Block 3

Rationale: restore levels of DA in basal ganglia

• Mechanism: 
• enters brain via amino acid transporters (crosses BBB)
• decarboxylated to dopamine in DA cells and other neurons that express L-AAAD

• Pharmacokinetics:
• 2% gets to brain - remainder is metabolized to dopamine by L-AAAD in peripheral tissue and by COMT --> too much dopamine in periphery and too little in CNS -- coadminister with carbidopa

T1/2=1-3 hrs

Absorption dependent on gastric contents - competition for amino acid uptake sites

Effectiveness: highly effective, treats all Parkinsons symstoms, beneficial effects outlast plasma half-life - wait to start treatment until patient shows debilitation

• SE: come from conversion to DA
• CNS: wearing off, dyskinesias, hallucinations and confusions (in elderly)
• Peripheral:
• GI problems
• CV problems - hypotension, arrhythmias, hypertension

Contraindications: glaucoma, psychosis, cardiac arrhythmias, malignant melanoma

Drug interactions: pyridoxine, MAO inhibitors, halothane, typical antipsychotics 

May make Parkinson's worse b/c of oxidative stress theory

• Mechanism:
• Inhibitor of L-AAAD
• Does not cross BBB

• Co--administer with L-DOPA for Parkinson's
• Results in increased dose of L-DOPA to CNS - decreased peripheral side effects

Rationale: mimic effects of dopamine without needing intact nerve terminals

• Mechansim:
• Selective D₂ receptor agonist in the striatum

Kinetics: titrated to therapeutic doses over a week or less

• Use:
• Parkinson's
• initial treatment of disease over L-DOPA-->
• fewer dyskinesia side effects 
• longer T_1/2
• Less oxidative stress
• Good for treatment of on/off phenomenon
• Better in young patients
• More useful in late disease b/c no conversion

• SE:
• nausea
• fatigue
• sudden attacks of sleep during daytime
• CNS toxicity: worse confusion than L-DOPA, not as bad dyskinesia

Rationale: mimic effects of dopamine without needing intact nerve terminals

Mechansim: Selective D2 receptor agonist in the striatum

Kinetics: titrated to therapeutic doses over a week or less

• Use: 
• Parkinson's
• initial treatment of disease over L-DOPA-->
• fewer dyskinesia side effects 
• longer T1/2
• Less oxidative stress
• Good for treatment of on/off phenomenon
• Better in young patients
• More useful in late disease b/c no conversion

• SE:
• nausea
• fatigue
• sudden attacks of sleep during daytime
• CNS toxicity: worse confusion than L-DOPA, not as bad dyskinesia

Rationale: mimic effects of dopamine without needing intact nerve terminal

Mechanism: D₄ receptor agonist (moderate D_2,3,4,5) in striatum

Use: reserved for patients that are refractory to other treatments for Parkinson's, given subcutaneous injection as rescue therapy for treatment of "off" episodes

• SE: 
• nausea, used with trimethobenzamide
• fatigue
• sudden attacks of sleep
• CNS toxicity
• QT prolongation and injection-site reactions

Rationale: potentiate actions of endogenously produced dopamine with inhibitors of its catabolism by MAO, may reduce oxidative stress 

Mechanism: selective, irreversible, inhibition of MAO-B (inhibit DA catabolism in striatum w/out effect on tyramine).  

Inhibition of MAO in the periphery causes hypertension if patient consumes tyramine containing foods

Use: Often given with L-DOPA to prolong therapeutic half-life and to decrease on-off effects.  Modest benefit in treatment and disease progression of Parkinson's disease

• SE:
• Well tolerated in early PD
• Worsen L-DOPA induced CNS side effects in advaned disease
• Metabolized to amphetamine and methamphetamine - causing anxiety, insomnia (redued via patch or fizzy to avoid first-pass)

• Adverse Drug Interactions:
• meperidine: combination can result in stupor, rigidity, agitation, hyperthermia
• tricyclic antidepressants
• serotonin-reuptake inhibitors

Rationale: potentiate actions of endogenously produced dopamine with inhibitors of its catabolism by MAO, may reduce oxidative stress 

Mechanism: selective, irreversible, inhibition of MAO-B (inhibit DA catabolism in striatum w/out effect on tyramine).  

Inhibition of MAO in the periphery causes hypertension if patient consumes tyramine containing foods

Use: Often given with L-DOPA to prolong therapeutic half-life and to decrease on-off effects.  Modest benefit in treatment and disease progression of Parkinson's disease

• SE:
• Well tolerated in early PD
• Worsen L-DOPA induced CNS side effects in advaned disease

• Adverse Drug Interactions:
• meperidine: combination can result in stupor, rigidity, agitation, hyperthermia
• tricyclic antidepressants
• serotonin-reuptake inhibitors - Serotonin Syndrome

Rationale: COMT metabolizes dopamine and L-DOPA so its inhibition will increase L-DOPA access to the brain and prolong the action of dopamine

Mechanism: COMT inhibitor, short T_1/2, inhibits peripheral COMT primarily (does not get into CNS well so only useful when administered with L-DOPA)

Use: Parkinson's

SE: nausea, orthostatic hypotension, vivid dreams, confusion, hallucinations (d/t decreased dopamine)

Rationale: cholinergic interneurons in the striatum are normally inhibited by dopamine; loss of dopamine results in overactivity of these neurons

Mechanism: antagonist of striatal muscarinic receptors

Use: modest efficacy for Parkinson's, used in early disease in the elderly or as an adjunct to dopaminergic therapy, 3rd choice

SE: sedation, mental confusion, atropine-like effects (mad as a hatter, etc.)

Rationale: cholinergic interneurons in the striatum are normally inhibited by dopamine; loss of dopamine results in overactivity of these neurons

Mechanism: antagonist of striatal muscarinic receptors

Use: modest efficacy for Parkinson's, used in early disease, in the elderly, or as an adjunct to dopaminergic therapy

SE: sedation, mental confusion, atropine like effects (mad as a hatter, etc.)

Rationale: none, discovered by serendipity

Mechanism: increases dopamine release; mildy anticholinergic; blocks NMDA receptors

• blocks viral uncoating by interfering w/ influenza A M2 protein (an ion channel)
• no significant hepatic metabolism; 90% excreted unchanged in urine - reduce dose in renal disease

Use: short-lived benefits for Parkinson's, often in combo w/ L-DOPA or anticholinergics, not useful when L-DOPA is ineffective

• Prophylaxis against influenza A but NOT B - reduces fever in 50% of patients and illness duration by 1-2 days if given w/in first 2 days of illness - for last few years, influenza A strains have been resistant to this drug
• SE: CNS effects, dizziness, lethargy, anticholinergic effects, peripheral edema, sleep disturbances, slurred speech, anxiety, depression, headache, hallucinations

Contraindicated in patients with CHF d/t sympathomimetic effects

Mechanism: increase amt of ACh in cerebral cortex by inhibiting catabolism with cholinesterase inhibitors

Use: Alzheimer's Disease

• SE: many, 1/3 have GI problems

Mechanism: increase amt of ACh in cerebral cortex by inhibiting catabolism with cholinesterase inhibitors

Use: Alzheimer's Disease

SE: many, 1/3 have GI problems

Mechanism: increase amt of ACh in cerebral cortex by inhibiting catabolism with cholinesterase inhibitors

Use: Alzheimer's Disease

SE: many, 1/3 have GI problems

Mechanism: non-competitive NMDA channel blocker

Use: Alzheimer's disease, associated with reduced rate of clinical deterioration

Mechanism: inhibitor of NMDA channels - inhibits glutamate release, increases glutamate uptake, inhibits glutamate receptors

Use: Amyotrophic lateral sclerosis - increases life span 2-3 months

minimal alveolar concentration that prevents movement in response to pain in 50% of subjects

• advantages of measurement:
• 1) can be continuously monitered by measuring end-tidal anesthetic concentration
• 2) provides direct correlate to anesthetic concentration at the site of action in CNS
• 3) simple to measure end point (lack of movement)

barbiturate - parenterally administered anesthetic

Use/administration: induce anesthesia, typical inudction produces unconsciousness in 10 to 30 sec; duration of action of single dose is abt 10 min.

T_1/2= 12 hrs --> residual effects (hang over) after anesthesia wears off

Dose should be reduced if patient has been premedicated with other CNS depressants, including opiates, benzodiazepines, and alpha2 agonists

Intra-arterial injection can produce severe inflammation and necrotic

Can be administered to pediatric patients rectally if needed

• SE: 
• 1) CNS depression: reduces cerebral oxygen utilization, bloow flow and intracranial pressure (protective agent for tx of cerebral ischemia/swelling in brain)
• 2) CV: produces vasodilation on venous side, decreasing preload and BP, demand on heart is reduces with coronary artery disease
• 3) Respiratory depression

parenterally administered anesthetic

GABA_A activation

Onset and duration of anesthesia same as barbiturates

• Use:
• maintain and induce anesthesia - short procedures
• Antiemetic
• Shorter half life than thiopental; used when rapid return to normal mental status is desired (out-patient surgery)

• SE:
• sexual dreams
• elicits pain on injection
• excitation during induction
• CNS
• CV (more severe decrease in BP than thiopental), 
• Vasodilation and depression of myocardial contractility
• Blunts baroreceptor reflexes - careful w/ patients intolerant to decreases in BP
• More respiratory depression than thiopental

parenterally administered anesthetic

Use: induce anesthesia in patients at risk for hypotension

High incidence of pain on injection and myoclonus (pain dealt w/ using lidocaine and myoclonus reduced by medication with benzodiazepines or opiates)

• SE: 
• CNS: like thiopental
• CV: less than thiopental and propofol - small increase in HR, little or no decreas in BP
• Less respiratory depression than thiopental
• Lots more nausea and vomiting
• Increased post-surgical mortality d/t suppresion of adrenocortical stress response; primarily when anesthetic given for prolonged time - only used to induce anesthesia in patients prone to hemodynamic problems

parenterally administered anesthetic

Use: reserved for patients with bronchospasm, children undergoing short painful procedures

• produces hypnotic state: dissociative anesthesia
• unresponsive to commants even though eyes open
• spontaneous respiration - no respiratory depression - bronchodilator

also used as a drug of abuse: drunken state, numbness of extremities, etc.

• SE: 
• nystagmus, salivation, lacrimation, spontaneous limb movements, and increased muscle tone
• increased intracranial pressure (d/t increased cerebral blood flow)
• emergence delirium: hallucinations, vivid dreams, illusions
• increased BP d/t indirect sympathomimetic activity

Short acting benzodiazepine (half life = 1-5 hrs), parenterally administered anesthetic

Use: conscious sedation, anxiolysis and amnesia during minoar surgical procedures

• induction agent
• adjunct during regional anesthesia (tooth extraction)
• anti-anxiety effects make it useful preoperatively

slower induction time and longer duration than thiopental

• SE: 
• respiratory depression/arrest (especially when used IV to produce conscious sedation)
• CV: like thiopental

Used w/ caution in patients w/ neuromuscular disease; Parkinson's; biopolar disorder

inhalation anesthetic

Use: commonly used in US, used to induce and mostly maintain anesthesia, co-administered w/ nitrous oxide to allow for reduced dose

• Kinetics: 
• moderate blood:gas partition coefficient
• 99% excreted unchanged from lungs

• SE:
• respiratory: airway irritant, coughing, decreases tidal volume and increases RR, respiratory depressant, increases PaCO2

CV: myocardial depression, decrease BP, arrythmias; sensitizes heart to catecholamines, dilates cerebral blood vessels increasing intracranial pressure

inhaled anesthetic

Use: outpatient surgeries, can cause coughing and bronchospasm in awake patients so anesthesia is induced w/ IV agent, produces direct skeletal muscle relxation

Kinetics: volatile at room temp., special equipment to administer, LOW blood:gast partition coefficient(rapid induction & recovery), predominantly excreted unchanged

• SE:
• CV: similiar to isoflurane
• Respiratory: similar to isoflurane and is a respiratory irritant

inhaled anesthetic

Use: inpatient and outpatient; induction and maintenance; children and adults, not a respiratory irritant

• Kinetics:
• LOW blood:gast partition coefficient
• 5% of administered dose is metabolized to fluoride ion in the liver - renal damage
• Ex vivo degradation by CO2 absorbants in the anesthesia circuit forms compound A (nephrotoxic in rats)
• SE:
• CV: similar to isoflurane
• Respiratory: similar to isoflurane but less respiratory depression

true gas inhaled anesthetic

• Use:
• weak anesthetic, only gets to full efficacy under hyperbaric conditions - cannot be used at greater than 80% oxygen requirements
• used to produce sedation and analgesia in outpatient dentistry
• used as an adjunct with other inhalation anesthetics, allows for a reduction in their dose

• Kinetics:
• very insoluble in blood and other tissues -- rapid equilibration -- rapid induction and recovery

rapid uptake from alveolae result in concentration of gases that are administered at the same time - co-administered with other inhalation anesthetics

dilute oxygen when its use is discontinued, need to place patients on 100% O2 during emergence

99% excretion through the lungs unchanged

• SE: 
• can exchange with nitrogen in any air-containing cavity - contraindicated in pneumothroax

negative inotrope but also sympatho-stimulant

respiratory effects are minimal except for oxygen dilution issue 

abuse liability

symptoms most commonly presented to family doctors & specialists

affects 4-8% of general population

Physiological correlates - general, persistent for 1 month duration

Somatic correlates - tachycardia & palpitations

Complications: abuse of alcohol, sedatives, and medications are common

• Act on sites on GABA Cl ion channel complex
• Enhances action of GABA
• Increases frequency of GABA induced Cl channel openings

Used for anxiety and used primarily to promote SLEEP, also for alcohol withdrawal

Pharmacokinetics are related to relatively lipophilicity

Most form active metabolites that can have very long half lives

• Pharmacological effects:
• decrease anxiety
• sedation
• hypnosis - decreased latency to sleep, increases stages 1 and 2, decreased time in stage 3/4REM
• muscle relaxation 
• anterograde amnesia - IV administration
• anticonvulsant action
• CV and respiratory actions - minimal at TD

• Drug interactions:
• Produce additive CNS depression w/ most other depressant drugs (ex: ethanol)
• Drugs that affect hepatic metabolism

• Tolerance
• Dependence and withdrawl: anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures
• Tx of abuse - gradual dose reduction, switch to longer acting drugs

Act at site on GABA receptor-chloride ion channel complex

• Use:
• Among earliest sedative hypnotic pharmaceuticals used (rarely used today)
• Anticonvulsant
• Induction of anesthesia

Weak acids and also salts of the compounds are formed

• Metabolism/pharm:
• absorbed and distributed to all tissues and body fluids.
• highly lipid soluble, distribute rapidly to brain and redistribute to fat
• induce their own metabolism and that of other drugs
• renal excretion

• Actions:
• General CNS depression - sedation, hypnotic, anesthesia
• Anticonvulsant
• Respiratory depressioin
• CV effects minimal but w/ high doses can produce decrease in MAP and pulse pressure
• Exacerbation of acute intermittent porpyria - increased synthesis of d-aminolevulinic acid synthestase
• Tolerance 0 both metabolic and pharmacodynamic
• Physical dependence
• Acute poisoning - stupor, compa, respiratory depression

• Drug interactions: Additive with other CNS depressants
• Drugs that affect microsomal drug metabolism

Mostly benzodiazepines that induce sleep

Includes flurazepam, triazolam, and lorazepam.

Has sites to which benzodiazepines and barbiturates bind.

GABAA receptor 

High concentration in striatum, hippocampus, and spinal cord

Binding of substrange increases chloride conductance

Complex made of several subunits

Induces nervous system to stay calm

Use: anxiety

partial agonist for 5-HT_1A - inhibits adenylate cyclase and opens K+ channels

also binds dopamine receptors with less afinity

not related chemically or pharmacologically to the benzodiazepines

• T1/2 = 2-11 hrs
• Less sedating than benzodiazepines
• No cross-tolerance with benzodizepines

Does not potentiate other sedative-hypnotics and depressants nor suppress symptoms of their withdrawl

Used in tx of generalized anxiety syndrome

Effects: 1-2 weeks to occur

Use: treat anxiety, PANIC DISORDER!!!!!!!

Use: treat anxiety, acute manic episodes - adjunct for quick control of manic symtoms - no extra pryamidal symptoms

long lasting effects against absence seizure & some myoclonic seizures

Use: anxiety, alcohol withdrawl (gradual reduction of dose "tapering off")

Benzodiazepine agonist

Use: treat anxiety, muscle relaxant, IV sedation & anesthesia, used in patients with muscle spasm of almost any origin including local trauma, management of alcohol withdrawl (gradual reduction of dose "tapering off")

IV: status epilepticus

• fast onset of action - oral
• high lipid solubility - rapid absorption/entry into brain (most rapidly absorbed benzodiazepine)
• rapid redistribution after single dose
• active metabolites change this in multiple dose situation

Action in reducing spasticity is partly mediated in spinal cord

Withdrawl: anxiety, insomnia, irritability, headache, hyperacusis, hallucinatinos, seizures 

Tx of abuse: gradual dose reduction, switch to longer acting drugs

Benzodiazepine antagnoist at receptor

Used for benzodiazepine overdoses

• Use: treat anxiety, hypnotic
• IV: status epilepticus

• less lipophilic than diazepam
• absorption and onset of action are slower
• longer duration of action after single dose
• no active metabolites- glucuronidation occurs

Use: skeletal muscle relaxant

• Gaba - mimetic agent that works at GABA_B receptors
• Results in hyperpolarization causing presynaptic inhibition
• Decreases release of excitatory transmitters such as glu
• As effective as diazepam in reducing spasticity and produces much less sedation

Use: muscle spasm

• alpha 2 agonist related to clonidine
• enhances presynaptic and postsynaptic inhibition

similar efficacy to diazepam 

SE: drowsiness, hypotension, dry mouth, anesthesia

Interacts w/ CYP1A2 inhibitors

Use: sedative hypnotic

Aledhyde hydrate with pungent taste and somewhat caustic taste

• Metabolized to trichloroethanol - active form
• Pharm similar to barbiturates
• Less effects on stages of sleep

Newer hypnotic drug

• Non-benzodiazepine, approved for long term use
• Interaction w/ GABA-receptor complex at binding domains located close to/allosterically coupled to BZD receptors

Similar mechanism to zolpidem and zaleplon

benzodiazepine used as hypnotic

rapid onset of action, long duration of action

barbiturate 

hypnotic

rarely used today

melatonin MT1 and MT2 receptor-agonist

Specifically indicated for tx of insomnia characterized by difficulty in falling asleep - not a controlled substance

benzodiazepine used as hypnotic

rapid onset of action and ultrashort duration of action

Very similar to zolpidem

• Non-benzodiazepine chemially
• Bind to BDZ receptor on GABA receptor complex
• Weak anxiolytic, muscle relaxant and anticonvulsant at hypnotic dose

Stage 3 and 4 sleep preserved, minor effects on REM sleep

Non-benzodiazepine chemically that binds BDZ receptor

Weak anxiolytic, muscle relaxant, and anticonvulsant at hypnotic dose

Sleep disruption of sleep architecture - Stage 3/4 sleep preserved, minor effects on REM sleep

• Typial duration of action 5-6 hrs
• Sustained release prep now available
• Duration of action: 7-8 hrs
• Antagnoized by flumazenil

Enzyme in primary pathway for ethanol oxidation to acetaldehyde; rate limiting

Primarily in liver (but also in other tissues)

Kinetics of ethanol elimination by this pathway are zero order at the concentrations of ethanol consumed

AKA Mixed Function Oxidase System (MFOS)

High km - little contribution at concentrations below 100mg/dl

Induced in alcoholics - CYP2E1 - influences metabolism of other drugs

• Mitochondrial enzyme
• Used for acetaldehyde metabolism
• Oxidizes acetaldehyde to acetate
• Genetic polymorphisms
• Inhibition by disulfiram

reduces "urge to drink"; increases control

opioid receptor antagonist

orally active w/ long half-life

best together w/ psychosocial therapy

agonist GABA_A & NMDA competitive antagonist

Decreases drinking frequency and reduces releapse

Well tolerated - primary SE is diarrhea

Aversion therapy

Mechanism of action: inhibition of alehyde dehydrogenase

Acetaldehyde syndrome - not very effective/ethical

• Blocks adenosine receptor
• Inhibits phosphodieasterase
• Increases Ca release from intracellular stores

Less fatigue, etc.

High doses stimulate medullary respiratory, vasomotor, and vagal center

Stimulate myocardium

Dilates general blood vessels but constricts cerebral blood vessels :) for headache

Modest bronchodilator

Post synaptic receptors hyperpolarize membrane

Presynaptic receptors inhibit glutamate release

Caffeine blocks these types of receptors

Use: local anesthesia in upper respiratory track (nose surgery)

• Weak base
• Well absorbed through mucus membranes/lungs
• IV = time to peak & duration shorter
• Metabolized by serum & liver esterases
• Metabolites seen in urine (drug test)

• Mechanism: 
• inhibitor of reuptake of NE, dopamine, serotonin, 
• increases ligand in synapse b/c competes w/ dopamine transporter
• increases tyrosine and tryptophan hydroxylase

• Pharm effects:
• vasoconstriction
• tachycardia
• increased alertness
• euphoria
• elation
• well being
• competency

• Toxicity:
• mild w/drawal symptoms
• seizures/CV effects
• fetal effects > alcohol (attachment disorder)

Use: narcolepsy, ADHD

• releases NE, dopamine, serotonin
• Blocks transmitter uptake into presynaptic terminals
• Direct partial agonist of alpha adrenergic receptors
• MAO inhibition

• Effects:
• wakefulness, alertness, less fatigue
• enhances athletic/intellectual performance
• Mood elevation/self confidence
• Speed
• Respiratory stimulation
• Decreases appetite

• SE:
• insomnia
• abdominal pain
• anorexia
• growth suppression
• fever

Toxicity: restlessness, dizziness, tremor, psychosis, permament intellectual problems

structurally different from amphetamines 

Use:ADHD

• Mechanism: 
• release NE, dopamine, serotonin
• blocks transmitter uptake into presynaptic terminals
• direct partial agonist of alpha adrenergic receptors
• MAO inhibition

• Effects:
• wakefulness, alertness, decrease fatigue
• enhances athletic/intellectual performance
• mood elevation/self confidence
• speed
• respiratory stimulation
• decrease appetite

• SE: 
• insomnia, abdominal pain, anorexia, growth suppression, fever

Toxcitiy: restlessness, dizziness, tremor, psychosis, permanent intellectual problems

better CNS bioavailability and effect than other amphetmines

higher abuse liability

• Mechanism:
• release NE, dopamine, serotonin
• blocks transmitter uptake into presynaptic terminals
• direct partial agonist of alpha adrenergic receptors
• MAO inhibition

• Properties:
• wakefullness, alertness, enhances athletic/intellectual performance, respiratory stimulation, decreased appetite

SE: insomnia, abdominal pain, anorexia, growth suppression, fever

Toxicity: restlessness, dizziness, tremor, psychosis, permanent intellectual problems

• agonist of nicotinic cholinergic receptors
• NMJ not affected as much
• Autonomic ganglia - release epinephrine & GI effects
• CNS receptors - membrane depolarization

Actions: alertness, activates domaine signalling, muscle relaxant

• Tolerance/dependence: 
• readily aborbed through mucus membranes (lungs -> brain in 7 secs)
• Reinforcing (several puffs)
• Tolerance throughout day
• W/drawal: irritability, anxiety, depression, difficulty concentrating, increased appetite, weight gain

unknown mechanism - enhance noradrenergic & dopaminergic signalling (blocks NE and DA uptake)

moderate effectiveness; reduce craving and withdrawal symptoms of nicotine addiction, atypical antidepressant, seasonal affect disorder

SE: dry mouth & insomnia

partial agnoist of CNS nicotinic receptors - reduces cravings/withdrawal from nicotine

significant improvement in abstinence

SE: nausea, insomnia, headache, constipation, increased thoughts of suicide, depression

A group of disorders characterized by excessive excitability of neurons w/in th CNS.

Symptoms can range from brief periods of unconscioussness to convulsions.  Incidence is 5/1000.

60% of those w/ the disorder can be rendered seizure free w/ drugs! :)

Focal 

• Simple: no impairment of consciousness
• Complex: dreamy dysaffective state

impairs consciousness and distorts the electrical activity of the whole or a larger portion of the brain

• Types:
• Tonic-Clonic
• Absence
• Myoclonic 
• Status epilepticus

grand mal

loss of concsciousness, falling

• rigid extension of trunk/limbs (tonic phase)
• rhythmic contraction or arms/legs (clonic phase)

petit mal

impaired consciousness with staring spells, with or without eye blinks

• jerks/shocklike contractions
• loss of muscle tone
• falling
• "drop attacks"

seizures recurring so close together that baseline consciousness is not regained between seizures

Use: tonic-clonic and partial seizures (NOT absence)

• Alters ion conductases
• Use dependent effect on Na channels
• Inhibits generation of reptitive APs

• Highly plasma bound
• Dose dependent

May interact w/ drugs metabolized by CYP & protein bound drugs

• SE:
• CNS: nausea, anorexia, apathy, sedation, ataxia, nystagmus, diplopia - dose dependent

• Gingival hyperplasia 
• Hirsutism 
• Teratogenicity- fetal hydantoin syndrome - cardiac symptoms, cleft palate 
• Hypersensitivity reactions - rash

All forms epilepsy EXCEPT absence seizures

• Blocks Na channels
• Unpredictable absorption
• Hepatic enzyme induction

• SE: 
• diplopia, ataxia, GI upset, drowsiness, rare blood dyscrasias

newer carbamazepine analog

• similar in action but less likely to cause CNS SE
• Less enzyme induction

• oldest antiseizure
• partial seizures and tonic clonic

• Acts on GABA receptor Cl ion channel complex
• Selectively suppress abnormal neurons by suppresing firing from the foci and inhibiting spread

Well absorbed, long half life, induces hepatic enzymes

SE: drowsiness, sedation, confusion, exacerbation of acute intermittent porphyria

Drug interactions: CNS depressants, valproic acid

tx for ABSENCE seizures

reduces low threshold(T-type) calcium currents in thalamic neurons

• well absorbed
• not protein bound
• liver metabolism - inhibited by valproic acid
• long half life

• SE
• among safest of antiseizure drugs
• gastric disease, lethargy, fatigue

• blocks reptitive neuronal firing
• may reduce T-type Ca currents
• Increase GABA concentration

• well absorbed
• bound to plasma protein - competes w/ phenytoin
• inhibits metabolism of phenobarbital, phenytoin, and carbamazepine

Use: absence seizures, tonic-clonic, partial, and myoclonic - may be used as a first-line drug in mania, mixed mania (sedating)

• SE:
• GI upset, weight gain, hair loss, hepatoxicity, teratogenicity (spinal bifida)

May act at glycine site of NMDA receptor, also potentiates GABA

Used for partial seizures REFRACTORY to other drugs

SE: aplastic anemia, hepatic failure

• GABA analog 
• Adjunct therapy for partial seizures

• Not protein bound or metabolized by liver
• Also used for neuropathic pain and ALS

structurally similar to gabapentin but more potent

may interact w/ calcium channels to reduce NT release

• adjunct therapy for partial seizures
• management of neuropathic pain associated w/ diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia

limited abuse potential

Blocks repetitive APs and may block Na channels

• Used for partial and tonic-clonic seizures
• Approved for bipolar disorder

SE: serious rash including Stevens-Johnson syndrome

• Structurally related to D-fructose
• May block kainate-AMPA-type glutamate receptors and enhance GABA effects - may also block Na channels

• Blocks spread of seizures
• Used for partial seizures
• Prevention of migraines
• SE: weight loss

inhibits GABA transporter GAT-1 and blocks GABA uptake

Adjunct therapy for simple and complex partial seizures

SE: dizziness, tremor, somnolence

adjunct tx of partial seizures & myoclonic seizures

few drug interactions

SE: somnolence, asthenia, dizziness

• inhibits T-type Ca channels and Na channels
• stops spread of seizures and suppresses their focus

Adjunct tx of adults w/ partial seizures

SE: ataxia, anorexia, nervousness, fatigue, speach impairment

irreversibly blocks GABA metabolism

adjunct tx of refractory complex partial seizures and infantile spasms

possible permanent effects on vision

Ester

Short acting; first synthetic local anesthetic

Supplanted by newer agents but still used for infiltration of anesthesia

Low potency, slow onset, short duration of action

Long acting ester local anesthetic

Ester

More potent & longer duration of action than procaine

Used in spinal anesthesia & topical/ophthalmic preprations

Not for peripheral nerve block

Ester

Anesthetic w/ low water solubility; too slowly absorbed when applied topically to be toxic

Applied to wounds & ulcerated surfaces where it provides relief for long periods of time

Amide

Intermediate duration of action

Produces faster, more intense, longer lasting, more extensive anesthesia compared to procaine

Often used w/ vasoconstrictors to decrease toxicity and decrease rate of absorption (epinephrine)

Wide range of clinical uses

metabolized by liver

Amide

Long lasting amide local anesthetic

Capable of producing prolonged anesthesia

Provides more sensory than motor block

More cardiotoxic than equieffective doses of lidocaine (severe ventricular arrhythmias and myocardial depression) - dissociates from Na channels slowly resulting in increased potency for blocking cardiac conduction

S-enantiomer is available that is less toxic

Amide

Long lasting amide local anesthetic consisting of S-enantiomer

Anesthetic actions similiar to bupivicaine w/ less cardiotoxicity

Suitable for epidural and regional anesthesia

Even more motor sparing than bupivacain

• depressed mood
• diminished interest or pleasure
• weight change
• insomnia/hypersomnia
• fatigue or loss of energy
• feelings of worthlessness
• inappropriate guilt
• agitation/retardation
• difficulty concentrating
• preoccupation with death/suicidal ideation

most commonly used antidepressant

both long half life and short life available

• SE: nausea, vomiting, insomnia, nervousness, sexual dysfxn
• Acute toxicity less than TCAs and MAO inhibitors - less risk of overdose

• Use:
• major depressive disorder
• OCD
• panic disorder
• social phobia
• PTSD
• generalized anxiety disorder
• PMS

• SSRI
• effects drug metabolism
• active metabolite with long half-life
• available as sustained release product

in conjunction w/ olanzapine - tx of depressive episodes associated with bipolar disease

• SSRI
• similar in action to fluoxetine w/ less effects on drug metabolism
• shorter half-life

• SSRI w/ highest specificity for serotonin
• low anticholinergic activity
• available in in sustained release form

SSRI

also used for anxiety

SSRI

active s-enantiomer form of citalopram

blocks both serotonin and norepinephrine uptake

SNRI

effective in severe depression and anxiety

SNRI

12-18 hr half life

use w/ caution in patients w/ liver disease

also approved for: fibromyalgia, diabetic neuropathy, back pain, and osteoarthritis pain

SNRI

fibromyalgia

atypical antidepressant

blocks presynaptic alpha2 receptors in brain

increases appetite

• first highly effective drugs for depression
• now secondary to SSRIs and other newer compounds

• rapidly absorbed after parenteral or oral administration
• relatively high concentrations in brain and heart

long plasma half life (8-100 hrs)

• produces mood elevation in 2-3 weeks
• decreases REM sleep and increases tage 4
• prominent anticholinergic effects
• sedation
• orthostatic hypotension
• demethylated to active metabolites

cardiac abnormalities: d/t anticholinergic effects and increased NE concentrations - palpitations, tachycardia, and arrythmias - EKG changes (lengthened QRS intervals, flattened/inverted T waves)

overdose/acute toxicity: hyperpyrexia, hyper/hypotension , seizures, coma

• drug interactions:
• guanethidine: blocks uptake
• sympathomimetic drugs (indirect acting)
• effects on absorption and metabolism of other drugs

tricyclic antidepressant

enuresis in childhood

tricyclic antidepressant

chronic pain

migraine prophylactic

tricyclic antidepressant

obsessive compulsive disorder

blocks oxidative deamination of naturally occuring biogenic amines (NE, DA, and 5-HT)

MAO found in mitochondrial fraction of neurons (MAO A) and also liver, lung, and other organs

MAO A inhibition for antidepressants

irreversible MAOI

• Use: antidepressant action takes 2 weeks - not drug of first choice for major depression
• narcolepsy

mood elevation, may progress to hypomania in bipolar disease

corrects sleep disorders - most potent REM sleep suppressant

SE: orthostatic hypotension, agitation, hallucinations, hyperpyrexia, convulsions

• Drug/food interactions:
• sympathetic amines and their precursors
• tricyclic antidepressants
• tyramine from food - HTN crisis

derangement of personality

loss of contact w/ reality

delusions

hallucinations

positive: delusions, hallucinations, hostility, disorganized speech

negative: blunted affect, emotional withdrawal

hyperactivity of DA neurons in limbic areas

cognitition, communication, social activity

diminished DA activity: negative symptoms

arousal, memor, stimulus processing, locomotor activity

dopamine hyperactivity: positive symptoms

late reaction

oral-facial dyskinesias, choreathetoid movements

Uses: acute psychotic episodes, chronic schizophrenia, mani episodes, augmentation of antidepressant action, Tourettes, antiemesis

• Less extrapyramidal syndrome (better compliance)
• Lower tardive dyskinesia
• Improves negatiive symptoms
• Improves positiv esymptoms in resistant or refractory patients

SE: aplastic anemia, weight gain

back and forth between irritable, depressed mood and very good mood

• Typical antipsychotic
• Phenothiazine
• Low/medium potency
• Sedative
• Pronounced anticholinergic actions

• Typical antipsychotic
• Low potency
• sedative
• Less extrapyramidal actions
• anticholinergic
• piperidine side chain

• Typical antipsychotic
• High potency
• Less sedative
• Less anticholinergic
• More extrapyramidal reactions
• Piperazine side chain

• Typical antipsychotic
• similiar pharmacology to phenothazines (chlorpromazine) - low potency
• non-nitrogen analog to phenothiazine

• Typical antipsychotic
• not chemically related to phenothiazines
• pharmacologically similar to high potency piperazine derivates (fluphenzine)

• Typical antipsychotic
• potent
• many SE
• used for Tourette's
• commonly used when haloperidol doesn't work

• Atypical antipsychotic
• Blocks D4 (little effect on D2)
• muscarinic antagonist
• Improves positive symptoms even in patients not helped by other drugs
• Improves negative symptoms
• Decreases seizure threshold more than other antipsychotics
• Can cause fatal agranulocytosis - requires monitoring

• Potent 5-HT2 antagonist
• D1, D2, D4 antagonist
• Few extrapyramidal symptoms (5-HT >D)
• Less seizures
• No agranulocytosis
• Weight gain and diabetes risk

In conjunction w/ fluoxetine - tx of depressive episodes associated with bipolar disease

• Combined D2 & 5-HT2 antagonist
• Greater decrease in negative symptoms
• Low incidene of extrapyramidal SE
• Less seizure activity
• Paliperidone is the active metabolite

structurally related to cloazpine with effects on D2 and 5-HT2 receptors

Approved for augmentation in depression

Shorter T1/2

• May also have 5-HT1a agonist activity
• No weight gain

• D2 partial agonist
• Approved as adjunct in the tx of depression

• low therapeutic index - plasma levels must be monitored
• blocks manic behavior (takes some time to take effect)
• reduces release of IP3 and DAG
• readily absorbed - increased Na exceretion increases Lithium level in the cell - toxicity
• Interactions w/ ACE inhibitors and Ang. II

• Use:
• manic episodes
• bipolar depression
• Aggressive, violent, anti-social behavior

SE: fatigue, tremor, GI symptoms, goiter, don't use in pregnancy, slurred speech

• Serious toxicit:
• impaired consciousness
• rigidity/hyperactive deep reflexes
• Coma

co-released w/ ACTH in response stress

endogenous ligand of mu receptor

endogenous ligand for kappa receptor

colocalizes with magnocellular cells of hypothalmus and posterior lobe of pituitary gland

endogenous ligand of delta receptor

distributed widely throughout CNS

• extensive first pass 
• injectable, oral, suppository
• 4-5 hrs
• Mu receptor agonist

More lipophilic than morephine

Activated by metabolism

High abuse potential

• Mild to moderate pain
• cough supression

Morphine-like efficacy not achievable at any dose

Some metabolized to morphine

Often used in combination with aspirin or acetaminophen

Moderate to severe pain

often used in combination with aspirin or acetaminophen

available as sustained release oral preparation-major abuse problem

cough suppression

• equipotent with morphine; good oral availability
• longer duration of action
• used in tx of opioid abuse

shorter duration of analgesia than morphine

forms toxic metabolite that can accumulate with frequent use

interactions with MAOI

structurally related to meperidine

100x as potent as morphine

short acting 1-1.5 hrs

available as injectable form and as transdermal patches - also available as buccal soluble film for breakthrough pain

2-3x as potent as morphine

stronger than codeine, but not as strong as morphine

mu and kappa agonist

similar in efficacy and potency to morphine

much lower abuse potential

can ppt w/drawal in opioid dependent patients

available only in injectable form

• partial mu agonist
• used to tx moderate to severe pain - now available as a patch

orally combined with naloxone used to tx opioid dependence

opioid antagonist

high affinity for mu receptors - significantly less for kappa/delta

• much greater activity parenterally than orally
• extensive first pass metabolism
• short duration of action (1-2hrs)
• used to tx opioid overdoses (used in combo w/ buprenorphine)

can be combined w/ opioids to decrease abuse liability

dextro-opioid isomer - antitussive, but not analgesic (cough suppression)

• weak mu agonist
• also blocks NE and 5-HT uptake
• used for milkd to moderate pain
• available for oral use including sustained release prep

tx of opioid abuse

decrease in response to a drug as a result of repeated tx w/ drug

physical symptoms produced by drug withdrawal

compulsive feelings of the need to take a particular drug

maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by 3 or more of tehh following in 12 month period:

• tolerance
• withdrawal
• substanec taken in large amts over long period than intended
• persistent desire/unsuccessful efforts to cut down or control

• unique marijuana plant
• related to hop plant
• main ingredient - 9-tetrahydrocannabinol

• main active ingredient of marijuana
• content determines potency
• rapidly metabolized by liver to highly active compound

use is age and sex related

rapidly metabolized by liver to 11-oh-9-THC - highly active

metabolites excreted in urine & feces - detectable for many days

3-5x more potent when smoked

• effects: euphoria, memory impairment, motor performance
• CV: tachycardia, orthostatic hypotension, angina
• pulmonary: bronchodilation, lung irritant, decreased ciliary fxn
• reproduction: lower testoserone and sperm count, decreased fsh, lh, proloactin, abnormal menstrual cycle

psychopathological: acute anxiety rxn, transient periods of paranoi

tolerance/dependence: restlessness, irritability, sleep difficulties, decreased appetite, nausea, craving

therapeutic use: control of nausea, MS pain and cancer pain

• PCP
• weak base
• soluble in water
• lipid soluble
• effects: tachycardia, HTN, potentiation of catecholamines
• drunken state, numbness of extremities, convulsions

NMDA antagonist

tx of overdose: gastric suction, acidify urine, diazepam, anti-HTN, haloperidol

indolamine

• onset of action 15-20mins
• duration: 2 hrs
• <1% crosses BBB

• tachycardia, increase BP
• psychomotor stimulation
• altered perception (visual)
• lability of mood
• impaired judgement
• hallucinations, anxiety, panic, depersonalization
• flashbacks

Ecstasy 

substitude phenethylamine

feelings of "well being," connection, altered time

• onset of action: 20-40 mins
• duration: 3-4 hrs

• psychomotor stimulation
• restlessness, anorexia, tremor, sweating

hangover: anhedonia

neurotoxicity: 5-HT damage

found naturally in brain as a precursor/metabolite of GABA

• liquid ecstasy
• tx of cataplexy associated w/ narcolepsy

may have own receptor

effects last 3 hrs

depressant - state of relaxation and tranquility, tendency to verbalize, interacts w/ alcohol

overdose: drowsiness, dizziness, nausea, vomiting, ataxxia, loss of bladder control, amnesia, conlus, seizures

drug of abuse

inhalant

K-opioid agonist

• 20-45 mins action
• dream like experience w/ open and close eyed visuals
• dissociation at high doses w/ fear, panic, and perspiration

most effective tx (prevention) 

active: vaccination (polio, smallpox, measles, influenza, herpes zoster, hep a/b, rabies, etc.) - buildup long term immunity

• passive: injection of immune globulin often blocks viral penetration, may modify course of disease if given during early incubation period, protective effect lts 2-3 wks, given IM or IV
• viral replication rate is reduced by blocking viral entry into cells; may allow for active immunity to develop.
• special hyperimmune globulins available for rabies, varicella-zoster, hep A, B, CMV, measles, RSV

• use:
• tx of uncomplicated influenza A and B
• given w/in 48 hrs of symptom onset
• influenza prophylaxis

• mechanism:
• prodrug, competitive inhibitor of influenza neuraminidases; interferes with viral release and viral penetration

SE: nausea/vomiting/diarrhea, bronchitis

interferes with DNA synthesis; thymidine analog

use: ophthalmic herpes simplex 1 & 2

toxicity: burning, stinging, hypersensitivity

• mechanism: inhibits DNA polymerase
• phosphorylated form is produced 40-100x faster in infected cells by herpes thymidine kinase
• initial herpes DNA polymerase 10-30x more than host cell DNA polymerase
• acts as a competitive inhibitor of dGTP and as a DNA chain terminator

• Use:
• IV: - drug of choice for serious systemic herpes simplex & severe initial genital herpes and HSV encephalitis

Oral: primary genital herpes, primary herpetic gingivostomatosis

topical: some effect when applied early to primary genital herpes

Miscellaneous: chickenpox (shortens disease by 1 day)

• Toxicity: 
• generally well-tolerated
• rash, itching, nausea, vomiting, headache, fatigue

Mechanism: similar to acyclovir: prodrug converted to penciclovir which is phosphorylated - inhibits viral DNA polymerase

better absorbed than acyclovir because it's a prodrug - that's why it treats some things that acyclovir is not good at

use: acute herpes zoster (shingles), < 3 days duration, tx and suppression of recurrent genital herpes & recurrent herpes cold sores

toxicity: similar to acyclovir (rash, itching, nausea, vomiting, headache, fatigue)

mechanism: very similar to acyclovir - very poor oral bioavailability

acyclic structure, but technically not a chain terminator b/c it does have an unusual -OH group - little chain extension actually occurs

use: recurrent herpes of the lips and face (for minor episodes where you don't want to use an oral drug)

administration: topical

mechanism: similar to acyclovir, except the monophosphorylation is catalyzed by CMV protein kinase - inhibits DNA synthesis and terminates DNA elongation 

Use: tx of CMV retinitis (in AIDS patients), CMV prophylaxis for transplant recipients

Toxicity: bone marrow suppression, leukopenia, thrombocytopenia, anemia, may enhance bone marrow suppression when given with zidovudine (AZT), abnormal liver fxn

• Mechanism: inhibits CMV DNA polymerase by binding to its pyrophosphate-binding site
• does not require conversion to triphosphate form to be active

use: CMV retinitis, acyclovir-resistant herpes simplex

toxicity: renal damage, electrolyte imbalances, seizures

Mechanism: nucleoside analog inhibitor of the reverse transcriptase domain of the hepB DNA polmerase

Use: approved for hep B & HIV (synergistic w/ AZT)


Toxicity: nausea & diarrhea

• mechanism: adenosine monophosphate, inhibits reverse transcriptase domain of hep B DNA polymerase
• nucleotide prodrug, results in chain terminiation

use: Hep B & combination therapy HIV

toxicity: GI upset

• Mechanism: interferes with viral mRNA synthesis
• inhibits inosine-5-p dehydrogenase and thus GTP synthesis
• inhibits GTP- dependent capping of viral mRNA

• use:
• aerosol use:  infants and young children - documented severe lower respiratory syncytial virus (RSV) infections - no longer commonly used

HepC (oral) in combination w/ interferon-alpha

IV/oral use: anemia, bone marrow suppression

• SE:
• aerosol: drug may ppt in and clog resipratory equipment
• pulmonary function deterioration, rash
• IV/oral: anemia, bone marrow suppression

• use for recombinant alpha-inteferons:
• condyloma acuminata (venereal warts, papilloma virus)
• hep B and C
• PEG-alfa-2a and PEG-alfa-2b interferons in combination with ribafarin are specifically useful for hep C

toxicity: flu-like syndrome, leukopenia, bone marrow suppression, neurotoxicity, myalgia

mechanism: reversible inhibitor of hep C NS3 protease, blocking formation of infectious virus particles

use: hep C genotype 1, combo w/ PEG-interferon + ribavirin

Toxicity: anemia, neutropenia, contraindicated with drugs that are CYP3A substrates or inducers

mechanism: thymidine nucleoside analgog; phosphorylated by cellular kinases, inhibits reverse transcriptase, acts as DNA chain terminator

Use: nucleoside RT inhibitor for tx of HIV in adults & kids

• Toxicity:
• bone marrow suppression, neutropenia, anemia
• drugs which inhibit glucuronyl transferase increase hematologic toxicity and should be avoided
• myopathy (w/ prolonged use)

ALL NRTIs: lactic acidosis & hepatic steatosis 

mechanism: fluorinated analog of 3TC - inhibits RT by competing for dCTP incorporation into DNA, resulting in chain termination

Use: combination therapy for HIV-infected patients

mechanism: nucleoside analog inhibitor of RT

use: combination therapy for HIV-infected patients

toxicity: hypersensitivity reactions (associated with HLA-B*5701 antigen)

echanism: non-nucleoside inhibitor of reverse transcriptase; does not require phosphorylation for activity

use: part of multi-drug therapy for HIV

SE: rash, CNS/psychiatric symptoms, nightmares, vivid dreams

use: combination with RT inhibitors, significantly decreases viral load

mechanism: prevents viral protease from cleaving Gag-pol polypeptide into separate functional proteins, competitive inhibitor, results in non-infectious viral particles

SE: diabetes, alterations in lipid metabolism, fat distribution, fat distribution, alters metabolism of many other drugs (potent CYP3A inhibitor), diarrhea

use: combination with RT inhibitors, significantly decreases viral load - used to boost levels of other PIs (b/c it blocks their metabolism by CYP3A) - used as BOOSTER

mechanism: prevents viral protease from cleaving Gag-pol polypeptide into separate functional proteins, competitive inhibitor, results in non-infectious viral particles

SE: diabetes, alterations in lipid metabolism, fat distribution, fat distribution, alters metabolism of many other drugs (potent CYP3A inhibitor)

use: HIV-1 only, detectable viral replication despite ongoing therapy

mechanism: inhibits fusion of viral (HIV-1) and cellular (CD4+) membranes, binds to gp41 subunit of HIV glycoprotein, blocking membrane fusion

SE: local injection site rxns, diarrhea, nausea, fatigue

use: tx of CCR5-tropic HIV-1

mechanism: chemokine co-receptor (CCR5) antagonist, blocks entry of HIV into cells - tends to predominate early in infection

SE: hepatotoxicity, CV events

use: tx of HIV-1, used on viruses resistant to other drugs

mechanism: inhibits HIV-1 integrase, preventing integration of HIV-1 DNA into genome

• clear solution
• IV use
• human sequence

cloudy suspension of insulin aggregated w/ protamine and zinc

longer time course d/t breaking down aggregates

human sequence

synthetic insulins -

1 or more amino acids of human insulins changed to yield short or long acting insulin

lispro insulin & insulin aspart

short acting

pro-lys dipeptide at positions B28 and B29 are reverse

short acting

B28 proline replaced by aspartic acid

long acting insulin analog 

asparagine at A21 is replaced by glycine & 2 arginines added to C-temrinus of B-chain

soluble at pH=4, poorly solubleat pH=7

forms ppt when injected subQ

intermediate/long term acting insulin

threonine at B30 omitted and C14 fatty acid chain attached to AA B29

long acting d/t self association at subQ injecting site and binding in albumin in blood stream

stimulate insulin secretion by pancreas

interact w/ beta cells K+ transporter causing depolarization and secondary calcium influx

SE: hyponatremia, disulfiram like reaction, rashes/GI upset/drug interactions, hypoglycemia

• glipizide
• glyburide
• glimepiride

type of sulfonylurea

stimulates insulin secretion

type of sulfonylurea

stimulates insulin secretion

type of sulfonylurea

stimulates insulin secretion

• makes liver more sensitive to insulin
• biguanide

SE: abdominal discomfort, diarrhea, lactic acidosis

CI: renal insuffiency, elderly, CHF, binge drinking, liver disfunction

makes peripheral tissues such as fat and muscle more sensitive to insulin by activating PPAR

SE: liver toxicity, weight gain, fluid retention

CI: heart failure

rosiglitazone, proglitazone

type of thiazolidinedione

increases cardiac ischemic effects

type of thiazolidinedione

increases risk of bladder cancer

glucosidase inhibitor

inhibits enteric enzymes that break down complex carbs -- partial malabsorption of carbs

decreases post-prandial hyperglycemia

SE: bloating, abdominal discomfort, diarrhea, flatulence

GLP-1 analog

augments insulin secretion, increases beta-cell mass, inhibits glucagon secretion, promotes weight loss

SE: nausea, emesis, diarrhea, headaches, pancreatitis

DPP4 inhibitor - prolongs action of GLP-1

oral