clonazepam, gabapentin, lamotrigine
48
What anti-epileptics are most likely to cause increased seizure activity or seizure induction?
Phenytoin, tiagabine
49
What are some other uses of anti-epileptics?
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)
50
What anti-epileptics are used for bipolar disorder?
Valproate, carbamazepine, lamotrigine
51
What anti-epileptics are used for neuropathic pain?
Carbamazepine (trigeminal neuralgia)
Gabapentin (post-herpetic neuralgia)
52
What anti-epileptics are used for migraine prophylaxis?
o Topiramate, valproate
53
What anti-epileptics are used for alcoholism?
Topiramate (off-label)
54
What occurs in Parkinson's disease, pharmacologically?
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
55
What are the 2 main targets of drugs used to treat Parkinson's?
Increase dopaminergic function (increase synthesis, inhibit degradation, directly stimulate receptors)
Inhibit cholinergic function (block muscarinic receptors)
56
Levodopa: mechanism, use, PK, adverse effects?
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
57
What is the rationale for administering levodopa versus just dopamine?
Dopamine cannot get thru BBB to CNS very well
Dopamine can't be given orally
58
Why is levadopa administered with carbidopa?
Carbidopa is a peripheral inhibitor of DOPA decarboxylase
Reduces systemic conversion to dopamine \> more reaches brain, less peripheral effects
59
What are the uses of direct dopamine agonists in treating Parkinson's?
- Monotherapy early in disease progression (when mild)
- Adjunct to L-DOPA + carbidopa (can help w/response fluctuations)
60
Pramipexole and ropinirole: mechanism, uses, PK, adverse effects?
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)
61
Carbidopa: mechanism, uses, adverse effects?
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
Apomorphine: mechanism, uses, PK, adverse effects?
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
What is the action of MAO-B inhibitors? What are their uses?
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
What is a major drug interaction of MAO-B inhibitors?
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
Selegiline: mechanism, uses, adverse effects?
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
Rasagline: mechanism, uses, adverse effects?
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
How do COMT inhibitors treat Parkinson's?
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
Entacapone: mechanism, uses, PK, adverse effects?
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
Amantadine: mechanism, uses, adverse effects?
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
What can cause drug-induced Parkinsonism?
**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
What is the rationale behind anticholinergics used to treat Parkinson's?
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
Trihexyphenidyl: mechanism, uses, PK, adverse effects?
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
What are some of the non-motor Sx of Parkinson's? How are these treated?
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
What is the pathophysiology of Huntington's disease?
Medium spiny neurons and cholinergic interneurons in striatum (not SN like parkinson's) die off \> excessive excitatory drive to the cortex
75
Tetrabenazine: mechanism, uses, adverse effects?
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
Botulinum toxin: mechanism, uses?
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
Dantrolene: mechanism, uses?
Interferes with Ca release from SR
Used to treat spasticity
Malignant hyperthermia
78
Baclofen: mechanism, uses?
GABA-B agonist (acting on CNS)
- Dampens corticospinal input to motor neurons
- Directly inhibits motor neurons
Spasticity
79
Tinzanidine: mechanism, uses?
Adrenergic alpha-2 agonist
-Inhibit spinal polysynaptic pathways
Spasticity
80
Secobarbital: class, duration of action?
Barbiturate
Intermediate
For PK, clinical uses, adverse effects, see cards on barbiturates in general
81
What do anxiolytic, sedative, and hypnotic mean?
* Anxiolytic: reduces anxiety, causes calm
* Sedative: induces sedation by reducing irritability or excitement; has calming effect
* Hypnotic: induces sleep or unconsciousness
82
What are the classes of sedative-hypnotics?
* Benzodiazepines
* Barbiturates
* Alcohol
* Non-benzodiazepine sedative-hypnotics
* Dexmedetomidine
* Non-benzodiazepine anxiolytics
83
What are the shared clinical effects of sedative-hypnotics?
* 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
What is overdose? How does overdose with benzodiazepines compare with barbiturates?
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
What is the mechanism of action of sedative-hypnotics?
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
What are the roles of the alpha 1, 2, 3 and 5 subunits of the GABA-A receptor?
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
What are the withdrawal sx of sedative-hypnotics?
anxiety/agitation,
restlessness,
insomnia,
CNS excitability,
tremor,
hyperactive reflexes,
tachycardia,
elevated BP,
seizure,
delirium;
minimal with newer hypnotics
88
What are the ultra-short acting, intermediate acting, and long acting barbiturates?
Ultra Short Acting: thiopental (no longer available in US)
Intermediate Acting: Secobarbital, Butalbital
Long Acting: Phenobarbital
89
What are the pharmacokinetics of barbiturates? (absorption/distribution, metabolism, elimination)
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
What are barbiturates used for clinically?
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
What are the adverse effects of barbiturates and what are the effects of mild-moderate and severe toxicity?
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
Why are barbiturates no longer frequently used in clinical practice?
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
How do the mechanisms of action of benzodiazepines and barbiturates differ?
* *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
What are the uses of benzodiazepines in clinical practice?
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
What are the pharmacokinetics of benzodiazepines? (absorption/distribution, metabolism, excretion)
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
Butalbital: class, duration of action, specific clinical use(s)?
Barbiturate
Intermediate
Combination headache rememdies
For PK, clinical uses, adverse effects, see cards on barbiturates in general
97
Midazolam: class, duration of action, specific clinical use, metabolism?
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
Alprazolam: class, duration of action, metabolism?
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
Lorazepam: class, duration of action, specific clinical use(s), metabolism, other effects?
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
Clonazepam: class, duration of action, specific clinical use(s), metabolism?
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
Diazepam: class, duration of action, specific clinical uses, metabolism?
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
How does the elimination half life of the parent drug benzodiazepine affect time course of pharmacologic effects?
may have little relation to the time course of pharmacologic effects because of the formation of active metabolites.
103
What are the advantages of benzodiazepines?
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
What are the adverse effects of benzodiazepines?
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
What are symptoms of benzodiazepine toxicity/poisoning?
Ataxia
Slurred Speech
Somnolence
Diplopia
Hallucinations
Respiratory depression, hypoxemia
Hypotension
Aspiration
Coma
Death
106
Flumazenil: class, mechanism of action, uses, adverse effects?
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
What effects should a general anesthetic have?
Amnesia
Analgesia (to avoid pain reflexes)
Muscle relaxation
Loss of autonomic responses to noxious stimuli
Loss of consciousness
-Monitored by EEG
108
What are the groups of drugs that can induce anesthesia?
Inhalation anesthetics
Intravenous anesthetics
Sedative-hypnotics
-Barbiturates (Thiopental formerly was most widely used induction agent)
Ethanol
-Historical use
109
What is balanced anesthesia?
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
Nitrous oxide: class, induction rate, adverse effects
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
Isoflurane: class, induction, adverse
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
Desflurane: class, adverse
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
What is the hypothesized mechanism of action of inhalation anesthetics?
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
How are inhalation anesthetics dosed?
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
What is the minimal alveolar concentration (MAC)? How is it determined?
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
How are MAC multiples combined with multiple inhalation anesthetics?
MAC multiples are additive (1x MAC and 2x MAC agents is 3x MAC combined)
117
What predicts inhalation anesthetic potency? How does it relate to MAC?
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
What determines the movement of anesthetic btwn compartments?
relative partial pressure in each compartment
119
How does the solubility of an inhalation anesthetic affect partial pressure?
The more soluble the drug in blood, the more molecules are needed to increase partial pressure.
120
What is the relation between inhalation anesthetic solubility and induction?
drugs that are relatively soluble in blood induce more slowly
121
Sevoflurane: class, adverse
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
What is the effect of ventilation on induction rate?
Increased ventilation speeds induction
Effect is larger for anesthetics with high blood solubility
123
What affects the rate of recovery from inhalation anesthetics?
Just as with induction, recovery is fastest for drugs with relative low blood solubility.
124
What are the MAC multiples for maintenance and induction?
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
What is the second gas effect?
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
What drug interactions do inhalation anesthetics have?
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
How are inhalation anesthetics eliminated?
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
How is malignant hyperthermia from inhalation anesthetics treated?
dantrolene
Interferes with the release of calcium from the sarcoplasmic reticulum via the ryanodine receptor.
129
What are the effects of nitrous oxide long term abuse?
Bone marrow depression and neuropathy
Due to B12 deficiency, a consequence of oxidation of cobalt in B12
130
Propofol: class, mechanism, uses, systemic (incl adverse) effects, PK,
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
Why does propofol recovery time increases with duration of administration?
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
Etomidate: class, mechanism, effects (incl adverse)
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
Ketamine: class, mechanism, effects (incl. adverse), PK, abuse?
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
Zolpidem: class, mechanism, PK, uses, adverse effects
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
What are the effects of Benzodiazepines and Barbiturates on sleep?
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
Buspirone: class, mechanism, pros/cons, uses, PK, adverse effects?
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
Dexmedetomidine: class, mechanism, pros/cons, use, admin, adverse effects?
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
What are some ways to ensure safe use of sedative-hypnotics?
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
Are sedative hypnotics safe to use in pregnancy?
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
What are PK features of ethanol (absorption, peak BAC, distribution, metabolism, excretion
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
What is the primary pathway of alcohol metabolism?
Alcohol dehydrogenase (mainly in liver but small amounts in other organs)
142
What is the secondary pathway of alcohol metabolism?
microsomal ethanol-oxidizing system (MEOS) - consists of cytochromes
Induced with chronic alcoholism
143
How is acetaldehyde formed from ethanol metabolized?
in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase
144
Disulfiram: mechanism, uses, effects, adverse effects?
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
What is the mechanism of action of alcohol in the CNS?
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
What are the acute effects of ethanol on heart, smooth m, and GI?
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
What are the chronic effects of alcohol on liver, GI, cardiovascular, endocrine, immune system?
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
What are the CNS effects of chronic alcohol use?
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
What drug interactions does alcohol have?
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
What are the features of alcohol withdrawal?
151
Naltrexone: class, use, adverse effects?
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
Acamprosate: mechanism, use, PK, adverse effects?
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
