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201 Cards in this Set

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What are the classifications of seizure types?
1)partial-begin focally in a cortical site and may spread
2)generalized-generally involve both hemispheres from the outset
What are the subtypes of partial seizures?
1)simple partial-jerking lasting about 20 mins with preservation of consciousness
2)complex partial: impairment of consciousness <2 min., usually originate from temporal lobe
3)partial with secondary generalized tonic-clonic, starts as a partial seizure and develops into tonic clonic, LOC, mm contractions alternating with relaxation
What are the subtypes of generalized seizures?
1)tonic-clonic-grand mal, LOC, mm contractions
2)absence-staring, cease activity
3)myoclonic-brief shock like mm contraction
What 3 antiseizure drugs induce the cytochrome P450?
phenytoin, carbamazepine and phenobarbital
What is the mechanism of phenytoin and fosphenytoin?
they block sustained high frequency reptitive firing of neurons by prolonging inactivation of the Na channel
What are phenytoin and fosphenytoin used to tx?
effective against partial seizures and generalized tonic-clonic seizures
-NOT effective against absence seizures
Describe the pharmacokinetics of Phenytoin.
-highly bound to plasma proteins
-elimination is dose dependent-first order metabolism occurs at low blood levels but at therapeutic levels it becomes zero order
-therapeutic range is small: 10-20 microliters/mL
Describe the drug interactions of phenytoin.
-90% protein bound, displaced by phenylbutazone or sulfonamides
-metabolism is saturated at therapeutic concentrations, addition of other drugs metabolized by the same enzymes may inhibit phenytion metabolism
-phenytoin may inhibit the metabolism of other drugs, most significantly is warfarin (will increase concen. if combined with phenytoin)
-induces microsomal enzymes
-carbamazepine increases metabolism of phenytoin
What toxicities are associated with phenytoin?
nystagmus, ataxia, double vision, sedation at high levels
-gingival hyperplasia and hirsutism
-abnormal vit. D metabolism and inhibition of Ca absorption leads to osteomalacia
-skin rash may indicate HS
-pregnancy category D: known teratogen with serious birth defects, DO NOT USE IN PREGO
What is the mechanism of action and uses of carbamazepine?
-mechanism similar to phenytoin, blocks Na channels and decreases NT release
-also has a mood stabilizing effect though-used for bipolar disorder
-DOC for partial seizures
-also used as first drug for generalized tonic-clonic seizures
-effective for trigeminal neuralgia
-not very sedating in normal doses
Describe the PHK of carbamazepine..
-best to give after a meal
-induces hepatic microsomal enzymes, esp cyp3a which metabolizes oral contraceptives
-it induces its own metabolism
-TR=6-12 microliter/mL
What are the drug interactions of carbamazepine?
-increases metabolism of phenytoin, primidone, ethosuximide, valproic acid and clonazepam
-increases metabolism of haloperidol and oral contraceptives
-cimetidine, fluoxetine, isoniazid and erythromycin inhibit carbamazepine metabolism
What are the toxicities of carbamazepine?
-double vision and ataxia
-GI upset
-blood dyscrasias-aplastic anemia and agranulocytosis, usually in elderly pts.
-skin rash = HS, discontinue drug
-FDA alert: screen pts for the HLA-B1502 allele, associated with higher incidence of stevens johnson syndrome
-DO NOT USE IN PREGO
What is the mechanism of phenobarbital and primidone?
-prolongs opening of Cl channel at GABAa receptor
-used for partial and generalized tonic-clonic seizures
-CNS depressant
-primidone is metabolized to phenobarbital
-do not use in prego
What type of seizures does phenytoin and fosphenytoin treat?
partial and generalized tonic clonic
-NOT effective against absence seizures
Which drug can be given IV: phenytoin or fosphenytoin?
fosphenytoin
What type of seizures are treated by phenobarbital and primidone?
partial and generalized tonic clonic
What is primidone metabolized to?
phenobarbital
What are the CI of phenobarbital and primidone?
do NOT give in prego
What is the DOC for absence seizures?
ethosuximide
What is the mechanism of action of ethosuximide?
-reduces low-threshold Ca current in the thalamus
-the T-type channels are part of the pacemaker that generate rhythmic cortical discharge in absence seizure
What is the only significant drug interaction of ethosuximide?
valproic acid decreases its clearance
What are the notable toxicities of ethosuximide?
gastric pain, N/V most common
-steven's johnson syndrome (very uncommon with this drug tho, see more with carbamazepine)
-prego cat. C: safe use not est., don't give unless HAVE to
What type of seizure does valproic acid treat?
absence
-also effective against generalized tonic-clonic seizures
-DOC if both occur together
-also effective against myoclonic seizures
-may also be useful in atonic and partial
-also used for mood stabilization in bipolar and prophylaxis of migraine
What is the mechanism of valproic acid?
blocks high frequency repetitive firing
-probably blocks Na channels
-may increase synthesis and levels of GABA
-may hyperpolarize membranes by inreasing K conductance
What is the DOC if both absence and generalized tonic clonic seizures occur together?
valproic acid
What are the drug interactions of valproic acid?
-inhibits its own metabolism at low doses
-may displace phenytoin from plasma proteins
-inhibits metabolism of phenytoin and carbamazepine
-inhibiting metabolism of phenobarbital may cause coma
What are the toxicities associated with valproic acid?
N/V, abdominal pain, and heartburn
-fine tremor may occur
-wt. gain, increased appetite and hair loss may occur
indiosyncratic hepatoxocity, this is CI in pts. with liver disease
-DO NOT give in prego
What type of seizure does clonazepam treat?
absence seizures
-also useful for myoclonic seizures and infantile spasms
What are the side effects of clonazepam?
-it is a benzodiazepine
-sedation is common
-tolerance may develop to antiseizure effect
-DO NOT give in pregos
What is the DOC for status epilepticus?
diazepam, given IV
-DO NOT give in prego
What 2 drugs are given for status epilepticus?
diazepam-DOC
lorazepam
-both given IV
What is stevens johnson syndrome?
-HS rxn consisting of erythema multiforme, arthritis, nephritis, CNS abnormalities, and myocarditis
-it is a serious AI rxn that requires discontinuing drug use
-this rxn is rare but may occur with several diff. drugs including most anticonvulsants
What are the 3 main drugs used to treat absence seizures?
ethosuximide
valproic acid
clonazepam
What are the biochemical effects of alcohol?
-it is a CNS depressant
-depresses synaptic transmission in the CNS by interacting with the GABAa receptor complex (like benzos and barbs) to increase Cl influx and augment GABA transmission
-also inhibits the effect of the excitatory amino acid glutamate on the NMDA receptor
What does chronic long term use of alcohol do to receptors?
NMDA-up regulates it
GABA-down regulates it
Why does alcohol "appear" to be a stimulant when we drink it at low doses?
b/c it inhibits inhibitory pathways at low doses causing disinhibition
-at higher doses it inhibits excitatory pathways as well and the more general CNS depressant and sedative properties become apparent
What does the dose response curve for alcohol look like?
very STEEP curve
-there is only a 5 fold difference btwn the concentration that produces intoxication and that which is fatal
Describe the PHK of alcohol.
-it is absorbed from the stomach and small intestine, faster on an empty stomach
-alcohol dehydrogenase is in the GI tract which metabolizes alcohol
-levels of this enzymes are much higher in men which is why gastric metabolism of alcohol is much lower in women
-crosses BBB easily, also crosses placenta rapidly and easily
Describe the metabolism of alcohol.
-metabolized in the GI tract and liver by alcohol deydrogenase to acetaldehyde-->then oxidized by the enzyme aldehyde dehydrogenase to acetic acid
-oxidation requires NAD+ which is limited (b/c the amount of NAD is saturated at fairly low concentrations of alcohol it follows ZERO order kinetics), rate of metabolism is independent of concentration
-typical adult metabolizes 8-10 g of alcohol/hr
What does chronic consumption of alcohol lead to in terms of enzymes?
it induces CYP2E1 which increases EtOH metabolism
-in chronic drinkers, elevated NADP+ decreases the availability of NADPH for regeneration of reduced glutathione, increasing oxidative stress, probably contributes to liver damage
What happens when acetaldehyde accumulates?
can accumulate in some people when they drink esp. those of asian descent who have an aldehyde dehydrogenase deficiency
-leads to facial flushing, HA, and nausea when alcohol is consumed
How does disulfiram work?
inhibits aldehyde dehydrogenase producing very unpleasant and possibly dangerous effects with alcohol
What can happen when alcoholics take acetaminophen?
-even therapeutic amounts of tylenol can cause hepatotoxicity
-b/c CYP2E1 is induced it increases conversion of acetaminophen to a toxic metabolite
-the effect is at its peak during alcohol withdrawal when someone with a hangover is most likely to reach for a painkiller
What does acute alcohol consumption do to the metabolism of other drugs?
-may compete for metabolism and inhibit the breakdown of some drugs
-conversely, chronic alcohol consumption may increase the metabolism of drugs metabolized by the p450 system (like phenytoin)
What effect does alcohol have on smooth muscle?
-ethanol is a vasodilator
-large amounts can cause hypothermia due to vasodilation
-also relaxes the uterus, has been used IV to prevent premature labor
What effect does alcohol have on the kidney?
-decreases the ADH in the kidney, has a diuretic effect
What are the sx of alcohol toxicity?
-emesis, stupor, coma, resp. depression, possible death
-tx of severe intox. includes management of resp. depression and preventing aspiration of vomitus
-thiamine also given to prevent further neuro damage
-may also cause metabolic and electrolyte disturbances
-if seizures occur tx with phenytoin
-
What are hangovers from alcohol though to be due to?
buildup of acetaldehyde, dehydration, the beginning of withdrawal and accumulation of mildly toxic compounds associated with alcoholic beverages
What are the effects of chronic alcohol consumption on nutrition?
malnutrition
-alcohol has a lot of calories
-defic. in folate and thiamine esp. common
What are the effects of chronic alcohol consumption on the stomach and pancreas?
-causes direct damage to pancreatic cells=pancreatitis
-stim. acid production and causes severe erosive gastritis, malabsorption
-lesions of the esophagus and duodenum commonly seen
What effect does chronic alcohol consumption have on the liver?
-liver disease is the most common medical complication of alcohol abuse, 15-30% of heavy drinkers eventually develop liver disease
-metabolism of alcohol lowers concentration of glutathione which normally scavenges free radicals that can destroy the liver-->results in oxidative stress and tissue damage
-acetaldehyde increases lipid peroxidation damaging mitochondrial and cell membranes
-fatty liver develops within days after heavy drinking, followed by fibrosis collagen gets deposited and leads to cirrhosis
-alcoholic hepatitis may occur, co-existence of hep. B and C will increase amount of liver damage
-liver cancer most likely in pts with cirrhosis and hep C about 10 yrs after alcohol consumption is stopped ( due to liver's attempt to heal itself)
What are the CV effects of chronic alcohol consumption?
small amounts of alcohol everyday can actually reduce the incidence of heart disease by increasing HDL levels
-chronic drinking can damage heart, significant depression of contractility can occur at high blood concentrations
-cardiomyopathy may develop due to direct effects of acetaldehyde on the heart
-heavy alcohol consumption leads to HTN, mechanism unknown
-increased risk of stroke in people who drink more than 4-6 drinks/day
Describe the teratogenic effects of alcohol.
-can cause Fetal alcohol syndrome characterized by microcephaly, mental retardation, poor coordination, flattened face, jt. abnormalities, heart defects, and impaired immune system
Describe some of the systemic effects of chronic alcohol consumption beyond the main organ systems.
-increases the carcinogenicity of tobacco products
-mild anemia often results from folic acid defic.
-sexual dysfunction:testicular atrophy, impotence and gynecomastia
-more prone to infections
-Korsakoff's psychosis (memory loss) and Wernicke encephalopathy (ataxia, paralysis of eye mm, confusion)-thought to be due to thiamine defic.
-peripheral neuropathy
-sk. mm. atrophy
-hypothermia
Describe alcohol tolerance and dependence.
-tolerance develops both to the effects of alcohol (pharmacodynamic) and b/c of increased metabolism (ph.kinetic)
-GABA receptors down reg.; NMDA up-reg
-there is severe withdrawal sx, as a result of pharmacodynamic tolerance
-there is cross tolerance to the effects of barbiturates, benzos, and general anesthetics
-lethal dose is NOT CHANGED!
What does use of alcohol cause in people with a predisposition to alcoholism?
-a marked increase in release of beta-endorphins in the dopamine reward pthway that goes from ventral tegmental area to nucleus accumbens of prefrontal cortex
Describe alcohol withdrawal.
-sx usually begin w/in 6-24 hrs and may last about 5 days
-mild withdrawal includes anxiety, irritability, insomnia, nightmares, Nausea, tachycardia, and palpitations
-severe withdrawal may involve anxiety, fear, hallucinations, delirium, and tremors, tonic clonic seizures, arrhythmias, increased BP
-can be life threatening!
How is alcohol withdrawal treated?
-objective is to prevent seizures, DTs and arrhythmias
-long acting benzos are used to taper the withdrawal (such as chlordiazepoxide, diazepam)
-anticonvulsants sometimes used to prevent seizures
-antipsychotics used such as haloperidol to tx hallucinations or aggression in ER setting
-tx malnutrition, electrolyte imbalances
What is naltrexone?
-an opioid receptor antagonist (alcohol stim. release of beta-endorphins which act on opioid receptors to facilitate dopaminergic reward pthway)
-can be admin. orally or once a month by depot injection
-it blocks the ability of alcohol to stimulate this reward pathway
-reduces craving for alcohol, decreases the rate of relapse by 50%
-major side effect is nausea
-large doses may cause liver damage, so do not give to alcoholics with acute liver disease
-other opioids will NOT be effective in tx pain in these pts.
What is acamprosate?
-structural analogue of GABA
-chronic alcohol use up-regulates NMDA receptors to compensate for chronic sedative effects of GABA stimulation
-acamprosate restores the normal balance of GABA and glutamate transmission
-no abuse potential, no liver tox., no abuse potential
-increases rate of abstinence and decreases likelihood of relapse
What is disulfiram?
-blocks aldehyde dehydrogenase
-it has no effect alone but will cause build up of acetaldehyde if person drinks alcohol
-this causes flushing, intense throbbing HA, nausea and confusion
-has a long duration of action, important not to drink for 3-4 days after a dose of this
-anything containing alcohol must be avoided
-other drugs such as metronidazole, cephalosporins and oral hypoglycemic agents must be avoided as well
-disulfiram inhibits p450 and can interfere with metabo. of other drugs
-DANGEROUS AND NOT RECOMMENDED
Describe the metabolism of methanol once ingested.
methanol is converted to formaldehyde by alcohol dehydrogenase and then to formate which is toxic
-sx of methanol poisoning are visual disturbances "like being in a snowstorm", bradycardia, coma, seizures, etc
Describe the metabolism of ethylene glycol.
(AKA antifreeze) metabolized by alcohol dehydrogenase to very toxic aldehydes and oxalate
-ingestion causes transient CNS excitation followed by depression then a severe metabolic acidosis
What is the use of fomepizole?
an alcohol dehydrogenase inhibitor that decreases the conversion of ethylene glycol and methanol to aldehydes
-few side effects
How are methanol and ethylene glycol poisoning treated?
give ethanol or fomepizole
-supportive measures
-do dialysis for ethylene glycol poisoning
What is the mechanism of baclofen?
-it is an agonist at the GABAb receptors
(the GABAb receptor is linked to Gi and decreases cAMP, inhibits Ca channels on presynaptic terminals, opens K channels postsynaptically)
-decreases spasticity w/o causing much sedation
What is baclofen administered?
orally
-intrathecally through implanted infusion pumps which allows better control of pain and spasticity than possible by other routes, reduces peripheral sx b/c effects stay localized
What is the mechanism of diazepam (valium)?
-acts at GABAa recceptors in the spinal cord to reduce spasticity
-used for spasms associated with local mm. trauma
-doses high enough to reduce spasticity cause significant sedation
What is the mechanism of tizanidine?
-analogue of clonidine that reduces mm. spasms by acting as an agonist at alpha2 receptors
-reinforces pre and post synaptic inhibition in the spinal cord and also inhibits pain transmission in the dorsal horn by stim. alpha 2 receptors
What is tizanidine used to tx?
-reduces chronic mm. spasticity due to spinal cord injury
-used in tx acute mm. spasms
-causes significant sedation
-may combine hypotension if combined with anti-HTN drugs
-can also cause dry mouth
Describe cyclobenzaprine (flexeril).
-acts as a sedative at the level of the brain stem
-structurally similar to the tricyclic antidepressants
-has anticholinergic activity
-used for temporary relief of acute mm. spasms caused by trauma or sprain
-causes significant sedation and may produce confusion and transient visual hallucinations
Describe carisoprodol.
-actions are related to central sedative activity and not to a direct effect on sk. mm.
-may interrupt neuronal communication w/in the reticular formation and spinal cord
-CNS depression produces sedation and the perception of pain could be altered
-metabolized rapidly to meprobamate which acts similarly to barbs
-very popular drug of abuse, poor choice for recovering addicts
Describe dantrolene.
-does not act in CNS, it affects excitation/contraction coupling in the mm
-interferes with release of Calcium in the SR
-used in tx of malignant hyperthermia which may be induced by general anesthetics with NM blocking agents
-antipsychotic drugs can produce a similar reaction, neuroleptic malignant syndrome which is tx with dantrolene as well
Describe botulinum toxin.
-blocks the release of Ach from presynaptic nerve terminals
-extremely small amounts are injected to control local mm. spasms often due to neurologic injury or stroke, mm. spasms
What is the mechanism of amphetamine and amphetamine-like drugs?
-inhibit reuptake and/or increase release of newly synthesized NE and dopamine from presynaptic storage vesicles
-sympathomimetic and mimic the actions of epinephrine
-causes euphoria, increased energy, decreased appetite
-side effects include anxiety, insomnia, and irritability
-at higher doses or long term use, psychosis may occur
-dopamine neurons in brain particularly affected-behavioral stim. and increased psychomotor activity result from stim. of dopamine receptors in mesolimbic system
What are the effects of amphetamines at high doses?
-continual purposeless repetitive tasks
-severe anorexia and wt loss
-paranoia, delusions, hallucinations
-behavioral fixations/behavioral repetition
-amphetamine psychosis-violence, hallucinations, mood swings, delusions, paranoia
Describe dependence and tolerance to amphetamines.
-very high abuse potential
-physical dependence occurs readily
-tolerance develops rapidly necessitating higher and higher doses
-causes higher "setpoint" of activity than normal
-craving occurs during abstinence and can be intense
-methylphenidate (ritalin) causes less CNS stimulation but now also being abused
Describe withdrawal from amphetamines.
-increased appetite
-decreased energy, increased need for sleep
-severe depression and suicidal bhvr may develop
-antipsychotic drugs may be necessary to treat paranoia during detox
What type of drugs are usually used to treat ADHD?
stimulants such as methyphenidate and amphetamine
-they improve behavior and learning ability in ADHD
-mechanism of action not clear tho
What is atomoxetine?
-AKA strattera
-SNRI (selective NE reuptake inhibitor)
approved for ADHD
-no abuse potential
-CV effects of beta agonists are potentiated by this drug
-should not be used with vasopressors due to increases in BP
-do not use with MAOIs
What is the mechanism of caffeine?
-blocks adenosine receptors in the CNS and also increases cAMP by inhibiting PDE
-adenosine causes sedation-caffeine inhibits this
-increases mental alertness, faster and clearer thought
-slight stim. on heart,constricts cerebral vessels-effective in tx HA, increased secretion of gastric acid, diuresis,
-large doses may cause anxiety, insomnia, tachycardia and HTN
-withdrawal includes HA, etc
Which 2 neurotransmitters seem to be most involved in the development of depression?
NE
5HT (serotonin)
-not known exactly what causes depression but it was shown in studies that these 2 have a big role in it
What is the neurotrophic hypothesis of depression?
suggests that loss of neurotrophic agents may contribute to depression
-brain derived neurotrophic factor supports neuronal survival and growth, levels of this factor may be decreased in depression
-levels of this growth factor also decrease following stress and chronic pain
-can lead to neuronal loss in hippocampus
-chronic tx with antidepressants increases BDNF levels in experimental animals and restores hippocampal volume
What finding is seen in patients with depression with regard to the glucocorticoids?
they have increased glucocorticoid release in response to stress and a decrease in brain glucocort. receptor activity
-these are normalized in pts who respond successfully to therapy
What are the tertiary amine TCAs?
imipramine
amitriptyline
What are the secondary amine TCAs?
desipramine
nortriptyline
What is the mechanism of action of the TCAs?
they inhibit the uptake of 5HT and NE
-also block muscarinic, alpha, and histamine receptors
-they are NOT CNS stimulants, more likely to cause sedation
-they do not produce euphoria, low abuse potential
-antidepressant effect takes 2-3 wks to develop
Describe the PHK of TCAs.
-half lives are long, 8-89 hrs
-metabolized in the liver therefore drug interactions common
-2 of the tertiary amines are broken down into active metabolites which are secondary amines
(amitriptyline-->nortriptyline-least cardiotoxic and
imipramine-->desipramine)
-the first drug is more sedating with more of a serotonin effect and the metabolite is less sedating with more of a NE effect
-
What are the pharmacological effects of TCAs?
-drowsiness and sedation due to block of histamine receptors
-tolerance generally develops w/in a week
-impairment of memory and cognition (due to anticholinergic effect)-very young and old more sensitive
-analgesia-direct action in spinal cord through NE
-cardiac depression and increased irritability, can lead to Torsades de pointes
-postural hypotension due to alpha blockade
What are the uses of TCAs?
-depression-not used much anymore for this due to side effects
-panic disorder
-pain-useful for treating chronic pain, HA at low doses
-fibromyalgia
-enuresis
-ADHD
What are the big side effects of TCAs?
all the the effects associated with alpha, histamine, and cholinergic receptor blockade
-wt gain
-decrease in seizure threshold may occur
-SIADH (can lead to hyponatremia)
-sexual dysfunction
-tolerance generally develops to the hypotension and the anticholinergic effects
-there is some physical dependence: mm aches and malaise may occur if drug is stopped rapidly
-these drugs can be used in prego
Describe TCA overdose.
-they are extremely dangerous when taken in overdose and depressed pts may be suicidal
-initial rx should be limited to small amounts with no refill
-overdose can cause cardiac conduction defects and arrhythmias (TdeP)
-hypotension
-seizures
-resp. depression, rapid development of coma with shock and metabolic acidosis
How is TCA overdose tx?
-cardiac monitoring, supportive care
-gastric lavage and charcoal
-tx the T de P
-phenytoin, lidocaine, propanolol to manage arrhythmias and/or prevent seizures
What are the drug interactions of the TCAs?
-MAOIs; if taken together can cause serotonin syndrome
-fluoxetine and other SSRIs compete for metabolism of TCAs; combo can cause TCAs to reach toxic levels
-can decrease the central antiHTN effect of clonidine=HTN
-may cause HTN when combined with indirectly acting sympathomimetic drugs like amphetamine
-cocaine
-potentiate sedative effects of alcohol and other CNS depressants
-anticholinergic drugs potentiated by TCAs;
What is the function of MAO-A?
breaks down NE and serotonin
What is the function of MAO-B?
breaks down dopamine
What are the side effects of MAOIs?
-HTN crisis: irreversible inhibition of MAO in the GI tract allows accumulation of tyramine that is ingested in food, tyramine causes release of catecholamines from nerve endings and the adrenal medulla
-therefore foods containing tyramine by pts on MAOIs can lead to a severe HTN crisis
-these foods include red wine, beet, sausage, aged cheese and prepared meats
-severe HTN can also occur with sympathomimetic drugs, usually tx with alpha blocker
-wt gain is very common
-anticholinergic effects-HA, urinary retention, blurred vision, dry mouth
What is serotonin syndrome?
a rare but severe disease
-characterized by CNS toxicity starting with restlessness, mm. twitches and myoclonus, hyperreflexia, sweating, tremor, convulsions, and coma
-allow at LEAST 2 wks after discontinuing MAOIs before starting pt on other antidepressants
What are the drug interactions of MAOIs?
-OTC cold meds containing sympathomimetic amines such as phenylephrine and ephedrine or amphetamines-->severe HTN
-TCAs or SSRIs-->serotonin syndrome/hyperpyrexia
-meperidine, tramadol, dextromethorphan also inhibit serotonin reuptake and can lead to serotonin syndrome
-buspirone may cause HTN
-just use caution with ALL meds, OTC and Rx
What are the first DOC for depression now and why?
SSRIs b/c they have mild side effects and are very effective
Describe TCA overdose.
-they are extremely dangerous when taken in overdose and depressed pts may be suicidal
-initial rx should be limited to small amounts with no refill
-overdose can cause cardiac conduction defects and arrhythmias (TdeP)
-hypotension
-seizures
-resp. depression, rapid development of coma with shock and metabolic acidosis
How is TCA overdose tx?
-cardiac monitoring, supportive care
-gastric lavage and charcoal
-tx the T de P
-phenytoin, lidocaine, propanolol to manage arrhythmias and/or prevent seizures
What are the drug interactions of the TCAs?
-MAOIs; if taken together can cause serotonin syndrome
-fluoxetine and other SSRIs compete for metabolism of TCAs; combo can cause TCAs to reach toxic levels
-can decrease the central antiHTN effect of clonidine=HTN
-may cause HTN when combined with indirectly acting sympathomimetic drugs like amphetamine
-cocaine
-potentiate sedative effects of alcohol and other CNS depressants
-anticholinergic drugs potentiated by TCAs;
What is the function of MAO-A?
breaks down NE and serotonin
What is the function of MAO-B?
breaks down dopamine
What are the side effects of MAOIs?
-HTN crisis: irreversible inhibition of MAO in the GI tract allows accumulation of tyramine that is ingested in food, tyramine causes release of catecholamines from nerve endings and the adrenal medulla
-therefore foods containing tyramine by pts on MAOIs can lead to a severe HTN crisis
-these foods include red wine, beet, sausage, aged cheese and prepared meats
-severe HTN can also occur with sympathomimetic drugs, usually tx with alpha blocker
-wt gain is very common
-anticholinergic effects-HA, urinary retention, blurred vision, dry mouth
What is serotonin syndrome?
a rare but severe disease
-characterized by CNS toxicity starting with restlessness, mm. twitches and myoclonus, hyperreflexia, sweating, tremor, convulsions, and coma
-allow at LEAST 2 wks after discontinuing MAOIs before starting pt on other antidepressants
What are the drug interactions of MAOIs?
-OTC cold meds containing sympathomimetic amines such as phenylephrine and ephedrine or amphetamines-->severe HTN
-TCAs or SSRIs-->serotonin syndrome/hyperpyrexia
-meperidine, tramadol, dextromethorphan also inhibit serotonin reuptake and can lead to serotonin syndrome
-buspirone may cause HTN
-just use caution with ALL meds, OTC and Rx
What are the first DOC for depression now and why?
SSRIs b/c they have mild side effects and are very effective
What is the mechanism of SSRIs?
-they inhibit the re-uptake of serotonin into the synaptic terminal
-antidepressant effect takes 2-3 weeks to develop
-SSRIs are as effective as the TCAs in treating depression
-advantage is that they have very mild side effects
Describe the PHK of fluoxetine (an SSRI).
-it is converted to norfluoxetine which is also biologically active and has a half life of 7-9 days
-the effects of fluoxetine, specifically, are very long lasting
-causes significant inhibition of the hepatic CYP2D6 enzyme and can therefore inhibit the metabolism or activation of many other drugs (includes TCAs, benzos, antipsychotics)
-the other SSRIs have fewer effects on liver enzymes and have shorter half lives and durations of action
What are the clinical uses of SSRIs?
-depression-no cardiac tox., few side effects
-panic disorder-now the DOC for this
-OCD
-social anxiety
-bulimia
-alcoholism
-children and teens
What are the side effects of SSRIs?
-GI, wt loss may occur initially and then wt. gain in chronic use, CNS stimulation, sexual dysfunction, SIADH, hyponatremia possible, photosensitivity, insomnia or sedation
-generally mild side effects tho
What are the drug interactions for SSRIs?
-they are metabolized by p450 system so many drug interactions possible, esp. with fluoxetine (inhibits CYP3A4 and 2D6)
-MAOIs:serotonin syndrome, may also occur with St. john's wort or amphetamines
-TCAs: inhibition of metabolism increases TCA concentration and tox.
-warfarin:increased risk of bleeding b/c of inhibition of metabolism of warfarin
-phenytoin or carbamazepine
-beta blockers:inhibits their metab
-opioids: inhibits conversion to the active compound by CYP system so less effective
-tramadol:seizures may occur
-tamoxifen:decreases metabolism of this pro-drug to active form
Describe fluoxetine.
-long duration SSRI
-it is best to wait 5 wks after stopping the drug before switching to a different antidepressant b/c of its long lasting effects
-also has effects on the re-uptake on NE
-may cause insomnia
What is sertraline?
-more selective for serotonin re-uptake than fluoxetine but effects are similar
-SSRI
-has less inhibitory effects on liver enzymes and less of everything basically
What is paroxetine?
-an SSRI
-shorter duration of action, often used on elderly
-more likely to cause sedation
-DO NOT give in prego
What are citalopram and escitalopram?
-SSRIs
-appears to have faster onset of action than other SSRIs
-very little effect on hepatic enzymes so expected to have fewer side effects
What are venlafaxine and desvenlafaxine?
-inhibit both the re-uptake of serotonin and NE
-they are SNRIs
-desvenlafaxine is the primary metabolite and is pharmacologically active so venlafaxine has a long duration of action
-now available for tx of depression
What are the side effects of SNRIs?
-they have more side effects than SSRIs
-increased BP
-SIADH, hyponatremia
-GI
What is duloxetine?
-similar to venlafaxine
-SNRI
-used to tx depression but also effective in improving physical sx (back pain, etc)
-metabolized by CYP2D6 and CYP1A2 and causes moderate inhibition of CYP2D6
-may be hepatotoxic-should not be given to anyone with liver disease
What is buproprion?
-inhibits the re-uptake of dopamine as well as NE
-extended release form marketed as an aid to quit smoking
-often works well in pts who have not responded well to other anti-depressants
-appears to reduce craving and may be usefel for recovery from drug or alcohol abuse
What are the side effects of buproprion?
-CNS stimulations: anxiety, insomnia
-wt loss
-unlikely to cause sexual dysfunction
-seizures
-CI in pts with hx of head injury or seizures
-do NOT give with drugs that lower seizure threshold (TCAs, antipsychotics)
What is trazodone?
-may be partial agonist at 5HT receptors and may block the 5HT2a receptor
-not very good antidepressant, more useful as a sleep aid
-also used for pain management
-side effects include sedation, priapism is the big one (rare tho)
What is St. John's Wort?
-may block reuptake of NE, 5HT, and possibly DA but mechanism not really known
-effective in mild to mod. depression
-increases sensitivity to sun
-should not be used with MAOIs, SSRIs, or TCAs, L-dopa or selegiline (serotonin syndrome)
-induces cytochrome P450 and decreases effectiveness of several drugs including digoxin, warfarin, theophylline, oral contraceptives, etc.
How do most sedative-hypnotics and anxiolytics work?
-most act by binding to a modulatory site on the GABAa receptor complex to either intensify or prolong the actions of GABA
-binding of GABA to the GABAa receptor complex opens Cl channels which hyperpolarizes the membrane and depresses synaptic transmission
-these drugs act as depressants of the CNS
What is the mechanism of barbiturates and what are their general characteristics?
-they bind to GABAa receptor and increase the duration of GABA action
-at high concentrations, they may increase Cl influx and produce inhibition independent of GABA at a different site
-have a marked CNS depressant effect
-low margin of safety
-decrease resp. drive at high doses
-they cause euphoria=drugs of abuse, schedule II or III controlled drugs
-therapeutically have been replaced by benzos
-the effects of CNS depressants are SUPRA-additive, esp. true when combined with alcohol
Describe the PHK of barbiturates.
-well absorbed orally and enter CNS quickly and easily
-degree of lipid solubility determines duration of action and rate of onset, some are short acting, some are long
-extensively metabolized by liver
-induce hepatic enzymes with chronic use which alters metabolism of other drugs
What are the uses of barbiturates?
-thiopental is an ultra-short acting barb used for induction of anesthesia
-long acting such as phenobarbital are used as anti-convulsants
What are the side effects of barbiturates?
-CNS depression: drowsiness, distortion of mood, impaired judgement and motor skills
-decrease in REM sleep
-paradoxical excitement
-very low margin of safety
-esp. dangerous when combined with alcohol
-OD marked by coma, resp. depression and decreased BP; supportive tx necessary as stimulants actually increase mortality
-induce porphyrin synthesis and are CI in any form of poryphyria
-CI in present of pulmonary insufficiency
-withdrawal can be life-threatening (severity increases with dose and amount of time drug has been used)
How can barbiturates be cleared from the body in the case of OD?
by forced diuresis with alkalinization of the urine (they are acids)
Describe the general uses and properties of benzos.
-most commonly used group of anxiolytics and sedative-hypnotics
-produce CNS depression with a decrease in anxiety often accompanied by drowsiness
-at higher doses, hypnosis occurs
-some may produce mm. relaxation
-some have anticonvulsant effects
What is the mechanism of action of benzos?
-they bind to a specific receptor associated with the GABAa receptor complex
-there may be endogenous ligands for the benzo receptor but remains controversial
-they intensify the actions of GABA by enhancing its binding to the GABAa receptor
-they can act ONLY when GABA is present
-as benzo concentration increases, release of GABA is inhibited which produces a ceiling effect
-this makes benzos much safer than barbs
Describe the PHK of benzos.
-duration of action varies: either depends on lipid solubility or metabolism of active metabolites
-some are converted to active metabolites which are metabolized very slowly and therefore have long duration of action (ex: diazepam, chlordiazepoxide-->desmethyldiazepam half life of 24 hrs)
-this may provide a tapering of response as the drug is lowered or stopped, can be helpful in tx sx of withdrawal from alcohol, barbs, or other benzos
Describe the half life of flurazepam.
a benzodiazepine
-converted to a long acting active metabolite
-active metabolites will accumulate if drug is taken daily
Describe the half life of lorazepam.
conjugated directly to inactive metabolites so are intermediate acting
-benzo
What are the short acting benzos?
alprazolam and triazolam (shorter than alpraz)
-midazolam has a VERY SHORT duration of action (<2 hrs)
What are the drug interactions of benzos?
-there is extensive metabolism in the liver but they DON'T induce liver enzymes so have fewer interactions than barbs
-cimetidine lengthens elimination half-life of diazepam by decreasing metabolism
What are the uses of benzos?
1)anxiety-however, NOT USED in OCD, agoraphobia and panic disorders, PTSD, anxiety in kids and teens
2)insomnia-
3)epilepsy and seizures
4)sedation, amnesia, and anesthesia
5)mm relaxation
6)withdrawal from alcohol and barbs
Describe the use of benzos to tx insomnia.
-flurazepam, temazepam, and triazolam are commonly used as hypnotics, cause less depression of REM than barbs
-longer acting like flurazepam may cause a hangover next day, used in pts who have a problem with early morning awakening
-short acting like triazolam used for pts with difficulty falling asleep, may cause rebound insomnia tho
What is midazolam commonly used for?
-a benzo used for anesthesia -must be given IV
-very short duration of action and rapid onset
-also causes anterograde amnesia
Which benzos are commonly used for withdrawal from alcohol and barbs?
-longer acting benzos such as chlordiazepoxide and diazepam (valium) are used to provide a tapered withdrawal
-can prevent seizures and DTs
What are the side effects of benzos?
-CNS depression-effects most common in first few weeks, will decrease as tolerance develops
-the CNS depression becomes much more pronounced with combined with alcohol
-should be used sparingly in kids b/c impair memory and learning
-the elderly are esp. sensitive to CNS effect (may misdiagnose Alz. b/c of impaired memory)
-
What are the CI of benzos?
-should not be given during prego unless absolutely have to
-CI in kids
-CI in sleep apnea
Can tolerance and dependence develop to benzos?
yes when used chronically
-they are schedule IV
-abrupt discontinuation of benzos can cause rebound insomnia and anxiety
-when they have been used in high doses for a long time withdrawal sx can be severe-should be tapered after chronic use
What is flumazenil?
a benzo antagonist-competes with benzos for the receptor
-must be given IV
-should be given slowly
-used to reverse the CNS depressant effects of benzos
-duration of action about 30 mins
-major adverse effect is that it can trigger withdrawal and seizures in pts physically dependent on benzos
-can cause seizures in pts with barb and TCA overdose
What are zolpidem, zaleplon, and eszopiclone?
-all facilitate GABA-mediated inhibition and exhibit some, but not all, of the actions of benzos
-bind the BZ1 subtype of the benzo receptor
-little or no anxiolytic, anticonvulsant, and mm. relaxant properties
-very strong and rapid sedative activity
-preserve deep sleep with only MINOR effects on REM sleep
-eszopiclone approved for long term tx of insomnia
-tolerance rare and sleep benefit may persist after drugs are stopped
-zolpidem has a very short half life (2 hrs), zaleplon even shorter (1 hr)
-ppl unlikely to be impaired the morning after with these 2 drugs, more likely with eszopiclone b/c longer half life
What are the side effects of zolpidem, zaleplon, and eszopiclone?
-GI
-CNS, drowsiness or dizziness
-sleep walking, eating, driving
-very high margin of safety
-much less likely than benzos to cause tolerance or dependence
-rebound insomnia may occur
-withdrawal sx have been seen with abrupt cessation after long-term use of eszopiclone
What is ramelteon?
-agonist at melatonin MT1 and MT2 receptors, believed to regulate sleepiness and maintain circadian rhythms
-shortens delay to sleep onset and total sleep time
-metabolized in liver, do NOT use in ppl with severe liver disease
-additive sedation with alcohol and other sed-hyp
-rifampin increases metabolism
-side effects few: drowsiness, dizziness and nausea
-increase in serum prolactin and decrease in testosterone possible
-no effect on REM, little evidence for rebound insomnia
What is buspirone?
-first drug in a class that relieves anxiety without producing sedation
-acts as a partial agonist at 5HT receptor
-does NOT affect benzos or GABA receptors
-increases activity of NE and DA pthways
-full anxiolytic effect takes about 2 weeks to develop
-little or NO sedative effect
-very low addiction potential, does not potentiate CNS depression with alcohol or benzos, but will not prevent sx of withdrawal from alc or benzos
-good choice for tx anxiety in recovering alcoholics or addicts, or elderly
-good for moderate generalized anxiety and anx. with depression
-few side effects, restlessness may occur in some ppl, increases BP in pts taking MAOIs and should not be combined
How do the "classical" antipsychotics work?
by blocking the D2 subtype of dopamine receptor in the limbic system
-there is often a sedation which is different than that produced by sed-hyp, decrease in arousal and motility called "neuroleptic" effect
-antiemetic activity occurs from blockade of dopamine receptors in the chemoreceptor trigger zone
-this correlates well with relieving the positive sx of schizophrenia
What do the newer antipsychotic drugs do?
-block 5HT2a serotonergic receptors and are more effective against negative sx
-most antipsychotic drugs also block muscarinic, alpha, and histamine receptors as well (often basis for the side effects)
What are the usual side effects of antipsychotics?
-fairly safe with a high TI
-Extrapyramidal effects-dopamine receptors in the nigrostriatal system are also blocked and these neurons are important for motor control so antipsychotics can produce EPS such as anxiety, constant rocking, dystonia, involuntary mm. spasms, parkinsonian sx like tremor, rigidity
-this is tx with anticholinergic drugs to bring striatal cholinergic and dopaminergic activity into balance
-drugs with more anticholinergic activity are less likely to produce these EPS effects
-tardive dyskinesia-occurs late in tx and consists of uncontrollable movements of the mouth, tongue, and face, etc-clozapine and olanzapine less likely to cause this
-endocrine effects
-automonic effects
-seizures
-neuroleptic malignant syndrome
Describe the endocrine side effects of antipsychotic drugs.
-DA blockade in hypothalamus suppresses appetite and deregulates temperature
-wt gain is common, unknown why
-antipsychotics increase prolactin release, in women this causes amenorrhea, lactation, decreased libido, and infertility
-impotence, loss of libido, infertility, and gynecomastia occurs in men
What are the autonomic side effects of antipsychotics?
-most block muscarinic, alpha, and histamine receptors
-side effects will follow, similar to TCA side effects often
Describe the side effect of seizures with antipsychotics.
-they generally slow the EEG causing hypersynchrony which can cause seizures
-must be used with extreme caution in epileptics
What is neuroleptic malignant syndrome?
-life threatening characterized by mm. rigidity, catatonia, marked increase in body temp, altered BP and HR
-treated with mm. relaxants and dantrolene
-occurs with the antipsychotic drugs
Describe the phenothiazines.
-block D2 (more likely to cause EPS effects), alpha, muscarinic, and histamine receptors
-used to tx schizophrenia, Nausea and vomiting, pre-anesthetic sedation, psychotic episodes associated with manic, alcholic hallucinations and those associated with drugs of abuse
-range from low to high potency
-low potency have more anticholinergic effect which makes them less likely to cause EPS as compared to the high potency drugs but they are more likely to have autonomic effects
Describe the PHK of phenothiazines.
-absorbed erratically when taken orally
-also effective IM injection
-metabolized slowly in the liver with slow elimination
What are the side effects of phenothiazines?
-anticholinergic side effects
-blockade of alpha receptor side effects
-quinidine like action causing prolongation of QT interval
-seizure threshold decreased
-thioridazine may produce retinal deposits
-all of the side effects of the "classic" antipsychotic drugs including EPS sx, tardive dyskinesia and neuroleptic malignant syndrome
What drug can cause retinal deposits?
thioridazine (an anti psychotic drug)
Describe haloperidol (haldol).
-effects are similar to those of phenothiazines
-selective blockade of D2 receptors
-often injected in acute psychotic situations (ie: those associated with drug or alcohol abuse)
-most likely of ALL antipsychotics to cause EPS!!
Describe clozapine.
-it is a new-gen atypical antipsychotic
-improves the neg. sx of schizophrenia
-binds to D4 receptors and to 5HT2a receptors to a much greater degree than to D2 receptors (greater mesocortical and limbic system specificity)
-very low incidence of EPS
-also inhibits muscarinic, histamine, and alpha receptors
-unlikely to cause tardive dyskinesia
-can be used to treat psychosis and delusions in pts with parkinson's disease
-causes agranulocytosis
What drug can cause agranulocytosis?
clozapine
What is olanzapine?
-very similar to clozapine blocks D2, D4 and 5HT receptors
-also has anticholinergic effects, but EPS sx rare
-drugs with a higher affinity for 5HT receptors than D2 receptors are more effective in tx neg. sx
-used to tx bipolar as well
-does NOT cause agranulocytosis
-side effects: wt gain-most likely of all antipsychotics to cause this, increased incidence of hyperglycemia and type II DM
What is risperidone?
-first line drug for tx psychosis
-very effective at relieving both pos/neg sx
-inhibits D2 and esp. 5HT receptors, also blocks alpha
-enhances DA transmission in basal ganglia so few EPS
-advantages are improvement of neg. sx and low incidence of EPS
-low incidence of tardive dyskinesia
What are the side effects of risperidone?
-lengthens the QT interval-most likely of antipsychotics to cause this
-sx of alpha blockade
-wt gain
What is ziprasidone?
-similar to risperidone, blocks D2 and 5HT receptors
-has some antidepressant activity
-metabolized in liver, drug interactions possible
-side effects: prolongs QT interval, causes sedation, may cause hyperprolactinemia, use with caution in pts. with hx of seizure disorders
What is quetiapine (seroquel)?
-similar to clozapine but doesn't cause agranulocytosis
-improves pos/neg sx
-does not cause elevation of prolactin
-now being used for depression
-most common side effects are wt. gain, drowsiness, and xerostomia
What is aripiprazole (abilify)?
-different from other antipsychotics
-first in a new class called dopamine system stabilizers
-dopamine receptors are activated when dop. tone is low and blocked in dop. tone is high
-partial agonist at D2 and 5HT receptors, antagonist at 5HT receptors
-blocks alpha, histamine receptors
-does not affect prolactic, does not lengthen QT interval, no wt. gain
-marketed fro tx of drug-resistant depression and for antipsychotic effect
What are the side effects of aripiprazole?
-orthostatic hypotension
-elevations in blood glucose and diabetes may worsen
-sedation, seizures
-decreases motility of esophagus, use with caution in elderly with risk of aspiration pneumonia
-low incidence of EPS
What are the drug interactions of antipsychotics?
-combo with sed/hyp will cause increased sedation
-combo with anticholinergics will increase side effects such as dry mouth, urinary retention, etc
-carbamazepine induces liver enzymes which decreases antipsychotic concentration due to increased metabolism, so does smoking
-interactions with antiHTN drugs are unpredictable due to alpha blockade
What are the uses of antipsychotics?
schizophrenia
depression with mania and psychosis
tourette's
alzhemier's
antiemetic
depression
Which antipsychotics are considered the first line drugs in tx schizophrenia and why?
-risperidone, quetiapine, and olanzapine b/c of low side effects
What is bipolar disorder most commonly treated with?
lithium, valproic acid and carbamazepine
Describe the PHK of lithium.
-optimal dose for tx and maint. is calc. by measuring serum lithium concentrations (optimal range from 0.6-1.2 mEq/L)
-excreted by kidney, reabsorbed by proximal tubule in kidney and competes with sodium for reabsorption
-decreases in sodium will increase Li tox., as will thiazide diuretics
-NSAIDS also decrease clearance
What are the side effects of Li?
tremor, nausea, HA, decreased thyroid function, renal effects-nephrogenic DI b/c it blocks action of ADH (can be treated with amiloride), wt gain, can be used in prego but dose usually has to be increased
How is lithium tox. treated?
with dialysis and saline
Describe lithium toxicity.
-it is extremely toxic in overdose
-plasma levels >2 cause mild tox with N/V, diarrhea, mm. weakness, fine tremor,etc
-plasma levels>2.5 cause severe tox wtih V, produce diarrhea, mental confusion, ataxia, speech impediment, gross tremor, renal failure, coma/death, etc
Describe the use of valproic acid;divalproex sodium (depakote) as an antipsychotic drug.
-now widely used as a mood stabilizer
-efficacy is equivalent to or greater than lithium
-effective in some pts who do not respond to Li
-very rapid onset of action
-side effects include:GI upset, wt gain, transient increase in liver enzymes
Describe the use of carbamazepine as an antipsychotic.
-may be useful in pts who don't respond to lithium
-may be combined with Li
-mechanism of action unknown
-not recommended in prego
What is topiramate?
-effective as monotherapy in some pts with bipolar disorder
-also used as anticonvulsant, for alcoholism tx, to offset wt loss from SSRIs, reduce binge eating, and for prevention of migraine
-usually causes wt loss
-an antipsychotic
What causes Parkinson's disease?
degeneration of dopamine neurons projecting from the substantia nigra to the corpus striatum (nigrostriatal pthway)
-leads to a nearly 80% decrease in striatal dopamine
-it is caused by the degeneration of DA neurons in the pars compacta of the substantia nigra which leads to overactivity in the indirect pathway culminating in increased glutamatergic output from the subthalamic nucleus and increased GABA input into the thalamus
Describe the synthesis and metabolism of dopamine.
-tyrosine is converted into l-dopa which is then converted into DA by dopa decarboxylase in the nerve terminal
-excess dopamine in the synaptic cleft is taken back up into pre-synaptic terminal via the DA transporter and inactivated by MAO-A in the nerve terminal or MAO-B and COMT in the synapse
What do tx strategies for Parkinson's focus on?
-increasing the levels and actions of DA and blocking the actions of Ach (anticholinergics)
What is L-dopa (levo-dopa)?
-the BBB will not allow DA into the brain so tx with DA does not work
-the immediate precursor of DA is L-dopa, so use of L-dopa which readily passes through the BBB and then is converted to DA
-there are problems when it is used alone tho b/c it is converted to DA in the GI tract and peripheral tissues so high doses are needed to provide sx relief of PD
-high doses can cause N/V
What is dopa/carbidopa?
-it is a dopa decarboxylase inhibitor that does not cross the BBB
-given with L-dopa to increase the % that gets into brain and decreases the dose of L-dopa needed to achieve therapeutic effects
-absorption is delayed by food, short half life,
-this combo of drugs may provide relief fro 3-4 yrs but does not change the progression of the disease
-the effectiveness of this drug therefore decreases over time as these pts. lose dopaminergic neurons
-side effects increase over time as well
-esp. useful for bradykinesia
What are the adverse effects of L-dopa/carbydopa?
-N/V occurs in about 80% of pts when L-dopa is taken alone
-incidence decreases when the drugs are taken together
-postural hypotension initially but diminishes with time
-HTN when combined with MAOIs or other sympathomimetic drugs
-dyskinesias-excessive, involuntary movements, more common with combo of drugs
-behavioral side effects-psychosis is treated with atypical antipsychotics such as clozapine, quetiapine, or aripiprazole that have a lower incidence of blocking D2 receptors
-on/off phenomenon-pts. treated with L-dopa, off are periods of akinesia, on are periods of improved mobility,
-drug holiday
What is drug holiday in regards to L-dopa/carbydopa?
-was once used in attempt to decrease side effects
-drug is withdrawn gradually: abrupt discontinuation may cause akinesia or neuroleptic malignant syndrome
-after 3-21 days the drug was restarted at 1/2 or less of previous dose
-risky and not recommended: apiration pneumo, venous thrombosis, PE may result from immobility
What are the drug interactions of L-dopa?
-MAOIs may cause HTN crisis
-vit. B6 increases peripheral metabolism of L-dopa and can decrease the effectiveness unless carbidopa also given
What are the CI to L-dopa?
psychosis-increases DA
closed angle glaucoma (increases intraocular pressure)
-cardiac disease
-active peptic ulcer
-malignant melanoma (l-dopa is a precursor of melanin)
What is selegiline?
-an MAOI
-it inhibits MAO-B which is the predominant form in the striatum and thus reduces striatal metabolism of DA
-doesn't usually affect the peripheral breakdown of catecholamines by MAO-A
-one of the by-products of ox. of dopamine by MAO-B is H2O2 which is toxic to nerve cells
-it decreases formation of free radicals and may slow the progression of PD
What are the adverse effects of selegiline?
-insomnia if taken late in the day
-DO NOT combine with meperidine-may produce stupor, rigidity, agitation, hyperthermia
What are bromocriptine/pramipexole?
-dopamine receptor agonists which act directly on DA receptors and also used to tx parkinson's disease
-effectiveness does not decrease as the disease progresses
-used in combo with Ldopa
-these will decrease the release of prolactin
-bromocriptine is an ergot derivative and can result in side effects related to vasospasm
What are the adverse effects of bromocriptine/pramipexole (DA receptor agonists)?
GI:anorexia, N/V which is minimized by taking with meals, bleeding of peptic ulcers
CV:postural hypotension esp. at begin. of tx may be severe, cardiac arrhythmias-discontinue tx
-dyskinesia
-mental disturbances
-erythromyalgia-red, tender, swollen feet due to vasospasm
What is amantadine?
-antiviral drug used to treat influenza, elderly pts with parkinson's improved
-mechanism is unclear-may increase DA synthesis, release and uptake
-less potent than Ldopa
-toxic psychosis and convulsions may occur with OD
-spotting of skin (livedo reticularis) clears up w/in a month of discontinuing drug
-peripheral edema that repsonds to diuretics
-use with caution in pts with a hx of seizures or CHF
What is benztropine?
-decreases the effects of Ach to match the loss of dopamine thus restoring chemical transmitter balance
-improves rigidity, tremor, drooling, but little effect on bradykinesia
-discontinue gradually
-diphenhydramine (benedryl) also sometimes used for this purpose
What are the neurochemical changes in the brain seen in Alzheimer's?
-degeneration of cholinergic neurons from the nucleus basalis of Meynert which project to the cerebral cortex and hippocampus
-levels of Ach are reduced up to 90%
-NE and Serotonergic pthways also degenerate as disease progresses
What is donepezil and rivastigmine?
-cholinesterase inhibitors, inhibits the breakdown of Ach in the synaptic cleft and thus prolong its action
-sx are improved in some pts for awhile and may actually slow the course of the disease so should be given ASAP
-adverse effects include N/V/diarrhea
-an old drug, tacrine, caused liver tox. and is really no longer used
What is memantine?
--non-competitive antagonist at NMDA receptors
-used in more severe alzheimer's disease
-not know why it works
-may prevent neurotox. of glutamate on NMDA receptors and slow neurodegeneration
-may enhance adverse effects of L-dopa such as dyskinesias or psychiatric disturbances
-most common side effects are urinary incontinence, agitation, UTI, insomnia, diarrhea