-
Levodopa (L-DOPA)
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
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Carbidopa
- 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
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Pramipexole
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 T1/2Less 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
-
Ropinirole
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
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Apomorphine
Rationale: mimic effects of dopamine without needing intact nerve terminal
Mechanism: D4 receptor agonist (moderate D2,3,4,5) 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
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Selegiline
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
-
Rasagiline
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
-
Entacapone
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 T1/2, 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)
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trihexyphenidyl
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.)
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benztropine
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.)
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amantadine
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
-
donepezil
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
-
-
rivastigmine
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
-
galantamine
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
-
memantine
Mechanism: non-competitive NMDA channel blocker
Use: Alzheimer's disease, associated with reduced rate of clinical deterioration
-
riluzole
Mechanism: inhibitor of NMDA channels - inhibits glutamate release, increases glutamate uptake, inhibits glutamate receptors
Use: Amyotrophic lateral sclerosis - increases life span 2-3 months
-
MAC
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)
-
Sodium thiopental
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.
T1/2= 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
-
Propofol
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
-
Etomidate
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
-
Ketamine
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
-
Midazolam
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
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Isoflurane
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
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Desflurane
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
-
Sevoflurane
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
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Nitrous Oxide
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
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Anxiety
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
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Benzodiazepine
- 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
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Barbiturate
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
-
Hypnotics
Mostly benzodiazepines that induce sleep
Includes flurazepam, triazolam, and lorazepam.
-
GABA receptor-chloride channel complex
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
-
Sedation
Induces nervous system to stay calm
-
Buspirone
Use: anxiety
partial agonist for 5-HT1A - 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
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Alprazolam
Use: treat anxiety, PANIC DISORDER!!!!!!!
-
Clonazepam
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
-
Chlordiazepoxide
Use: anxiety, alcohol withdrawl (gradual reduction of dose "tapering off")
-
Diazepam
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
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Flumazenil
Benzodiazepine antagnoist at receptor
Used for benzodiazepine overdoses
-
Lorazepam
- 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
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Baclofen
Use: skeletal muscle relaxant
- Gaba - mimetic agent that works at GABAB 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
-
Tizanidine
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
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Chloral hydrate
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
-
Eszopiclone
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
-
Flurazepam
benzodiazepine used as hypnotic
rapid onset of action, long duration of action
-
Pentobarbital
barbiturate
hypnotic
rarely used today
-
Ramelteon
melatonin MT1 and MT2 receptor-agonist
Specifically indicated for tx of insomnia characterized by difficulty in falling asleep - not a controlled substance
-
Triazolam
benzodiazepine used as hypnotic
rapid onset of action and ultrashort duration of action
-
Zaleplon
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
-
Zolpidem
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
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Alcohol dehydrogenase
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
-
Microsomal Ethanol Oxidizing System
AKA Mixed Function Oxidase System (MFOS)
High km - little contribution at concentrations below 100mg/dl
Induced in alcoholics - CYP2E1 - influences metabolism of other drugs
-
Aldehyde Dehydrogenase
- Mitochondrial enzyme
- Used for acetaldehyde metabolism
- Oxidizes acetaldehyde to acetate
- Genetic polymorphisms
- Inhibition by disulfiram
-
Naltrexone
reduces "urge to drink"; increases control
opioid receptor antagonist
orally active w/ long half-life
best together w/ psychosocial therapy
-
Acamprosate
agonist GABAA & NMDA competitive antagonist
Decreases drinking frequency and reduces releapse
Well tolerated - primary SE is diarrhea
-
Disulfiram
Aversion therapy
Mechanism of action: inhibition of alehyde dehydrogenase
Acetaldehyde syndrome - not very effective/ethical
-
Caffeine
- 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
-
Adenosine
Post synaptic receptors hyperpolarize membrane
Presynaptic receptors inhibit glutamate release
Caffeine blocks these types of receptors
-
Cocaine
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)
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Amphetamine
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
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Methylphenidate
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
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Methamphetamine
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
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Nicotine
- 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
-
Bupropion
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
-
Varenicline
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
-
Epilepsy
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! :)
-
Partial Seizure
Focal
- Simple: no impairment of consciousness
- Complex: dreamy dysaffective state
-
Generalized Seizures
impairs consciousness and distorts the electrical activity of the whole or a larger portion of the brain
- Types:
- Tonic-Clonic
- Absence
- Myoclonic
- Status epilepticus
-
Tonic-Clonic Seizure
grand mal
loss of concsciousness, falling
- rigid extension of trunk/limbs (tonic phase)
- rhythmic contraction or arms/legs (clonic phase)
-
Absence Seizure
petit mal
impaired consciousness with staring spells, with or without eye blinks
-
Myoclonic Seizure
- jerks/shocklike contractions
- loss of muscle tone
- falling
- "drop attacks"
-
Status Epilepticus
seizures recurring so close together that baseline consciousness is not regained between seizures
-
Phenytoin
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
-
Carbamazepine
All forms epilepsy EXCEPT absence seizures
- Blocks Na channels
- Unpredictable absorption
- Hepatic enzyme induction
- SE:
- diplopia, ataxia, GI upset, drowsiness, rare blood dyscrasias
-
Oxcarbazepine
newer carbamazepine analog
- similar in action but less likely to cause CNS SE
- Less enzyme induction
-
Phenobarbital
- 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
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Ethosuximide
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
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Valproic acid
- 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)
-
Felbamate
May act at glycine site of NMDA receptor, also potentiates GABA
Used for partial seizures REFRACTORY to other drugs
SE: aplastic anemia, hepatic failure
-
Gabapentin
- GABA analog
- Adjunct therapy for partial seizures
- Not protein bound or metabolized by liver
- Also used for neuropathic pain and ALS
-
Pregabalin
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
-
Lamotrigine
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
-
Topiramate
- 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
-
Tiagabine
inhibits GABA transporter GAT-1 and blocks GABA uptake
Adjunct therapy for simple and complex partial seizures
SE: dizziness, tremor, somnolence
-
Levetiracetam
adjunct tx of partial seizures & myoclonic seizures
few drug interactions
SE: somnolence, asthenia, dizziness
-
Zonisamide
- 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
-
Vigabatrin
irreversibly blocks GABA metabolism
adjunct tx of refractory complex partial seizures and infantile spasms
possible permanent effects on vision
-
Procaine
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
-
Tetracaine
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
-
Benzocaine
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
-
Lidocaine
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
-
Bupivicaine
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
-
Ropivacaine
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
-
Major depressive disorder
- 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
-
SSRI
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
-
Fluoxetine
- 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
-
Sertraline
- SSRI
- similar in action to fluoxetine w/ less effects on drug metabolism
- shorter half-life
-
Paroxetine
- SSRI w/ highest specificity for serotonin
- low anticholinergic activity
- available in in sustained release form
-
Citalopram
SSRI
also used for anxiety
-
Escitalopram
SSRI
active s-enantiomer form of citalopram
-
SNRI
blocks both serotonin and norepinephrine uptake
-
venlafaxine
SNRI
effective in severe depression and anxiety
-
Duloxetine
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
-
milnacipran
SNRI
fibromyalgia
-
Mirtazapine
atypical antidepressant
blocks presynaptic alpha2 receptors in brain
increases appetite
-
tricyclic antidepressants
- 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
-
Imipramine
tricyclic antidepressant
enuresis in childhood
-
amitriptyline
tricyclic antidepressant
chronic pain
migraine prophylactic
-
clomipramine
tricyclic antidepressant
obsessive compulsive disorder
-
MAO inhibitors
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
-
phenelzine
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
-
psychosis
derangement of personality
loss of contact w/ reality
delusions
hallucinations
-
schizophrenia
positive: delusions, hallucinations, hostility, disorganized speech
negative: blunted affect, emotional withdrawal
hyperactivity of DA neurons in limbic areas
-
Mesocortical pathway
cognitition, communication, social activity
diminished DA activity: negative symptoms
-
Mesolimic pathway
arousal, memor, stimulus processing, locomotor activity
dopamine hyperactivity: positive symptoms
-
Tardive dyskinesia
late reaction
oral-facial dyskinesias, choreathetoid movements
-
Atypical antipsychotic
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
-
Bipolar disorder
back and forth between irritable, depressed mood and very good mood
-
Chlorpromazine
- Typical antipsychotic
- Phenothiazine
- Low/medium potency
- Sedative
- Pronounced anticholinergic actions
-
Thioridazine
- Typical antipsychotic
- Low potency
- sedative
- Less extrapyramidal actions
- anticholinergic
- piperidine side chain
-
Fluphenazine
- Typical antipsychotic
- High potency
- Less sedative
- Less anticholinergic
- More extrapyramidal reactions
- Piperazine side chain
-
Thiothixene
- Typical antipsychotic
- similiar pharmacology to phenothazines (chlorpromazine) - low potency
- non-nitrogen analog to phenothiazine
-
Haloperidol
- Typical antipsychotic
- not chemically related to phenothiazines
- pharmacologically similar to high potency piperazine derivates (fluphenzine)
-
Pimozide
- Typical antipsychotic
- potent
- many SE
- used for Tourette's
- commonly used when haloperidol doesn't work
-
Clozapine
- 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
-
Olanzapine
- 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
-
Risperidone
- Combined D2 & 5-HT2 antagonist
- Greater decrease in negative symptoms
- Low incidene of extrapyramidal SE
- Less seizure activity
- Paliperidone is the active metabolite
-
Quetiapine
structurally related to cloazpine with effects on D2 and 5-HT2 receptors
Approved for augmentation in depression
Shorter T1/2
-
Ziprasidone
- May also have 5-HT1a agonist activity
- No weight gain
-
Aripiprazole
- D2 partial agonist
- Approved as adjunct in the tx of depression
-
Lithium
- 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
-
beta endorphin
co-released w/ ACTH in response stress
endogenous ligand of mu receptor
-
dynorphins
endogenous ligand for kappa receptor
colocalizes with magnocellular cells of hypothalmus and posterior lobe of pituitary gland
-
enkephalins
endogenous ligand of delta receptor
distributed widely throughout CNS
-
Morphine
- extensive first pass
- injectable, oral, suppository
- 4-5 hrs
- Mu receptor agonist
-
Heroin
More lipophilic than morephine
Activated by metabolism
High abuse potential
-
Codeine
- 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
-
Oxycodone
Moderate to severe pain
often used in combination with aspirin or acetaminophen
available as sustained release oral preparation-major abuse problem
cough suppression
-
Methadone
- equipotent with morphine; good oral availability
- longer duration of action
- used in tx of opioid abuse
-
Meperidine
shorter duration of analgesia than morphine
forms toxic metabolite that can accumulate with frequent use
interactions with MAOI
-
Fentanyl
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
-
Hydromorphone
2-3x as potent as morphine
-
hydrocodone
stronger than codeine, but not as strong as morphine
-
nalbuphine
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
-
buprenorphine
- partial mu agonist
- used to tx moderate to severe pain - now available as a patch
orally combined with naloxone used to tx opioid dependence
-
Naloxone
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
-
Dextromethorphan
dextro-opioid isomer - antitussive, but not analgesic (cough suppression)
-
tramadol
- weak mu agonist
- also blocks NE and 5-HT uptake
- used for milkd to moderate pain
- available for oral use including sustained release prep
-
suboxone
tx of opioid abuse
-
tolerance
decrease in response to a drug as a result of repeated tx w/ drug
-
physical dependence
physical symptoms produced by drug withdrawal
-
psychological dependence
compulsive feelings of the need to take a particular drug
-
addiction
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
-
cannabis
- unique marijuana plant
- related to hop plant
- main ingredient - 9-tetrahydrocannabinol
-
9-tetrahydrocannabinol
- main active ingredient of marijuana
- content determines potency
- rapidly metabolized by liver to highly active compound
-
marijuana
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
-
Phencyclidine
- 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
-
Lysergic Acid Dyethylamide (LSD)
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
-
Methylenedioxymethamphetamine (MDMA)
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
-
Gamma-hydroxybutyrate (GHB)
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
-
Toluene
drug of abuse
inhalant
-
Salvia Divinorum
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
-
Immunization
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
-
Oseltamivir
- 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
-
Trifluridine
interferes with DNA synthesis; thymidine analog
use: ophthalmic herpes simplex 1 & 2
toxicity: burning, stinging, hypersensitivity
-
Acyclovir
- 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
-
Famciclovir
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)
-
Penciclovir
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
-
Ganciclovir
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
-
Foscarnet
- 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
-
Lamivudine
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
-
Tenofovir
- 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
-
Ribavirin
- 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
-
Interferon
- 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
-
Boceprevir
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
-
Zidovudine (AZT)
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
-
Emtricitabine
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
-
Abacavir
mechanism: nucleoside analog inhibitor of RT
use: combination therapy for HIV-infected patients
toxicity: hypersensitivity reactions (associated with HLA-B*5701 antigen)
-
Efavirenz
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
-
Lopinavir
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
-
Ritonavir
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)
-
Enfuvirtide
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
-
Maraviroc
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
-
Raltegravir
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
-
regular insulin
- clear solution
- IV use
- human sequence
-
NPH insulin
cloudy suspension of insulin aggregated w/ protamine and zinc
longer time course d/t breaking down aggregates
human sequence
-
Insulin Analogs
synthetic insulins -
1 or more amino acids of human insulins changed to yield short or long acting insulin
lispro insulin & insulin aspart
-
lispro insulin
short acting
pro-lys dipeptide at positions B28 and B29 are reverse
-
insulin aspart
short acting
B28 proline replaced by aspartic acid
-
insulin glargine
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
-
insulin detemir
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
-
sulfonylureas
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
-
glipizide
type of sulfonylurea
stimulates insulin secretion
-
glyburide
type of sulfonylurea
stimulates insulin secretion
-
glimepiride
type of sulfonylurea
stimulates insulin secretion
-
metformin
- makes liver more sensitive to insulin
- biguanide
SE: abdominal discomfort, diarrhea, lactic acidosis
CI: renal insuffiency, elderly, CHF, binge drinking, liver disfunction
-
Thiazolidinediones
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
-
rosiglitazone
type of thiazolidinedione
increases cardiac ischemic effects
-
pioglitazone
type of thiazolidinedione
increases risk of bladder cancer
-
acarbose
glucosidase inhibitor
inhibits enteric enzymes that break down complex carbs -- partial malabsorption of carbs
decreases post-prandial hyperglycemia
SE: bloating, abdominal discomfort, diarrhea, flatulence
-
exenatide
GLP-1 analog
augments insulin secretion, increases beta-cell mass, inhibits glucagon secretion, promotes weight loss
SE: nausea, emesis, diarrhea, headaches, pancreatitis
-
sitagliptin
DPP4 inhibitor - prolongs action of GLP-1
oral
-
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