Neuro Pharm ReviewNeuro Pharm Review

John ReedJohn Reed

How does a local anasthetic work?How does a local anasthetic work?

• At normal usage [] Na+ channels are blocked on pain fiber neurons

What are the properties of an ideal What are the properties of an ideal local anesthetic?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 Where should LAs be injected to acquire certain areas of blockage?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 Cl- channels 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 How does the extrapyramidal system work?system work?

Dopamine hyperpolarizes the cholinergic neuron, leading to shut down of GABAergic inhibition

Parkinson’s results from damage toThe nigrostriatal dopaminergic neurons

• 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 byantipsychotics 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 β-blockers 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 What are the major differences between typical and atypical antipsychotic drugs typical and atypical antipsychotic drugs (APDs)?(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. anti-cholinergics) 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 What causes tardive dyskinesia (TD)?(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?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 What was clozapine and what is one major side effect?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 Where do NSAIDs, corticosteroids and other drugs work in the eicosanoid pathway?drugs work in the eicosanoid pathway?

P HO S P HO LIPID

A rach idon ic A cid

R EC E P TO RS

A CT IO N S

R EC E P TO RS

A CT IO N S

C yclicE ndoperoxides

5-H P E T E--LTA 4

LT B 4 LT C 4 LT D 4

LT E 4 LT F4

P rostacyclin T hrom boxane

P rostag land ins

P LA 2 C o rt icos te ro id s( - )

Z af ir lu kas t

Z ileu ton( - )

( - )

( - )C O X 1,2N S A ID S 5-L ip oxyg en ase

NSAIDsNSAIDs

What do NSAIDs help with?1. Antipyresis (control body temp)2. Analgesia (control pain), especially headaches and

muscle pain3. Anti-inflammation (high doses for RhA)4. They can also be used to treat goutWhat are some side effects of NSAIDs?

1. GI Irritation2. Hypersensitivity3. Renal toxicity

Summary of common NSAIDsSummary of common NSAIDsDRUGDRUG ANALGANALG ANTIPYRANTIPYR ANTI INFLAM ANTI INFLAM TOXICITIES &TOXICITIES &

SPECIAL FEATURESSPECIAL FEATURES

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

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

airwaysWhat are their advantages?1. possible monotherapy in mild persistent

asthma2. reduce corticosteroid use in moderate to

severe disease3. 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

Analgesia supraspinal/spinal spinal/supraspinal spinal

Respiratory depression

++ +/− +

Constipation +

Behavioral effects

EuphoriaSedation

EuphoriaDysphoria

Dysphoria(Out of body)

Sedation

Positive reinforcement

++ +

Endogenous ligands

enkephalinsendorphins

enkephalins Dynorphins

GI Tone ++

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 PainManaging 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 (non-myelinated) 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 (10-15%), 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 tooHow 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 CNSWhat 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)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 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 metabolismSummary of AED metabolism

Drug CYP3A4

CYP2C9 CYP2C19

UGT

Carbamazepine +

Phenytoin + +

Valproate + +

Phenobarbital +

ZNS +

Tiagabine +

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 What are some adverse side effects of AEDs?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 What are the more long term adverse effects of AEDs?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/HypnoticsSoporifics/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– barbituratesbarbiturates– benzodiazepinesbenzodiazepines– zolpidem & zaleplonzolpidem & 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, Benzodiazepines, zolpidem & zaleplonzolpidem & 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 don’t take if mental

alertness req’d (driving, machinery use)alertness req’d (driving, machinery use)• BDZs can produce habituation,

dependence, withdrawal so don’t prescribe don’t prescribe if history of alcohol, drug, substance abuseif history of alcohol, drug, substance abuse

• BDZs cross placenta & enter breast-milk so don’t prescribe to pregnant or lactating don’t prescribe to pregnant or lactating womenwomen

• Be careful not to mix with other CNS Be careful not to mix with other CNS depressants (like alcohol); this can be deadlydepressants (like alcohol); this can be deadly

How can benzo overdoses be treated?How can benzo overdoses be treated?• Flumazenil, a selective benzo antagonistFlumazenil, 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 benzodiazepinesbenzodiazepines, but act by binding

the BDZ-site on a subset of GABAA-receptors w 1 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 durationWhy 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

• zaleplonzaleplon preferred for rapid onsetpreferred for rapid onset• zolpidemzolpidem preferred for trouble sleeping through nightpreferred for trouble sleeping through night

What is Kava Kava used for?• Traditional beverage and CNS depressantWhat 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: Diphenhydramine, doxylamine, chlorpheniramine: 1st

generation anti-histamines with considerable anti-cholinergic effects that can inhibit the reticular formation

• Trazedone: anti-depressant used off-label, since NOT a Schedule IV controlled drug NOT a Schedule IV controlled drug (BDZs, (BDZs, zolpidem/zaleplon, chloral hydrate)zolpidem/zaleplon, chloral hydrate) Selective serotonin reuptake inhibitor, but antagonist at other receptors? Effective for antidepressant-induced insomnia

Alcohol Abuse and AlcoholismAlcohol 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

• MostMost ethanol oxidation occurs in the ethanol oxidation occurs in the liverliver

• ~ 90 % ethanol removed by oxidation~ 90 % ethanol removed by oxidation• < 10 % ethanol excreted in breath, < 10 % ethanol excreted in breath,

sweat and urinesweat 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- Cl-

No Alcohol Chronic AlcoholAcute Alcohol

Cl- Cl- Cl-Extracellular

Intracellular

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 is the moderate drinker and which the alcoholic?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

TremorInsomnia

Irritability

MajorAnxietyAgitationDiaphoresis

DeliriumDisorientation

SE

VE

RIT

Y

0 1 2 3 4 5 6 7DAYSseizures

Streissguth, 1994

Faces in Fetal Alcohol Faces in Fetal Alcohol SyndromeSyndrome

DiscriminatingFeatures

Short PalpebralFissures

Flat Midface

Short Nose

IndistinctPhiltrum

Thin Upper Lip

AssociatedFeatures

Epicanthal Folds

Low Nasal Bridge

Minor Ear Abnormalities

Micrognathia

Remember, fetal alcohol syndrome stinks!!!

AnxiolyticsAnxiolytics

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 openingWhat 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 detoxificationHow 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 seizuresHow about BZD intoxication?• confusion• slurred speech• ataxia• drowsiness• dyspnea• HyporeflexiaHow 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

BuspironeBuspirone

How does it work and what is it used for?• Full/Partial agonist at 5-HT1A receptors (no GABA

activity)• Approved for generalized anxiety disorderWhat is it not good for?• Not effective for panic disorder or obsessive compulsive

disorder• No sedative, anticonvulsant or muscle-relaxant

propertiesWhat 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 OCDWhat 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• CBTWhat 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 first-line

• FDA approved drugs include sertraline, paroxetine, venlafaxine

• Benzodiazepines or β-blockers sometimes uses (e.g.,  performance anxiety)

Mood disorder treatmentMood 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 immediateWhy 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 antagonism1-adrenergic antagonismWhat 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 cleftWhat do we use them for? Effective for major depression, panic disorder,

social phobiaWhat 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 MAOIsIrreversible, 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 TCAsWhat are some disadvantages? Also have a temporal delay in action Side effects

NauseaSexual dysfunction

Delayed ejaculation/anorgasmiaAnxiety – early activation Insomnia

How do seratonin NE reuptake inhibitors (SNRIs) work?• They inhibitor reuptake of serotonin and norepinephrineWhat 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 2 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