Transcript Neuro Pharm Review - UNC School of Medicine

Neuro Pharm Review
John Reed
How does a local anasthetic work?
• At normal usage [] Na+ channels are
blocked on pain fiber neurons
What are the properties of an ideal
local anesthetic?
• 1. Action must be reversible
• 2. Non-irritating to the tissues and no secondary
local action
• 3. Low degree of systemic toxicity (since LA will
eventually distribute from site of administration
to other tissues)
• 4. Rapid onset and sufficient duration of action
for the procedure
• Are local anesthetics (LAs) mainly acids or
bases?
• Bases (pKa 7.6 to 9.0) with 56 to 98%
ionization
• Do the free bases or cations cross
membranes?
• Unionized free bases preferentially cross
cell membranes, while cations get stuck in
the channels
•
•
•
•
•
•
Which LAs have ester (COOC) linkages?
Cocaine, benzocaine, procaine, tetracaine
Which LAs have amide (CNCO) linkages?
Lidocaine, etidocaine, mepivocaine, bupivocaine
Where is the base binding site?
It is just exterior to the activation gate in Na+ ion
channels
• How do the bases get to this area?
• They either flow through the membrane and up
through an open inactivation gate or directly
through the membrane and protein channel as
free base that then links with available H+
• Which nerve fibers are most sensitive to LAs?
• The narrowest diameter (unmyelinated) fibers (C
(pain)>B>Aδ (pain and temp)>Aα (proprioception
motor)) are the most sensitive
• What is the order of recovery from LA nerve
block?
• The reverse, thickest fibers recover first
• What is the most important factor in determining
potency of a LA?
• Lipid solubility –
procaine<lidocaine,mepivacaine<tetracaine,
bupivocaine, etidocaine
• What is the effect of tissue inflammation
on LA action?
• Inflamed tissue has a lower pH, leading to
less free base formation and migration into
nerve endings and thus, slower action
• Do amides or esters have the longer half
lives?
• Amides have much longer half lives since
they have to be transported to the liver for
metabolism whereas esters are broken
down in the plasma
Where should LAs be injected to
acquire certain areas of blockage?
• Epidural – somewhat
wide area
• Subarachnoid space –
very wide area
• Nerve trunk – regional
block
• Local – infiltration, subcut
at area to be numbed
• Surface or topical – apply
directly to mucous
membranes
• Why are vasoconstrictors often coadministered
with LAs?
• They restrict the site and prolong the duration of
action of the LA
• Which LAs are broken down rapidly in blood and
therefor remain local?
• Esters
• How are amides distributed?
• They remain intact in the blood and are rapidly
distributed to highly perfused tissue (like brain
and heart) and then redistributed into fat
• Where are the LAs metabolised?
• Esters in the plasma by pseudoChE and amides
in the liver by microsomal esterase
• What are the first side effects from LAs?
• CNS effects, then cardiovascular
• What are the CNS side effects of LAs?
– First drowsiness, lightheadedness, visual
disturbances and restlessness
– Then nystagmus and shivering
– Finally convulsions, paralysis of ventilatory
muscles and death
• Which general anesthetic (GA) has
minimal cardiac effects?
• N2O (nitrous oxide)
• What GAs cause some cardiac
depression?
• Enflurane, isoflurane, desflurane (don’t
use in patients with COPD, is a lung
irritant), sevoflurane (used in peds due to
less pungent odor)
• What GA causes significant cardiac
depression?
• Halothane (bradycardia, ↓ CTY, ↓ SVR)
• How do GAs work?
• They seem to bind directly to GABA Clchannels and do NOT work by sticking in
membranes and disrupting ion channels
(Meyer-Overton principle)
• What is the relationship between blood solubility
and induction rate in an inhaled GA?
• Inverse, lower solubility → higher induction rate
(= faster rise in arterial tension)
• How are ventilation rate and depth related to
induction rate for an inhaled GA?
• Direct relationship so ↑ RR and depth or
respiration → ↑ induction rate
• What is the relationship between pulmonary
blood flow and induction rate?
• Inverse, ↑ blood flow = ↓ induction rate (more
blood flow means more anesthesia going away
from the brain)
• What are the major and minor routes of
metabolism and elimination in GAs?
• Exhalation is the major route and
liver/kidney metabolism are minor routes
(except in mthoxyflurane and halothane)
• Which GA causes hepatotoxicity?
• Halothane, 1 in 30000 get severe hepatitis
• Which GA leads to nephrotoxicity?
• Methoxyflurane metabolism releases
harmful fluoride ions
• Which GA can lead to vitamin B-12 deficiency with
attendant megaloblastic anemia and peripheral
neuropathies?
• N2O oxidizes B-12 and decreases methionine synthase
activity
• What is malignant hyperthermia and what agents can
cause it?
• Rare, autosomal dominant genetic disorder of skeletal
musculature → tachycardia, hypertension, severe
muscle rigidity, hyperthermia, hyperkalemia, & acid-base
imbalance with acidosis after anesthesia w inhalants
(especially halothane) & muscle relaxants
• How is this treated?
• Treat with dantrolene (block muscle calcium release),
restore electrolyte and acid-base balance, & reduce
body temperature
• What is 1.0 MAC?
• Minimum alveolar concentration or Conc’n
of GA agent @ 1 atm. of inhaled gas mix
preventing response to skin incision in
50% of patients
• Note that the effects of surpassing 1 MAC
by much can be rapidly fatal
• Also note that 0.5 MAC of N2O + 0.5 MAC
of isoflurane does equal 1 MAC of
anesthesia
• Most inhalable agents are given at 0.8 –
1.2 MAC along with some injectable agent
• Do injectable anesthetics act more or less
rapidly than inhaled ones?
• They act much more quickly
• What are commonly used injectable
anesthetics?
• Barbiturates (thiopental, methohexital, thiamylal,
propotol,etomidate), benzodiazapenes (BZDs),
ketamine (NMDA receptor blockers), opioids
(morphine, meperidine, fentanyl, sufentanil,
alfentanil, remifentanil)
• How do barbiturates and BZDs work?
• They bind to the GABA Cl- channel and keep it
open resulting in cell hyperpolarization
How does the extrapyramidal
system work?
Parkinson’s results from damage to
The nigrostriatal dopaminergic neurons
Dopamine hyperpolarizes the cholinergic neuron, leading to shut down of
GABAergic inhibition
• How do we treat Parkinson’s?
• Dopamine does not cross the BBB so
levadopa (L-Dopa) is used instead
• What is the problem with administering
only L-dopa to treat PD?
• >95% is metabolized by peripheral
decarboxylases in the GI tract leading to
anorexia, nausea, vomiting and a build up
of dopamine with attendant tachycardia,
atrial fib, postural hypotension and
hypertension
• What can be coadministered with levadopa to inhibit GI
break down?
• Carbidopa inhibits the decarboxylases but does not
cross the BBB so L-Dopa is still broken down to
dopamine in the brain
• What are long term dopamine side effects?
• chorea, ballismus, & other dyskinesias and mental
effects can include depression, anxiety, agitation,
insomnia, confusion, delusions, euphoria
• To whom should you never give L-dopa?
• Psychotics
• How can you treat the behavioral complications?
• Give atypical antipsychotics (never typicals)
– Typical antipsychotics (chlorpromazine, haloperidol) are D2
receptor antagonists and cause PD
• What is another way to treat PD?
• Use MAO-B inhibitors (selegiline) alone or with
L-dopa/carbidopa to decrease dopamine
breakdown
• Use COMT inhibtors (entacapone and
tolcapone) with L-dopa/carbidopa to prevent
peripheral breakdown of L-dopa
• Use direct D2 receptor agonists to stimulate the
cholinergic interneurons
– Ergot alkyloids bromocriptine and pergolide
– Pramipexole and ropinerole do not cause
vasoconstriction like bromocriptine
– Better in advanced disease and don’t require
decarboxylase activity
– Never use in psychotic patients
– Have similar side effect profile to L-dopa
• How can PD induced by antipsychotics be
treated?
Trihexyphenidyl, benztropine, procyclidine, biperiden inhibit muscarinic receptors on GABAergic neurons,
improve tremor and rigidity but not bradykinesia,
and are preferred for treating parkinsonism induced by
antipsychotics since L-Dopa may aggravate psychosis
• What causes Huntington’s chorea (HC)?
Dominantly-inherited genetic disorder
leading to dysfunction and degeneration of
striatal cholinergic and GABAergic
neurons (outcome opposite of
parkinsonism)
• What are teatments for HC?
• Typical antipsychotics haloperidol, fluphenazine,
perphenazine block inhibitory control over
remaining striatal circuitry and relieve psychosis
that can accompany Huntington’s chorea
• Newer “atypical” antipsychotic olanzapine;
Reserpine & tetrabenazine deplete cerebral
dopamine stores
• Benzodiazepines like diazepam to
potentiate GABA signaling
• How do we treat essential tremor?
• β-blockers propranolol, or primidone if βblockers can’t be tolerated
• What is the most common treatment for
Tourette’s syndrome?
• Haloperidol
• How do we treat restless leg syndrome
(RLS or akathisia)?
• With a D2 receptor agonist ropinirole (no
one knows why this works; it IS
counterintuitive)
What are the major differences between
typical and atypical antipsychotic drugs
(APDs)?
• Typical APDs lead to PD, tardive
dyskinesia and do not treat negative
psychotic symptoms at all
• Typicals generally inhibit D2 dopamine
receptors while atypicals inhibit different
NT receptors
• Atypicals show less extrapyramidal motor
disorders as side effects
• What are typical APDs?
•
•
•
•
•
Chlorpromazine
Haloperidol
What are atypical APDs?
Clozapine
risperidone, olanzapine, ziprasadone
• What are the effects of APDs?
• Antipsychotic effects: Reduce delusions,
hallucinations; improve perception &
thought organization
• What diseases do APDs treat?
• Schizophrenia, psychotic episodes in
affective illnesses, mania in bipolar
disease, Tourette’s syndrome,and
disturbed behavior in senile
dementia/Alzheimer’s disease
• What other interesting side effect do most
APDs have?
• They are antiemetics
– They block D2 receptors in the CTZ
• What is prochlorperazine?
• It is also a D2 receptor blocker (similar to
typical APDs) but it doesn’t cross the BBB
so it only has entiemetic properties
• What do you do if you start to see
extrapyramidal side effects after administration
of antipsychotics?
• Switch to atypical APD with lower D2-R antagonism;
Co-administer anti-muscarinics (a.k.a. anticholinergics) to directly inhibit receptors on
GABAergic neurons
• What is tardive dyskinesia?
• It is a late onset and sometimes irreversible side
effect of APDs (usually typicals) defined by
Abnormal involuntary persistent
movements of hands, tongue, lips, face.
Choreoathetoid (writhing, dance-like)
movements while seated are common
What causes tardive dyskinesia
(TD)?
• Thought caused by supersensitive D2 receptors
on striatal cholinergic interneurons in response
to APD blockade…too little GABAergic output
leads to OPPOSITE outcome to parkinsonism
How do we treat TD?
Discontinue or reduce APD or switch to
atypical APD with lower D2-R antagonism;
Discontinue all drugs w anti-cholinergic
effects in CNS (esp. antiparkinsonism
drugs, tricyclic antidepressants)
Give benzodiazepines like diazepam to
potentiate GABA
What is the Neuroleptic Malignant Syndrome
(NMS)?
• Rare (0.5~1%), life-threatening condition that
can occur on 1st dose or APD overdose,
associated with EPS sensitivity. Haloperidol &
phenothiazines >> atypicals (but latter can NMS)
• Symtoms include marked muscle rigidity, severe
EPS, autonomic motor dysfunction,
hyperthermia, elevated creatine phosphokinase,
altered consciousness, leukocytosis
How do we treat this condition?
• Withdraw APD; give D2-R agonist eg.,
bromocriptine; give muscle relaxants diazepam /
dantrolene
What are other typical side effects of APDs?
• Sedation, weight gain, confusion, blurred
vision, dry mouth, constipation, urinary
retention, postural hypotension, dizziness
• These stem from antihistaminic,
anticholinergic, antiadrenergic effects
What was clozapine and what is
one major side effect?
• Clozapine is an atypical APD
• It can cause agranulocytosis and requires
intensive blood monitoring
What about olanzopine?
• It is also an atypical but w/o the
agranulocytosis side effect
• Weight gain with ↑ risk of diabetes and
hyperlipidemia
What do prostoglandins and prostocyclins do?
• They cause vasodilation, edema, airway
relaxation, ↑ kidney perfusion and mucous and
bicarb production in the GI tract, and
temperature regulation via the hypothalmus
What do leukotrienes do?
• They cause monocyte and granulocyte
chemotaxis and airway constriction
What do thromboxanes do?
• They activate platelets while prostocyclins
oppose this.
Where do NSAIDs, corticosteroids and other
drugs work in the eicosanoid pathway?
PHOSPHOLIPID
(-)
PLA2
Corticosteroids
Arachidonic Acid
NSAIDS
(-)
COX 1,2
Cyclic
Endoperoxides
Prostacyclin
Thromboxane
5-Lipoxygenase
(-)
Zileuton
5-HPETE--LTA4
LTB4
LTC4
LTE4
LTD4
LTF4
Prostaglandins
(-)
RECEPTORS
RECEPTORS
ACTIONS
ACTIONS
Zafirlukast
NSAIDs
What do NSAIDs help with?
1.
2.
Antipyresis (control body temp)
Analgesia (control pain), especially headaches and
muscle pain
3. Anti-inflammation (high doses for RhA)
4. They can also be used to treat gout
What are some side effects of NSAIDs?
1. GI Irritation
2. Hypersensitivity
3. Renal toxicity
Summary of common NSAIDs
DRUG
ANALG
ANTIPYR
ANTI INFLAM
Acetylsalicylic Acid
+
+
+
GI/Salicylism/
Reyes Synd./
Resp. Suppress./
Prophylactic uses
Acetaminophen
+
+
-
Little GI tox.
Hepatotox.
Chronic kidney tox.
CNS Action
Ibuprofen (advil)
+
+
+
Modest GI tox.
Chronic kidney tox.
Who should you never give aspirin to and why?
•Never give aspirin to babies
•It can cause a demyelinating disease
TOXICITIES &
SPECIAL FEATURES
What is the cox 2 inhibitor (NSAID) recently
pulled off the market?
• rofecoxib (Vioxx)
Why are they better in some ways than
other NSAIDs?
• They are effective anti inflammatories with
reduced GI adverse side effects
Why was it pulled off the market?
• Adverse cardiovascular effects
What are some leukotriene receptor
antagonists and what are they used for?
• Zileuton, Zafirlukast and montelukast
• They are used in asthma therapy to open
airways
What are their advantages?
1. possible monotherapy in mild persistent
asthma
2. reduce corticosteroid use in moderate to
severe disease
3. well tolerated
What are disease modifying anti rheumatic drugs
(DMARDs)?
• They are TNF and IL-1 inhibitors that help retard
the inflammatory process
• Both lead to an increased risk of TB and other
opportunistic pathogens
What do anti-histamines do?
• Binds H1 receptors on endothelial cells to block
vasodilatation and edema, and on sensory
neurons to block pain, itching
What are their side effects?
• Sedation (1st Gen cross the BBB),
Hypersensitivity, GI upset
What are the CNS effects of opioids?
1. Decreased sensitivity to painful stimuli
2. Sense of well-being
3. Drowsiness without amnesia
4. Depression of cough reflex (brainstem)
What are opioid side effects?
• Hypotension, bradycardia, decreased GI
motility, increased tone, constipation, Urinary
retention, depressed renal function, decreased
uterine contractions, may prolong labor,
release of mast cell histamine, altered
hormone release, pinpoint pupils (miosis)
What risk is there for patients on (or recently
on) MAO-Is who take opioids?
• Seratonin syndrome
What are the 3 types of opiod receptors?
•  (mu),  (delta),  (kappa)
What do they do and what are the
endogenous ligands?
μ
δ
κ
supraspinal/spinal
spinal/supraspinal
spinal
Respiratory
depression
++
+/−
+
Constipation
+
Euphoria
Dysphoria
Dysphoria
(Out of body)
Sedation
Analgesia
Behavioral
effects
Euphoria
Sedation
Positive
reinforcement
++
Endogenous
ligands
enkephalins
endorphins
GI Tone
+
enkephalins
Dynorphins
++
Positive reinforcement is dopamine release via opioid modulation
How do opioid receptors work?
• In the presynaptic nerve terminal they
inhibit the release of pain NTs (glutamate
and substance P) via G-protein coupled
Ca2+ channel inhibition
• They cause hyperpolarization in
postsynpatic nerve terminals via opening
K+ channels
• All 3 opioid receptor types are on
presynaptic terminals and only μ receptors
are on postsynaptic terminals
Which opioids are full agonists?
• Fentanyl, morphine (heroine), codeine
Which opioids are partial agonists?
• Buprenorphine
What are the opioid antagonists?
• Naloxene (for treating ODs), naltrexone (more
for long term withdrawal treatment)
How does pentazocene act?
• pentazocine is a κ-agonist, μ-weak partial
antagonist (good for moderate to severe pain)
• It and others can precipitate withdrawal
What is severe pain treated with?
• Short acting, high affinity for μ receptor opioids
like fentanyl (100 times more powerful than
morphine due to higher lipophilicity), heroine (a
morphine prodrug), morphine (reduces
coughing) or meperidine (reduces shivering)
What is more moderate pain treated with?
• Codeine (lower abuse liability than those above),
oxycodone (more potent than codeine) or
tramodol (also an MAO-I with possible seratonin
syndrome side effect but less respiratory and
other side effects)
What is buprenophine good for?
• Helps with cocaine and opiate withdrawal
or moderate to severe pain
What do you use to reverse an opioid
overdose?
• Naloxene, an opioid receptor antagonist
• Remember that it is shorter acting than
most opioids so will need to be
readministered
• Non selective antagonist with μ>δ>κ
What are symptoms of opiate withdrawal?
• Often is the opposite of direct effects of
opiates
• Lacrimating, yawning, dilated pupils,
sweating, rhinorrhea, abdominal pain,
nausea, diarrhea, goose-flesh, irritability,
cramps
• Almost never results in death
What drugs do opioids interact with and what are
their effects?
• Benzos, alcohol and sedatives
– Potentiates respiratory depression and
sedation
• Tricyclic antidepressants and antipsychotics
– Same as above and decrease siezure
threshold
• MAO-Is
– Seratonin syndrome (hypertension,
hyperthermia seizures and death, especially
from meperidine)
What is seratonin syndrome?
• A build up of seratonin due to an overdose of TCAs,
SSRIs or MAOIs
• Combination of increased stores plus inhibition of
reuptake after release
• Or interaction between these drugs, so don’t mix them
• Must wait at least 2 weeks (4-5 weeks for fluoxetine)
when changing from an antidepressant to MAOI and two
weeks when changing from MAOI to another
antidepressant
What are the mild and severe symptoms of this syndrome?
• Mild: hyperthermia, muscle rigidity and myoclonus,
restlessness, insomnia, GI upset
• Severe: convulsions, coma, some serious cardiac
complications, rapid changes in mental status and death
Thanks Shari!!!
Managing Pain
What are the different physiological types of pain?
• Somatic pain – usually cutaneous or superficial.
Sharp or dull sensation that is well localized
• Visceral pain- deep pain; dull aching; poorly
localized; refers to cutaneous sites. C-fiber (nonmyelinated) is primary nerve fiber involved. This
is the most common form of pain.
• Neuropathic pain – results from injury to a
peripheral nerve; burning or dysesthetic; trauma,
metabolic; infection (HIV, herpetic)
Why are women more likely to feel pain than men
(no this is not sexist!)?
• Estrogen suppresses the ability to inhibit pain
and B-endorphins (which help suppress pain)
lead to infertility and women don’t have much
What are common causes of chronic pain?
1. Musculoskeletal: fibromyalgia (3%), TMJ (1015%), RA and OA (arthritis), LBP (if anyone
knows what this is please tell me)
2. Headache
3. Neuropathic pain
Who has fibromyalgia and TMJ (TMD)?
• Women (5-9:1) more than men, usually
30-40yo (fibro).
• 80% of patients with fibro have TMJ too
How do you treat these conditions?
• Establish a good and trusting relationship
• Pharmacotherapy (ASA, NSAIDs,
acetaminophen, opioids)
• Physical exercise program
• Physical therapy/physical medicine
• Cognitive behavioral therapy
How do the non-opioids work (ASA, NSAIDs,
acetaminophen)?
• COX 1,2,3 inhibitors (1,2 peripheral; 3 CNS)
– Acetaminophen and tylenol mainly work on COX 3 in
the CNS
What are COX inhibitor side effects?
• They inhibit platelet aggregation and can double
bleeding time
• COX 2s have little effect on platelets, PT or
APTT (so fewer side effects), but stil may
interact with coumadin
• 10% (long term use) lead to GI ulcers, often with
no symptoms before perforation and with little
relief from H2 blockers
Do you recall the general properties of
opioid analgesics (let’s review)?
– Analgesia
– Respiratory depression
– Cardiovascular depression
– Emesis
– Gastrointestinal – constipation, leads to 2/3 of
patients dropping the drug
– Antitussive action
– Miosis
– Euphoria
Do you recall the opioids and their uses?
• Propoxyphene – not much indication
• Tramadol • Hydrocodone – treat pain, medium
potentcy
• Oxycodone - same
• Methadone – more potent, long half life,
good for chronic pain, fewer side effects
than others
• Morphine – same potentcy
• Fentanyl – very potent but short acting
How do you define drug tolerance?
• requiring a higher dose as usage history
lengthens. GI system does not show
opioid tolerance and GI side effects get
worse and worse
What are the two types of dependence and
which usually leads to addiction?
– Physiological
– Psychological – leads to addiction
Antiepileptic Drugs (AEDs)
A brief review, what are the 2 main
categories of seizures?
• Focal (lead to partial seizures) and
generalized (absence, atonic, tonic, clonic,
tonic-clonic, myoclonic)
What do these drugs do?
• Decrease the frequency and severity of
seizures but don’t treat the underlying
cause
What causes seizures?
• Too much stimulation (aspartate and
glutamate, inward NA+, Ca2+ channels)
• Too little inhibition (GABA, inward CL-;
outward K+ channels)
What are the principle CYTP450s that
metabolize AEDs?
– CYP2C9, CYP2C19, CYP3A4
What is another pathway for AED
metabolism?
– UDP- Glucuronyltransferase (UGT)
What are different AEDs used for?
What AED prolongs GABA-mediated chloride
channel openings?
– Barbiturates
What AED increases frequency of GABA-mediated
Cl- channel opening?
– Benzodiazepines
What AED exerts an effect on K+ channels
– Oxcarbazepine
What AEDs increase neuronal GABA
concentration; enhance GABA transmission, etc.
– gabapentin, valproate; tiagabine; levetiracetam;
pregabalin; vigabatrin
Summary of AED metabolism
Drug
CYP3A CYP2C9 CYP2C1
4
9
+
Carbamazepine
Phenytoin
+
Valproate
+
Phenobarbital
+
ZNS
+
Tiagabine
+
UGT
+
+
Which AEDs are general CYTP450 inducers?
– carbamazepine
– phenytoin
– phenobarbital/primidone
Which AEDs are Selective CYP3A4 Inducers:
– felbamate, topiramate, oxcarbazepine
Which AEDs are CYTP450 Inhibitors
– valproate
– topirimate
– felbamate (CYP2C19)
What are some AEDs that are neither inducers nor
inhibitors of CYP:
– gabapentin, lamotrigine, tiagabine, levetiracetam,
zonisamide, Pregabalin
When should you consider drug – drug
interactions?
• Consider drug interactions when
– Adding new medication when inducer/inhibitor
is present
– Addition of inducer/inhibitor to existing
medication regimen
– Removal of an inducer/inhibitor from chronic
medication regimen
What are some adverse side
effects of AEDs?
• Neurologic/Psychiatric (most common)
–
–
–
–
–
–
–
–
Sedation, fatigue
Unsteadiness, uncoordination, dizziness
Tremor
Paresthesia
Diplopia, blurred vision
Mental/motor slowing or impairment
Mood or behavioral changes
Changes in libido or sexual function
• Gastrointestinal (nausea, heartburn)
• Mild to moderate laboratory changes
– Hyponatremia (may be asymptomatic); Increases in ALT or AST;
Leukopenia; Thrombocytopenia
• Weight gain/appetite changes
What are the more long term
adverse effects of AEDs?
• Neurologic:
– Neuropathy
– Cerebellar syndrome
• Endocrine/Metabolic Effects
– Vitamin D – Osteomalacia, osteoporosis
– Folate – Anemia, teratogenesis
– Altered connective tissue metabolism or growth
• Facial coarsening
• Hirsutism
• Gingival hyperplasia
Soporifics/Hypnotics
Lack of sleep leads to…?
• Can cause CNS dysfunction – progressive
malfunction of mind (sluggish; slowed speech);
irritability, anxiety, tremor, paranoia,
hallucinations
What are some common sleep and hypnotic
problems?
• (a) Narcolepsy
• (b) Obstructive sleep apnea
• (c) Restless Legs Syndrome
What are the hypnotic drugs commonly used
to treat sleep problems?
• GABAA receptor potentiation drugs
– barbiturates
– benzodiazepines
– zolpidem & zaleplon
• anti-histamines
• anti-depressants
• herbals/non-prescription agents
What are barbiturates?
• Short-acting (3-8 hr duration) CNS depressants
used to sustain sleep interrupted by frequent
awakenings/nightmares
What are their shortcomings?
• Undesirable “drug hangover” that can impair
daytime activity;
• Respiratory depression / coma (10x dose) /
death (15x) at high doses;
• Induction of liver cytochrome P450s affecting
drug metabolism;
• Increased porphyrin synthesis (contraindicated
in acute porphyria)
• Psychological and physical dependency –
severe withdrawal.
Which hypnotics have a better safety profile
in case of OD?
– Benzodiazepines, zolpidem & zaleplon
What are the benzodiazepines?
• They are lipophilic, short-acting GABAA receptor
potentiators that lead to CL- channels opening more
often and reduce CNS activity
– Lorazepam, clonazepam, quazepam, temazepam, flurazepam,
and the zolams
• Flurazepam has a longer duration of action than the others
What do the benzodiazepines do?
• reduce time to sleep and increase total sleep time
(but tolerance to both effects develops over 1~2
wks)
• reduce %REM-sleep  rebound in REM-sleep off
BDZ
Where is the major site of benzo metabolism?
• The liver, which means elderly and those with liver
function probs need less drug
What are 3 contraindications for taking benzos?
• reduce CNS activity so  don’t take if mental
alertness req’d (driving, machinery use)
• BDZs can produce habituation,
dependence, withdrawal so  don’t prescribe
if history of alcohol, drug, substance abuse
• BDZs cross placenta & enter breast-milk so
 don’t prescribe to pregnant or lactating
women
• Be careful not to mix with other CNS
depressants (like alcohol); this can be deadly
How can benzo overdoses be treated?
• Flumazenil, a selective benzo antagonist
What is the major difference between
barbiturate and benzodiazepine action?
• Barbiturate binding-site occupancy prolongs
duration of channel opening, without affecting
opening frequency
• Benzodiazepine binding-site occupancy
increases frequency of channel opening caused
by GABA binding
How do zolpidem and zaleplon work?
• structurally not benzodiazepines, but act by binding
the BDZ-site on a subset of GABAA-receptors w a1
subunits
• These are similar to benzos in that they can’t be
mixed with CNS depressants and they are
metabolized by the liver
• They both have rapid onset and short duration
Why would you take them rather than BZDs?
•
•
•
•
both zolpidem and zaleplon preserve sleep architecture
*
minimal “next-day effects”
*
little “REM rebound” upon discontinuation
*
low risk of tolerance, dependence vs. BDZs
• zaleplon preferred for rapid onset
• zolpidem preferred for trouble sleeping through night
What is Kava Kava used for?
• Traditional beverage and CNS depressant
What should not be taken with kava kava?
• combination w alcohol or BDZs  coma!
What are some other hypnotic drugs?
• chloral hydrate – metabolized to the CNS depressant
trichloroethanol; older, but low cost
• Diphenhydramine, doxylamine, chlorpheniramine: 1st
generation anti-histamines with considerable anticholinergic effects that can inhibit the reticular formation
• Trazedone: anti-depressant used off-label, since
NOT a Schedule IV controlled drug (BDZs,
zolpidem/zaleplon, chloral hydrate) Selective serotonin
reuptake inhibitor, but antagonist at other receptors?
Effective for antidepressant-induced insomnia
Alcohol Abuse and Alcoholism
• Approximately 14-15 Million Americans suffer from
alcohol abuse-alcoholism,7.4% of the population (Grant
et al.,1994) 15% lifetime prevalence (Anthony, 1994)
• It is estimated that in 1998 the cost of alcohol abuse was
$184 Billion (Harwood et.al.)
• The National Health Interview Survey (1988) indicated
that among employed individuals 18 and older 10.3% of
men and 4.1% of women were alcohol dependent.
• Peak age of dependence 25-45 years (Anthony, 1994),
may be declining
• More than 50% of American Adults have a close family
member who has or has had alcoholism (Dawson and
Grant,1998)
How is alcohol absorbed?
• Ethanol is absorbed by passive diffusion
from the stomach (25%) and the small
intestine (75%).
• Food in the stomach delays gastric
emptying and absorption.
• Ethanol is distributed to total body water
(goes through BBB).
• The rate of distribution to tissues is
dependent upon the blood supply.
What does ethanol elimination depend on
and how fast is it eliminated from the
body?
• Alcohol is metabolized at a fixed rate not
dependent on concentration in the body
about 12g/h
• Most ethanol oxidation occurs in the
liver
• ~ 90 % ethanol removed by oxidation
• < 10 % ethanol excreted in breath,
sweat and urine
What is the mechanism of action of ethanol?
• Ethanol has its most pronounced actions on ion
channels, particularly inhibiting the glutamate-NMDA
excitatory neurotransmitter receptor and potentiating the
GABAA-inhibitory neurotransmitter receptor.
• Other ion channels and membrane proteins are
sensitive, depending on the concentration.
• Note the concentrations of ethanol that are
pharmacologically active are much larger than that of
most other drugs
What does chronic alcohol consumption induce?
• Chronic Ethanol Consumption Reduces GABA-mediated
Inhibition and Abolishes Ethanol Potentiation
GABA
GABA + ethanol
GABA + ethanol
Cl-
Cl-
ClExtracellular
Intracellular
ClNo Alcohol
ClAcute Alcohol
Cl-
Chronic Alcohol
Define alcohol abuse.
a person's maladaptive alcohol use causes
clinically important distress or impairment, as
shown in a single 12-month period by one or
more of the following:
– failure to carry out major obligations at work, home, or
school because of repeated alcohol use
– repeated use of alcohol even when it is physically
dangerous to do so
– repeated experience of legal problems, or
– continued use of alcohol despite knowing that it has
caused or worsened social or interpersonal problems
What part of the brain do most drugs (including alcohol) act
on to make ingesting them pleasurable?
• The ventral tegmental area & nucleus accumbens
pathway
What are the CNS medical problems of chronic heavy
alcohol abuse?
• Cognitive and memory impairment/dementia
• Erratic, unpredictable behaviors
• Ataxic, broad-based gait
• Paresthesias, sensory impairment
• Muscle weakness and tenderness
• Decreased visual acuity
• Variations in levels of consciousness
• Convulsions
Which is the moderate drinker and
which the alcoholic?
Moderate drinker
Chronic alcoholic
How do opioid antagonists help
suppress alcohol seeking
behavior?
• Alcohol consumption affects
the production, release, and
activity of opioid peptides
• Opioid peptides mediate some
of alcohol’s rewarding effects
by enhancing midbrain
dopamine release
• Opioid antagonists suppress
alcohol-induced reward and
general consummatory
behaviors
• Genetic high-risk / FH+
individuals have an
exaggerated alcohol-induced
rise in -endorphin level, and
are more responsive to
naltrexone treatment
What drug is FDA approved for treating
alcoholism?
• Naltrexone 50 mg/day for 12 weeks was
FDA approved in 1994 for treating
alcoholism
• Anton et al. 1999 reported efficacy for
naltrexone in a carefully selected cohort of
non-severely dependent, socially stable,
and motivated alcoholics
• The glutamate antagonist acamprosate
seems to help too
What is disulfiram and how does it work?
• It inhibits alcohol metabolism and leads to:
– Given alone it is non-toxic
– Alters metabolism of alcohol leading to an increase in
acetaldehyde
– Within 5 to 10 minutes of alcohol ingestion, the face feels hot
and is flushed
– Vasodilatation spreads, pulsating headache, respiratory difficulty,
nausea and vomiting
– Hypotension, uneasiness, confusion
– Inhibits metabolism of other drugs and can cause adverse
reactions
What do we treat alcohol withdrawal with?
• Benzodiazepines
How does alcohol withdrawal progress?
Minor
Major
Anxiety
Agitation
Diaphoresis
Delirium
Disorientation
SEVERITY
Tremor
Insomnia
Irritability
0
1
2
seizures
3
DAYS
4
5
6
7
Faces in Fetal Alcohol
Syndrome
Discriminating
Features
Associated
Features
Epicanthal Folds
Short Palpebral
Fissures
Low Nasal Bridge
Remember, fetal alcohol syndrome stinks!!!
Flat Midface
Short Nose
Indistinct
Philtrum
Thin Upper Lip
Streissguth, 1994
Minor Ear
Abnormalities
Micrognathia
Anxiolytics
What are the anxiolytic drug classes?
• Barbiturates (seldom used anymore)
• Benzodiazepines
• Antidepressants
– TCAs, SSRIs, SNRIs, MAOIs
• Buspirone
• Herbals remedies
– Scant evidence
How do barbiturates work?
• Bind to receptor on GABAA resulting in
increased duration of Cl- channel opening
What are some bad side effects?
– OD may result in respiratory depression &
death, narrow therapeutic range
– Enzyme induction
– Tolerance and dependence with prolonged
administration
– Severe withdrawal symptoms
What makes a better anxiolytic?
• benzodiazepines
What are benzos used for besides anxiolytics?
• sedative/hypnotics, and for alcohol detoxification
How do they work (again)?
• Results in  frequency of chloride channel opening,
resulting in  Cl- influx and hyperpolarization (inhibitory)
What do benzos do?
• Sedative-hypnotic
–
–
–
–
decreased sleep latency
decreased stage-4 (slow-wave) and REM
increased stage 2
increased total sleep time
• Anxiolytic
• Muscle relaxant
• Anticonvulsant
Remember the adverse reactions to benzos?
• drowsiness - ~10%, especially a problem in the
long acting ones
• dizziness <1%
• ataxia <2%
• respiratory depression
• Disinhibition – similar to alcohol, but more
comon with injured or mentally retarded patients
• mild cognitive deficits
• anterograde amnesia
• rare, paradoxical increase in aggression (pts
with brain damage)
• allergic reactions rare - maculopapular rashes
and generalized itching
When should you not take BZDs?
• Impaired liver function
• Age
• COPD
• Sleep apnea
• History of SA, cognitive disorders, renal
dz, porphyria, CNS depression,
myasthenia gravis
What are symptoms of severe BZD withdrawal?
• depression, paranoia, delirium, and seizures
How about BZD intoxication?
• confusion
• slurred speech
• ataxia
• drowsiness
• dyspnea
• Hyporeflexia
How can BZD overdoses or anesthesia be
treated?
Flumazenil is a BZD receptor antagonist
For what psychiatric indications do you give
benzodiazepines?
– Generalized anxiety disorder
– Panic disorder (Alprazolam)
– Social phobia
– Acute stress disorder
– Post-traumatic stress disorder
– Adjustment disorder with anxiety
– Anxiety associated with life events
– Bipolar disorder
– Akathesia
What are some important drug interactions with
BZDs?
• Cimetidine, disulfiram, isoniazid, and estrogen
inhibit oxidative metabolism and increase
plasma levels of keto-BZs
• Rifampin and tobacco decreases BZ levels via
enzyme induction
• Food and antacids decrease levels
• Bzs may increase levels of phenytoin and
digoxin
• Additive effects with other sedative drugs
• SSRIs
Buspirone
How does it work and what is it used for?
• Full/Partial agonist at 5-HT1A receptors (no GABA
activity)
• Approved for generalized anxiety disorder
What is it not good for?
• Not effective for panic disorder or obsessive compulsive
disorder
• No sedative, anticonvulsant or muscle-relaxant
properties
What are the drawbacks of this drug?
• Clinical improvement occurs only after days to weeks of
therapy
• It is very well tolerated with side effects
What are tricyclic antidepressants used for?
– To treat Panic Disorder (and depression)
What is clomipramine used for?
• To treat OCD
What are SSRIs used for?
– Panic disorder, OCD, social anxiety disorder, PTSD,
GAD
What are seratonin and norepinephrine reuptake
inhibitors (SNRIs) used for?
• GD, panic disorder, post traumatic stress
disorder
What are MAOIs used for?
• Panic disorder, social anxiety disorder
What are the 5 classes of medications effective for
treating panic disorder?
– TCAs
• Imipramine, nortryptiline
– SSRIs
• gold standard
• Sertraline, paroxetine
– SNRIs
• venlafaxine
– Benzodiazepines
• Alprazolam, clonazepam, lorazepam
– Monoamine Oxidase Inhibitors (MAOIs)
• Phenelzine
• Effective but limited by side effects and toxicity
How is panic disorder best treated?
• SSRIs are considered the treatment of
choice due to their safety and their
favorable side effect profile.
• SSRIs, TCAs, and SNRIs must be initiated
at low doses and gradually titrated to full
dosage in order to avoid temporary
worsening of panic symptoms.
• Benzodiazepines are effective but limited
by dependency issues. Cognitive
Behavioral Therapy (CBT)
How should OCD be treated?
• Only effective agents for OCD are antidepressants
that inhibit serotonin reuptake
• Clomipramine (Anafranil) - 3-chloro analogue of the TCA
imipramine
– Superiority over placebo confirmed in a number of double-blind
clinical trials
• SSRIs
– Four have approval to treat OCD: Prozac (fluoxetine), Zoloft
(sertraline), Paxil (paroxetine), and Luvox (fluvoxamine)
• Cognitive Behavioral Therapy (CBT)
– Very effective alone or in conjunction with medications
• Not effective: buspirone, bupropion, TCAs except
clomipramine, MAOIs
What is the best treatment for post traumatic
stress disorder (PTSD)?
• SSRIs first-line: sertraline and paroxetine have
FDA approval
• Benzodiazepines
• CBT
What is the best therapy for generalized anxiety
disorder?
• Historically BZDs were used
• Buspirone (Buspar) FDA approved only for GAD
• The SNRI, venlafaxine (Effexor XR) approved by
FDA
• SSRIs (paroxetine and citalopram FDA
approved)
What is the best treatment for social anxiety
disorder?
• MAOs effective, but SSRIs are now firstline
• FDA approved drugs include sertraline,
paroxetine, venlafaxine
• Benzodiazepines or β-blockers sometimes
uses (e.g., performance anxiety)
Mood disorder treatment
What is the most important factor in treating mood
disorders?
• Making the correct diagnosis since treating the wrong
condition can exacerbate it
How long do antidepressants take to work?
• Temporal delay of weeks for clinical effects, although
biochemical effects are immediate
Why the delay?
 -adrenergic receptor down-regulation
 5-HT2 receptor down-regulation”
 Takes time to produce more receptors
What are the tricyclic antidepressants and how do they
work?
• Imipramine & amitriptyline (3º amines), nortriptyline &
desipramine (2º amines)
 Inhibit monoamine uptake at nerve terminals
 2º amines inhibit NE uptake
 3º amines inhibit 5-HT uptake
 May potentiate action of drugs that cause neurotransmitter
release
 Muscarinic cholinergic antagonism
 H1 histamine antagonism
 a1-adrenergic antagonism
What are the clinical effects?
 Normalization of mood and resolution of neurovegetative
symptoms
What are the TCA side effects?








Dry mouth
Constipation
Dizziness, delirium, respiratory suppression
Tachycardia, cardiotoxicity
Urinary retention
Impaired sexual funtion
Orthostatic hypotension
Sedation and weight gain
Why so many?
• It is a “dirty drug” due to action on so many
receptor types
• It has a low therapeutic index
What do the MAOIs do?
 Irreversibly inhibit monoamine oxidase enzymes
leaving more monoamines in the synaptic cleft
What do we use them for?
 Effective for major depression, panic disorder,
social phobia
What are the different types?
 MAO-A
• Present in both DA and NE neurons
 MAO-B
• Present to a greater extent in 5-HT neurons
• Not involved in intestinal tyramine interaction
What do we need to be careful of with MAOIs?
 Increased stores of catecholamines sensitize patients to
effects of sympathomimetics
 Hypertension, occipital headache, palpitations, nausea &
vomiting, chills, sweating – can be fatal in rare instances
 Accumulation of tyramine (sympathomimetic) = high risk
of hypertensive reactions to dietary tyramine
 requires dietary restrictions (wine and cheese)
 Interactions with other sympathomimetic drugs
 Antidepressants
 Must wait at least 2 weeks (4-5 weeks for fluoxetine) when changing
from an antidepressant to MAOI and two weeks when changing
from MAOI to another antidepressant.
 Stimulants, OTC cold remedies (Pseudoephedrine,
dextramethorphan)
 Meperidine, Levodopa
Name some MAOIs
Irreversible, non-selective MAOIs
 phenelzine
 isocarboxazid
 tranylcypromine
Selective MAO-B inhibitors
 deprenyl (selegiline)
 loses its specificity for MAO-B in
antidepressant doses
What do SSRIs do?
• Selectively inhibit 5-HT (not NE) uptake
What are some examples?
Examples






fluoxetine (Prozac).
sertraline (Zoloft).
paroxetine (Paxil)
fluvoxamine (Luvox)
citalopram (Celexa)
Escitalopram (Lexapro)
What are some advantages of SSRIs?
 Much higher therapeutic index than TCAs or
MAO-I’s
 Better tolerated in early therapy
 Equal or almost equal in efficacy to TCAs
What are some disadvantages?
 Also have a temporal delay in action
 Side effects
 Nausea
 Sexual dysfunction
 Delayed ejaculation/anorgasmia
 Anxiety – early activation
 Insomnia
How do seratonin NE reuptake inhibitors (SNRIs) work?
• They inhibitor reuptake of serotonin and norepinephrine
What are some examples?
 Venlafaxine (Effexor):
 relatively devoid of antihistaminergic, anticholinergic, and
antiadrenergic properties
 nonselective inhibitor of both NE and 5-HT uptake
 Side effect profile similar to that of SSRIs
 Idiopathic hypertension may occur usually at higher doses
 Duloxetine (Cymbalta)
– Approved for MDD and diabetic peripheral neuropathic pain
– Reportedly not associated with hypertensive effect
What is Bupropion?
• Inhibits uptake of DA and NE
• Only non-serotoninergic antidepressant
What is its side effect profile?
 Lacks sexual side effects
 Risk of seizures 0.01%
 Contraindicated for patients with a history of
seizures, severe head injury, or eating disorder
What else is it used for?
• Smoking cessation
What is mirtazapine?
• An antidepressant
 Dual enhancement of central noradrenergic and
serotonergic neurotransmission
 Blockade of presynaptic a2 receptors
 Results in  5-HT and NE release
 5H2 and 5HT3 antagonist
 Net effect selective increase in 5HT1A function
 H1 antagonist (especially at lower doses)
 Side effects
 Weight gain, sedation
 Lacks sexual side effects
 Lacks serious drug interactions
How do we treat bipolar disorder?
• Only FDA approved treatment is olanzapine and
fluoxetine (Symbiax)
• In reality, other antidepressants are often added in
conjunction with mood stabilizers
• Lithium
– Side effects?






Tremor
Edema
Polydipsia and polyuria
Hypothyroidism
Renal toxicity
Low therapeutic index
 Therapeutic range (0.6-1.2 meq/L close to toxic range of >1.5 meq/L)
 Mental status changes, ataxia
 Hemodialysis is effective for overdose
 Drug interactions
 Diuretics, NSAIDs
What are the atypical antipsychotics and
what mood disorder can they be used to
treat?
• Olanzapine, Quetiapine, Risperidone,
Aripiprazole, Ziprasidone
– Recently both have been approved for
treatment of acute mania
– Also useful for quick control of psychosis
associated with bipolar disorder