Week 1 Antiepileptic 3 of 4 Flashcards
Plasma protein binding of valproic acid?
> 80%
peak plasma concentration of valproic acid occurs in how many hours?
1-4 hours
What route is valproic acid known to have prompt absorption?
PO
Therapeutic plasma concentration of valproic acid is ?
50-100mcg/ml
What is a better determinant of valproic acids therapeutic concentration (compared to plasma concentration?)
clinical condition may be a better determinant of therapeutic concentration.
What are the side effects of valproic acid?
anorexia n/v
fine distal tremor seen in higher doses
thrombocytopenia seen frequently at higher doses
What is the issue with valproic acid and and children under 2 years of age?
Most serious side effect is hepatotoxicity occuring in around 0.2% of children 2 years old who are treated chronically. This is potentially fatal. Hepatic necrosis decreases dramatically after 2 years of age.
What are two infrequent side effects with valproic acid? (you see these side effects with other seizure medications but not valproic acid)
sedation and ataxia is not seen with valproic acid.
Because this medication is partially eliminated as a ketone containing metabolite, may have a false positive ketone result, what medication does this describe?
valproic acid
What can valproic acid do to phenytoin and diazepam?
can displace phenytoin and diazepam from protein binding sites resulting in increased pharmacologic effects produced by displaced drug.
What does valproic acid do to the plasma concentration of phenobarbital?
increases it by around 50%
Does valproic acid interfere with the action of oral contraceptives?
NO!
What is Parkinson’s dz and who does it effect?
Results from loss of dopaminergic neurons in the substantia nigra pars compacta region of basal ganglia.
Effects roughly 1% of population usually greater than 60 years old.
What is a consistent feature found in the substantia nigra region of patient’s with parkinson’s dz?
Lewy Bodies
what type of neurotransmitter is dopamine and acetylcholine?
dopamine is thought to act principally as an inhibitory NT.
acetylcholine is thought to be an excitatory NT
Where is roughly 80% of the dopamine in the brain found?
basal ganglia, mostly in the caudate nucleus and putamen.
In patient’s with Parkinson’s dz the basal ganglia content of dopamine may be as low as what?
10% of normal
What happens to people who have super low dopamine in their brain?
an excess of excitatory cholinergic activity manifesting as progressive tremor, skeletal muscle rigidity, bradykinesia, and disturbances of posture result.
What is the objective in treatment of Parkinson’s dz?
to treat debilitating symptoms. Current meds are palliative and do not affect the progression of the dz. Treatments are selected based on age and severity of symptoms.
When is pharmacologic treatment started for a parkinson’s patient?
when motor symptoms become bothersome.
Other than treatment aimed at addressing motor symptoms in Parkinson’s patients, treatment will also be addressing other adverse effects: what would these other adverse effects be?
nausea depression autonomic disturbances cognitive impairment medication related side effects
True or False
Dopamine readily crosses the BBB?
False, it does NOT readily cross the BBB. This is why Levodopa is used (precursor to dopamine) because it can cross the BBB. Other drugs that mimic the action of dopamine can also be used.
What is levodopa usually administered with?
a peripheral decarboxylase inhibitor (carbidopa or benserazide) This medication maximizes the entrance of levodopa into the brain before it is converted to dopamine.
What medication is considered the cornerstone of symptomatic therapy for Parkinson’s dz?
Levodopa
What converts levodopa to dopamine? (think enzyme)
L-amino-acid decarboxylase (dopa decxarboxylase enzyme)
What replenishes dopamine stores in the basal ganglia?
Levodopa
Tell me what Decarboxylase inhibitor does?
maximize entrance of levodopa into the brain before its converted to dopamine.
Other than maximizing entrance of levodopa into the brain, what does decarboxylase inhibitors do in relation to side effects of drug treatment for Parkinson’s?
Decarboxylase inhibitors ensure that side effects associated with increased peripheral concentrations of dopamine are lessened.
You take levodopa PO, what is significant about the dosing (due to elimination half-time)?
GI absorption is efficient but has brief elimination half-time (1-3 hours) and requires frequent dosing intervals to maintain therapeutic levels.
True or False
There is also an IV form of levodopa but it is not used bc the absorption rate is too quick?
False, no IV form of levodopa is available.
What is important about the therapeutic benefits of Levodopa? Basically how long are you allowed to take drug therapy and why? (this is probably why they wait to treat symptoms)
Therapeutic benefits diminishes after 5- 10 years. May be d/t disease progression and continuing loss of nigrostriatal neurons with a capacity to store dopamine.
Which NT can cross the BBB, Dopamine or L dopa?
L dopa (levodopa) can cross the BBB, NOT dopamine. (this is important bc if dopamine can not cross the BBB then it stays in place also, does not exit the CNS once there!)
Tell me what has occurred in the situation below:
A patient has been in the hospital for 2 days with no PO medications given and has Parkinson’s dz. They are about to be taken to the OR for an emergency surgery. You notice upon your quick assessment they have all the text book symptoms of neuroleptic malignant- like syndrome, what is going on?
Abrupt d/c of levodopa may result in a precipitous return of symptoms of Parkinson’s disease and associated with neuroleptic malignant-like syndrome.
True or False
Thus levodopa should be continued through the perioperative period?
True, due to return of symptoms if abruptly stopped.
What happens to 95% of PO administered levodopa during initial passage through the liver?
rapidly decarboxylated to dopamine during the initial passage through the liver.
Due to the amount of PO levodopa that decarboxylates to dopamine during first pass through the liver, what will you give in order to increase the fraction that can cross the BBB as levodopa?
an inhibitor of decarboxylase enzyme (think decarboxylase bad, you want to inhibit with parkinson’s)
30 metabolites of levodopa are known (most excreted by the kidneys) and are converted to dopamine, a small amount are metabolized to what and what?
norepinehrine and epinephrine
this makes sense bc the natural progression of tyrosine to L-dopa to dopamine to norepi and then to epinephrine
homovanilic acid comes from the metabolism of what?
dopamine
Most common SE (in the first few weeks) with levodopa and dopamine agonists?
Nausea and hypotension
Most common problems with long term therapy for Parkinson’s dz?
Dyskinesia Fluctuations in mobility Increasing confusion Psychosis These become more frequent after the 3 years
If someone was just started (first few weeks) on parkinson’s treatment then what do you want to do for them during intubation?
They are likely to have nausea which could lead to vomiting, thus during intubation you will want to do a RSI and place an NG tube.
You may also want to give them lots of anti emetics for when they wake up.
Urinary metabolites of levodopa can cause what?
false positive ketoacidosis tests
What may you notice about the urine of a person who is being treated for Parkinson’s dz?
Metabolites color urine RED then BLACK upon exposure to air.
If a patient with parkinson’s dz has an increase in BUN, what will you do, what do you know about this increase?
Transient increases in BUN may occur and can be controlled by increasing fluid intake.
What test may show up positive for a Parkinson’s patient being treated pharmacologically? (think anemia)
May have a positive Coomb’s test: Test for antibodies in blood stream determining if the immune system is destroying the patient’s own blood cells causing anemia.
What are some antipsychotic drugs do you NOT want to give to a patient who is being treated for Parkinson’s with Levodopa?
Butyrophenones and phenothiazines (antipsychotic drugs) can antagonize effects of dopamine and should not be given to Parkinson’s patients (known or suspected).
What drug if given to a patient being treated with Levodopa can cause muscle rigidity and pulmonary edema?
Droperiodol
What drug can produce parkinson’s like symptoms in a normal patient?
Droperiodol
Would you want to give Metoclopramide with levodopa? Why?
Metoclopramide may also interfere with dopamine activity (reglan).
What drug can Can exaggerate PNS and CNS effects of levodopa. Hypertension and hyperthermia are side effects with concurrent administrations?
Monoamine Oxidase Inhibitors
What are two things that can happen if you give anticholinergic drugs with levodopa? (one is good, one is not so good)
Anticholinergic Drugs: Act synergistically with levodopa to improve certain symptoms of Parkinson’s disease especially tremor (GOOD)
Large doses of anticholinergics can slow gastric emptying such that absorption of levodopa from the GI tract is decreased. (not so good)
Whats the big deal about Vitamin B and levodopa?
Pyridoxine (Vitamin B): in doses as a low as 5 mg can abolish the therapeutic efficacy of levodopa by enhancing the activity of pyridoxine-dependent dopa decarboxylase and thus increasing the metabolism of levodopa in the circulation before it can enter CNS.
What vitamin do you not want to give to someone being treated with Levodopa?
Vitamin B
What is Carbidopa and Benserazide?
Peripheral Decarboxylase Inhibitors
What does Carbidopa and Benserazide do? (drug action or purpose for giving)
Allows more levodopa to escape metabolism into dopamine in the peripheral circulation and thus is more available to enter CNS
What is diminished or absent in Parkinson’s patients treated with carbidopa and benserazide
N/V and cardiac dysrhythmias are diminished or absent
bc of less dopamine floating around peripherally I assume
True or False
Carbidopa and Benserazide treats abnormal involuntary movements and psychiatric disturbances.
False, it DOES NOT treat abnormal involuntary movements and psychiatric disturbances.
What are two combination drugs that are used for Parkinson’s dz, and what are their ratios?
Sinemet: levodopa and carbidopa in a 10:1 or 4:1
Madopar: levodopa and benserazide in a 4:1 ratio
Whats significant about controlled release preparations of levodopa and carbidopa?
provide a more constant therapeutic effect but onset of action is slower and bioavailability is decreased compared with standard combinations.
Does Carbidopa and Benserazide cross the BBB?
NO!
Noncompetitive inhibitors of decarboxylase such as carbidopa and benserazide, if you give higher doses will that help even more?
Noncompetitive inhibitors of decarboxylase does not improve with progressively higher doses. (the more the better is not true here)
If administered alone (Carbidopa and Benserazide) will they still have pharmacologic activity?
Lack pharmacologic activity when administered alone
What two meds block COMT enzyme activity in the GI tract and why does it even matter to Parkinson’s patients?
Tolcapone and/ or Entacapone
it matters bc COMT is Partially responsible for peripheral breakdown of levodopa. Thus these drugs slows elimination of carbidopa-levodopa increasing the plasma concentration by 10-15%.
This then means the dose of carbidopa- levodopa daily needs to be decreased by 10-30% to avoid dyskinesias or other side effects of increased dopamine.
What two drugs slow the elimination of carbidopa-levodopa thus increasing the plasma concentration by 10-15%?
Tolcapone or Entacapone
Levodopa can cause dyskinesias and cause nausea and diarrhea if given with what two meds?
Tolcapone and Entacapone
What medication is known to turn urine orange associated with Parkinson’s dz?
Entacapone
What two meds associated with Parkinson’s dz can cause goosebumps?
Tolcapone and Entacapone
Tolcapone and Entacapone would be considered what kind of drug?
Dopamine promoters
Which dopamine promoter should have liver function tests done while you are using it? This drug has also been associated with rhabdo.
Tolcapone can cause hepatotoxicity (rare) and liver function tests need to be done. Associated also with rhabdomyolysis
Which medications (name 5 of them) Do not require transformation or facilitated transport across the BBB.
Bromocriptine and Pergolide (tetracyclic ergot alkaloids)
Pramiperxole, ropinirole, and rotigotine (non ergot alkaloids)
Know as synthetic dopamine agonists
Bromocriptine and pergolide:
Is the elimination half time longer or shorter than that for levodopa?
longer
What synthetic dopamine agonist does the below describe:
GI absorption is rapid but incomplete
Extensive hepatic first-pass metabolism occurs and >90 of the metabolites are excreted in the bile. 10% unchanged in urine
0.5 mg to 1.0 mg is equivalent to 100 mg in combo with 25 mg of carbidopa or benserazide
Bromocriptine
