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479 Cards in this Set
- Front
- Back
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What are the steps of catecholamine synthesis?
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1. Tyrosine to DOPA via tyrosine hydroxylase
2. DOPA to DA via DOPA decarboxylase 3. DA to NE via DA hydroxylase 4. NE to EPI via phenylethanolamine methyltransferase |
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Why does injecting DOPA have more of an effect on DA secreting neurons than on NE secreting neurons?
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-NE secreting neurons are tightly regulated, so that increase in NE release inhibits tyrosine hydroxylase
-There is less feedback inhibition in DA releasing neurons |
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DA Projecting Pathways:
1. Neostriatal |
-Project form substantia nigra pars compacta to caudate/putamen
-regulates motor movements |
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DA Projecting Pathways:
2. Mesolimbic |
-Projects from VTA to nucleus accumbens
-Regulates mood, euphoria, and reward |
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DA Projecting Pathways:
3. Mesocortical |
-Projects from VTA to limbic cortex
-Regulates cognitive processes, such as attention, learning, and associations |
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DA Projecting Pathways:
4. Tuberhypophysial |
-Projects from the arcuate nucleus of the hypothalmus to the pituitary
-Inhibits prolactin release |
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D1 receptor family
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-D1 and D5 receptors
-Gs/q: increase cAMP, increase Ca2+ mobilization and PKC activation |
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D2 receptor family
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-D2, D3, D4
-Gi: decrease cAMP, increase K+ currents, decrease voltage gated Ca2+ currents |
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Norepinephrine projection pathways:
1. Dorsal tract |
-From locus coeruleus
-projects profusely to cortex, thalamus, cerebellum, and spinal cord |
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Norepinephrine projection pathways:
2. Ventral tract |
-From lateral tegmentum
-Prohects to hypothalaus, basal forebrain structures (amygdala, septum), but not to caudate/putamen |
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Parkinsonian symptoms
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1. Resting tremor (ex. pill rolling tremor)
2. Rigidity due to increased muscle tone (plastic rigidity-can move limb into a new position and it will stay there) 3. Bradykinesia or akinesia-difficulty in intitiating movement 4. Abscence of facial expression, drooling, toneless speech 5. Shuffling gate and difficulty in initaition of walking; no arm swing; stopping difficulty 6. Depression 7 With increasing age, may have cognitive difficulties |
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Mechanism of pathology of Parkinson's Disease most related to its pharmacotherapy
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-Loss of DA secreting neurons in the substantia nigra
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L-DOPA
-absorption |
-L-DOPA is rapidly absorbed from the intestines
-only 1-3% of the oral dose of DOPA reaches the brain; the rest is metabolized by DOPA decarboxylase in the periphery -high doses are therefore required |
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Why is Carbidopa administered with L-DOPA?
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-Carbidopa is an inhibitor of the peripheral DOPA decarboxylase
-This allows a great reduction in the amount of DOPA administered and thus a decrease in side effects |
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How long does it take for L-DOPA to be effective?
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-signs of improvement may take several weeks, with optimal benefit at 1-2 months
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In what order are the symptoms of Parkinson's improved by L-DOPA?
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-First: Mood and vigor improved
-Then Bradykinesia and akinesia improved -Last is improvement in resting tremor |
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Tolerable doses and efficacy of L-DOPA ______ with time; i.e. the therapeutic window and t1/2 of L-DOPA ______ with time
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decrease
(The longer a patient takes L-DOPA, the more likely similar doses will cause undesired side effects, including on/off phenomenon from the shortened half life) |
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What are the GI side effects of L-DOPA? What causes them?
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-Anorexia, nausea, and vomiting
-It is caused by the activation of the chemoreceptor trigger zone in the medulla, which is outside the BBB |
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How can you reduce the GI side effects of L-DOPA?
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-Give the drug after meals
-Dividing the dose -Giving L-DOPA with Carbidopa reduces GI effects (even though 1/5 will still experience GI effects) -Tolerance to the GI effects develop over time |
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What are the cardiovascular side effects of L-DOPA?
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-Orthostatic hypotension (most likely centrally mediated; tolerance develops to this effect)
-Tachycardia (due to increased NE in the periphery; prevented with Carbidopa administration) |
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80% of patients on L-DOPA experience dyskinesias, such as_____
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-Facial grimacing
-Restless feet syndrome -Choreoform movements (irregular, unpredictable, involuntary jerks) -Tolerance does not develop -L-DOPA in combo with the decarboxylase inhibitor may worsen dyskinesias |
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What are the psychiatric and behavioral side effects caused by L-DOPA?
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-Nightmares
-Anxiety -Paranoia, hallucinations, and mania with higher doses -Aphrodisiac effect |
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How should patients taking L-DOPA change their diet?
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-They should follow a low protein diet, because DOPA competes with amino acids in high protein diets for absorption
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What is the on/off phenomenon experienced by patients taking L-DOPA?
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-If L-DOPA wears off abruptly, the Parkinsonian patient's akinesia worsens
-Can be amanged by using dopamine agonists, eating low protein diet, or by using slow release L-DOPA -May occur despite changes in intake timing |
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How are drug holidays from L-DOPA useful?
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-L-DOPA is withdrawn gradually for a period of 3-21 days
-When the patient goes back on the drug, a lower dose may be effective with reduced side effects -It does not help with response fluctuations and on/off phenomenon |
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What are drug interactions with L-DOPA?
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-Vitamin B6 (pyridoxine) is a cofactor for DOPA decarboxylase, but will not have an effect in the presence of a peripheral DOPA decarboxylase inhibitor
-Not to be used with non-selective MAOIs, because may result in a hypertensive crisis |
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What are contraindications of L-DOPA?
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-Psychosis
-Narrow angle glaucoma (increased NE) -Cardiac disease (increased NE) -Peptic ulcer (DA in the enteric system) -History of melanoma (DA precursor of melanin) -Non-specific MAOIs |
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Sinemet CR
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-Control released, longer acting formula of L-DOPA
-Takes 90 minutes for onset (vs. 30 minutes for short release formulas); may be used with short released formulas for immediate effect |
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Bromocriptine
-MOA -uses |
-D2 and D3 agonist (ergot derivative)
-Used for Parkinsons, esp. when unresponsive to Sinemet -also used at low doses for hyperprolactinemia |
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Bromocriptine
-administration and excretion |
-given orally
-excreted in bile and feces -May be given with L-DOPA; the relative doses must be optimized |
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Bromocriptine (and other ergot derivatives)
-Cardiovascular effects |
-hypotension
-postural hypotension -cardiac arrhythmias -erythromelalgia (painful swollen feet) -digital vasospasm in feet and hands -can cause stroke or MI |
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Bromocriptine
-GI side effects |
-anorexia, nausea, and vomiting (reduced when taken with food)
-Constipation -Indigestion -Peptic ulceration with bleeding -Reflux esophagitis |
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Bromocriptine
-Mental side effects |
-Mental disturbances are more common than with L-DOPA
-hallucinations -confusion |
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Bromocriptine
-Side effects other than CV, GI, or mental |
-causes fibrosis of organs
-hypoprolactinemia -causes less dyskenesia than L-DOPA/Carbidopa |
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Pergolide (Permax)
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-Ergot derivative, DA agonist that was taken off the market because of heart valve problems and also causes sudden sleep episodes (because stimulates 5HT-2B receptors)
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Pramipexole
-MOA -Uses |
-DA agonist (D3>D2)
-Used for Parkinsons, esp. when L-DOPA cannot be used anymore |
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Ropinirole
-MOA -Uses |
-DA agonist (D3, D2)
-Used for Parkinons, esp. when L-DOPA cannot be used anymore |
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Side effects of Prmipexole and Ropinirole
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-Sudden sleep episodes
-Hypotension is common -Hallucinations -Dyskenesias -other cardiovascular effects are less common than ergot derivatives |
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Selegeline
-MOA -Uses |
-MAO-B inhibitor (specific for the isoform in the striatum which breaks down DA)
-Adjunctive therapy with L-DOPA: may allow DOPA dose reduction, may reduce on/off phenomena |
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Selegeline
-side effects |
-Metabolized into amphetamine and my cause insomnia
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Selegeline
-Contraindications |
-TCAs
-SSRIs and SNRIs -Meperidine (Demerol) (can lead to seratonin syndrome) |
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Amantadine
-MOA -Uses |
-Causes DA release in the striatum
-Can be used in initial treatment of Parkinsons with L-DOPA in order to relieve the dyskinesias because also blocks Glutamate NDMA receptors -Not as effective as L-DOPA or DA agonists, and effect may only be transient |
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Amantadine
-Adverse reactions |
-Restlessness, agitation, hallucination
-Livedo reticularis (Reddish blue skin, peripheral vascular condition) -Peripheral edema |
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Amantadine
-Contraindications |
-Avoid use in patients prone to seizure and who have CHF
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Benztropine
-MOA |
-Anticholinergic
-Inhibits Cholinergic interneurons that inhibit the substantia nigra |
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Trihexyphenidyl
-MOA -Uses |
-Anticholinergic
-Inhibits Cholinergic interneurons that inhibit the substantia nigra |
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Uses of Benzotropine and Trihexyphenidyl (anticholinergics)
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-Used adjunctly with L-DOPA to improve rigidity and tremor
-Has little effect on bradykinesia |
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Adverse effects of Benzotropne and Trihexyphenidyl
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-Drowsiness
-Restlessness -Hallucinations -Dyskinesias -Anti-muscarinic effects (dry mouth, etc.) |
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Contraindications of Benzotropine and Trihexyphenidyl
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-antimuscarinic effects may be additve with other anticholinergics
-avoid use in prostatic hypertrophy -Glaucoma -Obstructive GI disease |
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Tolcapone
-MOA -Uses |
-Inhibits COMT, which converts DOPA to 3-Omethyl dopa; increases DOPA availability in the brain
-Increase the duration of effect of each DOPA dose, and may be useful in preventing "wearing off" |
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Entacapone
-MOA -Uses |
-Inhibits COMT, which converts DOPA to 3-Omethyl dopa; increases DOPA availability in the brain
-Increase the duration of effect of each DOPA dose, and may be useful in preventing "wearing off" |
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Adverse effects of Tocapone and Entacapone
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-May be necessary to recue the level of DOPA in order to reduce dyskinesias and other DOPA related side effects
-Tolcapone requires frequent blood tests to monitor liver function |
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What is the duration of beinefit for Sinnemet?
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-works for 3-8 years
-after stops working, can give DA agonist |
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Psychiatric uses of antipsychotic drugs
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-Acute and chronic maintenance of schizophrenia
-Psychotic depression (with SSRIs) -Acute mania (with Lithium) -Autism Spectrum Disorders for control of aggression and agitation -Tourette's Syndrome (control of chronic tics) -Severe agitation in mentally retarded -Severe agitation in Alzheimers patients - |
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Antipsychotics are antagonists at which receptors?
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-Dopamine D2
-Seratonin 5HT-2A -Histamine H1 -Muscarinic M1 -Adrenergic alpha1 |
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Phenothiazine
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-Anti histamine with strong sedative properties
-Many phenothiazine derivatives are used as anti-psychotics |
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Which receptors do Typical antipsychotics have the highest affinity for?
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-Have more D2 antagonistic activity than 5-HT2A receptor activity
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Chlorpromazine
-drug class |
-typical antipsychotic
-phenothiazine derivative |
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Thioridazine
-drug class |
-typical antipsychotic
-phenothiazine derivative |
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Fluphenazine
-drug class |
-typical antipsychotic
-phenothiazine derivative |
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Perphenazine
-drug class |
--typical antipsychotic
-phenothiazine derivative |
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Trifluoperzine
-drug class |
-typical antipsychotic
-phenothiazine derivative |
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Thiothixene
-drug class |
-typical antipsychotic
-phenothiazine derivative |
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Pimozide
-drug class -uses |
-typical antipsychotic
-phenothiazine derivative -used for Tourette's Syndrome control of chronic tic |
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Haloperidol
-drug class |
-typical antipsychotic
-butyrophenone derivative |
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What roles do D2 receptors and Ach receptors play in the extrapyramidal control of movement?
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-DA from the substantia nigra pc acts on D2 receptors on the striatum to inhibit movement
-Cholinergic interneurons within the striatum act on muscarinic receptors to increase movement -Blocks that do not block M1 receptors along with D2 receptors will have more extrapyramidal symptoms |
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How do thioridazine and Haloperidol differ in their side effects?
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-Thioridazine has strong anti-muscarinic activity along with blockage of D2, thereby producing less extrapyramidal symptoms
-Haloperidol has very little anti-muscarinic activity and very little 5HT2A activity, but strong anti-D2 activity; therefore it is most likely to cause extrapyramidal symptoms |
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How is the activity of Atypical antipsychotics different from that of typical antipsychotics?
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-Atypical antipsychotics have greater antagonistic activity at 5HT2A receptors than at D2 receptors
-Since they have lower activity at D2 receptors, they are less likely to cause extrapyramidal symptoms and less likely to cause hyperprolactinemia -They also have more of an effect on the negative symptoms of schizophrenia, whereas typicals only have an effect on positive symptoms |
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Risperidone
-drug class |
-Atypical antipsychotic
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Olanzapine
-drug class |
-Atypical antipsychotic
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Quetiapine
-drug class |
-Atypical antipsychotic
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Sertindole
-drug class |
-Atypical antipsychotic
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Clozapine
-drug class |
-atypical antipsychotic
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What are the unique adverse effects of Clozapine?
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-Agranulocytosis
-Epilepsy -Only used in non-responsive patients |
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Ziprasidone
-drug class |
-atypical antipsychotic
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Compare the adverse effect profile of Risperidone, Olanzapine, Quetiapine, and Ziprasidone
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-Risperdone: Most likely to cause hyperprolactinemia; also causes significant weigt gain and extrapyramidal symptoms
-Olanzapine: most likely to cause weight gain; few EPS and no increase in PRL -Quetiapine: Significant weight gain, no EPS and no increase in PRL -Ziprasidone: Less likely to cause weight gain and low EPS; no increase in PRL |
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Aripiprazole
-drug class -relative adverse effect profile |
-Atypical antipscyhotic thats an antagonist at 5HT2A and a partial agonist at D2 (partial agonist=doesn't completely antagonize D2 receptor; reduces the efficiency of DA but does not eliminate it)
-Less likely to cause weight gain, EPS, and no hyperprolacinemia |
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Aripiprazole
-drug class -relative adverse effect profile |
-Atypical antipscyhotic thats an antagonist at 5HT2A and a partial agonist at D2 (partial agonist=doesn't completely antagonize D2 receptor; reduces the efficiency of DA but does not eliminate it)
-Less likely to cause weight gain, EPS, and no hyperprolacinemia |
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absorption and distribution of typical and atypical antipsychotics
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-Lipid soluble, readily absorbed; but high first pass effect
-Large Vd; bound to plasma proteins (drug interactions) |
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metabolism of typical and atypical antipsychotics
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Metabolized by CYTP450 system (many drug interactions)
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Which antipsychotics are metabolized to active compounds?
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-Risperidone
-Thioridazine -Aripiprazole -Clozapine -small percent of unmetabolized drug excreted into the urine unchanged |
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1. How long does it take for anti-psychotics to have an effect?
2. How long do their therapeutic effects last? |
1. Few days to several weeks
2. But takes 6 weeks or longer to have a full relapse once stop taking antipsychotic |
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Benztropine
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Muscarinic antagonist used to treat extrapyramidal motor symptoms caused by antipsychotics
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Side effects of antipsychotics:
-Acute motor/extrapyramidal side effects |
-Parkinson's syndrome (resting tremor, rigidity, bradykinesia)
-acute akathisia (motor restlessness) -acute dystonia (sustained contraction of muscles leading to twisted, distorted postures) -Caused by acute D2 receptor blockade |
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Side effects of antipsychotics:
-Chronic motor/extrapyramidal side effects |
-Tardive dyskinesia (may be irreversible; involuntary movements of the mouth and/or tongue)
-Tardive dystonia -Caused by supersensitivity of D2 receptors (receptors are upregulated from chronic blockade) |
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Antipsychotic side effects
-muscarinic blockade |
-Toxic-confusional state (central)
-Blurred vision, dry mouth, difficulty urinating, constipation |
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Antipsychotic side effects
-Adrenergic (alpha1) receptor blockade |
-Orthostatic hypotension, failure to ejaculate, hypotension, arrhythmias
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Antipsychotic side effects
-Histaminergic (H1) blockade |
-Sedation
-Weight gain and diabetes: check blood glucose and lipid profiles of people on antipsychotics |
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Antipsychotic side effects
-Non-motor effects caused by D2 blockade |
-Hyperprolactinemia: amenorrhea-galactorrhea, infertility, impotence
-anti-emetic (blocks D2 receptors in the chemotrigger zone) -Flattening of affect and inability to experience emotion |
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Antipsychotic side effects
-Miscellaenous effects with no known cause |
-Neuroleptic melignant syndrome
-Photosensitivity -Heat sensitivity and thermoregulation disturbances -Cholestatic jaundice -Retinal pigmentation |
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Which dopaminergic pathway inhibited by antipsychotics contributes to their motor side effects?
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-Neostriatal pathway
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Which dopaminergic pathway inhibited by antipsychotics contributes to their flattening of affect?
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inhibition of the mesolimbic pathway
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Which dopaminergic pathway inhibited by antipsychotics causes hyperprolactinemia?
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-Tuberohypophyseal tract that inhibits PRL release from the pituitary
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Which dopaminergic pathway inhibited by antipsychotics contributes to their desired effects?
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-Inhibition of D2 receptors in the frontal cortex of the mesocortical pathway produces the desired effect of decreasing overactive cognitive processing
-Inhibition of D2 most strongly correlates with therapeutic effect |
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Isocarboxazid
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irreversible, non-selective MAOI used for depression
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Phenelzine
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irreversible, non-selective MAOI used for depression
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Tranylcypromine
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irreversible, non-selective MAOI used for depression
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Selegiline
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-irreversible MAOI
-selective for MAO-B and used as adjunct for Parkinsons at lower doses -it's a non-selective MAOI at higher doses used to treat depression |
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RIMA
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-Reversible Inhibitor of MAO-A
-Not used in the US; all MAOIs in the US are irreversible -because they are reversible and more isozyme selective, they have a much lower risk of drug-food interactions with tyramine |
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What are the differences in affinity of MAO-A and MAO-B for 5-HT, NE, DA, and Tyramine?
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-DA and Tyramine metabolized equally by both enzymes
-5-HT and NE more preferentially metabolized by MAO-A |
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Why should people on MAOIs avoid eating foods containing tyramine?
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-Tyramine is degraded by MAO-A and MAO-B all through out the GI system and the rest of the body
-Tyramine causes NE to be released from presynaptic vesicles -non-selective MAOIs inhibit Tyramine degredation AND inhibit NE degredation -Exessive NE release and lack of NE breakdown can lead to a hypertensive crisis -Tyramine should be avoided for 10-14 days after discontinuing MAOIs as well, since they are irreversible inhibitors and it takes time for MAO to be restored |
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What are the steps in the synthesis of seratonin?
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1. Tryptophan to 5-hydroxytryptophan by tryptophan hydroxylase
2. 5-hydroxytryptophan to 5-Hydroxytryptamine (5HT) by aromatic amino acid decarboxylase (same enzyme that converts DOPA to DA) |
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5hydroxytryptophan
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-5HT intermediate sold over the counter
-activates aromatic amino acid decarboxylase, thus non-selectively increasing DA, NE, and 5HT levels all over the body -Can lead to Serotonin syndrome if taken with MAOIs, TCAs, or SSRIs/SNRIs |
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Symptoms of Seratonin Syndrome
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-Anxiety and agitation
-Hallucinations -Hyperreactivity to sensory stimuli -Tremor -Muscle rigidity -Hyperthermia -Hypertension -Can be fatal |
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What can cause seratonin syndrome?
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-Taking a combination of MAOIs with TCAs or SSRIs/SNRIs
-Taking TCAs with SSRIs/SNRIs -Taking 5hydroxytryptophan with MAOIs, TCAs, or SSRIs/SNRIs -Taking an MAOI with other sympathomimetics, such as L-DOPA, tryptophan, etc. -Taking an MAOI with meperidine and other opiates -If you discontinue an MAOI, TCA, or SSRI/SNRI and want to switch to another drug that may cause seratonin syndrome in combination, you MUST wait 10-14 days until you start the new drug in order to "wash out" the previous drug |
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What are common properties of monoamine reuptake transporters?
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-12 TM units
-Use Na-dependent mechanism to transport back into cell -selective for either NE, DA, or 5HT |
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Which is the only monoamine channel not linked to a GPCR?
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-5HT3 class of receptors are Ca ionotropic receptors
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Amitriptyline
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-tertiary amine TCA (inhibits reuptake of NE and 5-HT equally)
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Clomipramine (chlorimipramine)
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-tertiary amine TCA
-inhibits both NE and 5HT reuptake, but inhibits 5HT reuptake more potently than the other TCAs -Only TCA that is effective for OCD |
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Imipramine
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-tertiary amine TCA (inhibits reuptake of NE and 5-HT equally)
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Desipramine
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-secondary amine TCA
-inhibits NE reuptake more than 5HT reuptake -active metabolite of Imipramine |
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Doxepin
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-tertiary amine TCA (inhibits reuptake of NE and 5-HT equally)
-Has especially strong H1 antagonistic properties |
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Protriptyline
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-secondary amine TCA
-inhibits NE reuptake more than 5HT reuptake |
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Nortriptyline
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-secondary amine TCA
-inhibits NE reuptake more than 5HT reuptake -active metabolite of Protriptyline |
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Trimipramine
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-Tertiary amine TCA
-inhibits both 5HT and NE transporters weakly -has multiple monoamine receptor blocking properties |
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Citalopram
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-SSRI
-parent cmpd has extremely high selectivity for 5HT reuptake transporter -Has 2 active metabolites that are less selective than parent cmpd |
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Escitalopram
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SSRI
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Fluoxetine
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-SSRI
-Less selective than the other SSRIs -Has active primary metabolite thats less selective than the parent cmpd |
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Fluvoxamine
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SSRI
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Paroxetine
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SSRI
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Sertraline
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-SSRI
-has active primary metabolite that's less selective than the parent cmpd -Also inhibits DA reuptake, though with less affinity |
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Duloxetine
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SNRI
-Is equally selective for 5HT and NE transporters and has high affinity for both |
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Venlafaxine
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SNRI
-Has much higher affinity for 5HT transporters than NE transporters -At low doses, acts as SSRI only -At higher doses, it inhibits both 5HT and NE transporters and has more side effects |
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Amoxapine
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-Heterocyclic antidepressant
-Has tricyclic moiety |
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Bupropion
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-Heterocyclic antidepressant
-Blocks the reuptake of DA>NE>>>5HT |
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-Maprotiline
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-heterocyclic antidepressant
-has tricyclic moiety |
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Nefazodone
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Heterocyclic antidepressant
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Trazodone
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Heterocyclic antidepressant
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Mirtazapine
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-blocks alpha2 receptors, which increases NE levels and some 5HT levels at synapses
-also blocks 5HT2A, 5HT2C, 5HT3 receptors -also blocks H1 receptors (has antihistaminergic properties) |
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What is the therapeutic lag of all anti-depressants?
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-it takes 2-8 weeks for antidepressants to show noticeable clinical benefit
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What is a popular theory explaining the therapeutic lag?
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-Acute 5HT reuptake blockade reduces 5HT release via autoreceptor function
-Chronic 5HT reuptake blockade may desensitize autoreceptors (5HT2A and 5HT1A), which increases the amount of 5HT at the synapse and the firing rate of seratonergic neurons -An antagonist of 5HT1A may reduce the therapeutic lag time |
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Adverse effects of MAOIs
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-Hypertensive crisis from eating tyramine-containing foods
-Seratonin syndrome from taking MAOIs in combination with other drugs -Postural hypotension -Weight gain |
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Adverse effects of TCAs
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-Has pharmacokinetic interactions with ethanol and other sympathomimetic amines
-Sedation (H1 and M blockade) -Tremor and insomnia -Dry mouth, constipation, and difficulty urinating -Orthostatic hypotension (alpha1 blockade) -Lowered seizure threshold -Weight gain, increased appetite (anti-histaminergic) -Arrhythmias and conduction defects, esp. in the elderly (due to M blockade, antivagal actions, sympathomimetic effects, or quinidine like membrane actions) -Higher suicide risk than with SSRIs |
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Pharmacokinetics of TCAs
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-lipophilic and well absorbed from the gut
-First pass effect variable -Binds avidly to serum proteins (drug interactions) -Metabolized by CYP450 system (DRUG INTERACTIONS) -Inactivated by glucuronidation and renal clearance |
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What are the pharmacokinetics of SSRIs?
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-Highly lipophilic
-Metabolized by and inhibit CYP450 system (DRUG INTERACTIONS) -Parent half lives=24 hours, but metabolite half lives=up to 10 days; in system for a long time |
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Adverse effects of SSRIs
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-Drug interactions
-Seratonin syndrome -Nausea and GI effects, because increases 5HT in emesis center and increases 5HT in the gut, which causes emetic vagal reflex -Sexual dysfunction -May have modest increase in risk for bleeding when combined with aspirin (because platets cannot resynthesize 5HT once its released and reuptake is blocked) [Have low or no affinity for histaminergic and muscarinic receptors; also lower suicide risk than TCAs] |
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|
Adverse effects of SNRIs
|
-Drug-drug interactions
-Seratonin syndrome -Nausea and GI effects, because increases 5HT in emesis center and increases 5HT in the gut, which causes emetic vagal reflex -Sexual dysfunction -May increase risk of bleeding when use with Aspirin(because platets cannot resynthesize 5HT once its released and reuptake is blocked) -Higher doses include sympathomimetic actions, such as elevated blood pressure |
|
|
Why should anti-depressants be used with caution for bipolar disorder?
|
-MAOIs, reuptake inhibitors, and other anti-depressants can increase the risk of provoking a manic episode
|
|
|
Why should you not abruptly discontinue MAOIs, TCAs, SSRIs, and SNRIs?
|
-Can get discontinuation syndrome: dizziness, N/V, fatigue, headache, gait instability, insomnia, paresthesia, visual disturbances
-Can last for a week if untreated -Fetal withdrawal syndrome also occurs, esp. with TCAs |
|
|
Indications for Lithium use
|
-Acute manic episode (high doses)
-Maintenance/prevention of bipolar mania (lower doses) -Severe recurrent depression with cyclic pattern -sometimes combined with antipsychotic drugs to treat psychosis -Unipolar depression that doesn't respond to monotherapy |
|
|
Lithium
-Absorption |
-Almost completely absorbed from GI tract
-Available as extended release tablet |
|
|
Lithium
-Distribution |
-Distributed in extracellular fluid (like Na) with gradual accumulation into tissues
-Final Vd approaches total body water -concentrations in CSF only 40% of that in plasma |
|
|
Lithium
-Excretion |
-Eliminated in the urine
-t1/2=20-24 hours -During repeated administration, t1/2 increases (2.4 days after one year) -t1/2 increases in geriatic patients and patients with impaired renal function -Li has shorter t1/2 if patient is in an acute manic state -Li has shorter t1/2 if patient is pregnant (because clearance increased) |
|
|
Why does a patient on Lithium need to get regular blood work?
|
-Lithium has a narrow therapeutic index
-Need to monitor blood drug concentrations (0.6-1.3 meq/L measured 10 hours after oral dose) -Also should monitor thyroid function every 6-12 months -Also should check Cr and urine volume |
|
|
What is the most widely accepted theory of the MOA of Li?
|
-Li inhibits inositol monophosphatase, which normally generates the free inositol to be recycled back into the membrane as PIP2 for cellular signalling
-Depletion of PIP2 precuros is proprtional to the activity of the cell; since mania is associated with neuronal hyperreactivity, Li may selectively inhibit these overactive pathwasy |
|
|
Why does Lithium cause polyuria and hypothyroidism?
|
-Li also inhibits adenylyl cyclase signalling
-This inhibits ADH signalling and causes polyuria -This inhibits TSH signalling and causes hypothyroidism |
|
|
CNS side effects of Lithium
(can occur at therapeutic doses, but more severe with Li toxicity) |
-Tremor: frequent, occurs at peak blood levels after therapeutic doses
-Nausea -Muscle hypertonicity -Transient neurological asymmetry: choreoathetosis, ataxia, aphasia -Mental confusion |
|
|
What are two side effects of Li caused by its inhibtion of AC signalling?
|
-hypothyroidism
-nephrogenic diabetes insipidus |
|
|
How should a patient change their diet while on Lithium?
|
-Avoid dehydration, because it causes more Li to be reabsorbed in the proximal tubule
-Avoid low sodium diets, because Na competes with Li for reaborption, and low Na diets can increase Li levels |
|
|
What drug can be used to combat the polyuria and polydypsia caused by Li?
|
-Amiloride is paradoxically DOC for Li-induced nephrogenic diabetes insipidus
(leads to a volume depleted state, which encourages water reaborption, but inihibts Li reabsorption in the distal tubules) |
|
|
Why should you monitor a patient's Cr and urine volume while taking Li?
|
doses beyond the therapeutic range can cause lithium nephropathy
|
|
|
What are cardovascular side effects of Li?
|
-Li depresses the sinus node and should not be used in patiets with sick sinus syndrome
-Prolongued use can cause benign and reverible depression of the T wave |
|
|
How does Lithium effect white blood cell counts?
|
-Reversible increase in PMNs (can be exploited to treat low leukocyte states)
|
|
|
What side effects of Lithium effect a patient's physical appearance?
|
-Edema and weight gain
-Dermatitis, exacerbation of psoriasis, and acne |
|
|
Can Li be used during pregnancy?
|
Yes, Li not shown to be teratogenic
|
|
|
Lithium overdose symptoms
|
-Convulsions
-Coma -Confusion -Coarse hand tremor -Muscle rigidity -Fasciculations -Ataxia -can treat with peritoneal or hemodialysis [taking Lithium with haloperidol may increase toxicity] |
|
|
Lithium drug interactions
|
-Diuretics, NSAIDs, and ACE Inhibitors decrease the clearance of Lithium
|
|
|
What are the indications of Sodium Valproate?
|
-used for acute manic episodes
-used for prevention/maintenance of acute manic episodes in bipolar disorder -Also used for absence seizures, when the patient has concomitant tonic-clonic attacks -Also used for migraine prophylaxis |
|
|
Why is divalproex sodium the preferred preparation for valproate administration?
|
-divalproex=dimer of valporate
-reaches peak blood levels in 4-6 hours -is absorbed in the more basic pH of the small intestine, which delays absorption -The delayed absorption reduces the incidence of stomach cramps, nausea, and tremor caused by the rapid gastric absorption of valproate itself |
|
|
Valproate MOA
|
-May increase GABA, by inhibiting degredation and stimulating synthesis/release
-Blocks sustained high frequency repetetive firing |
|
|
Valproate Metabolism
|
-Valproate is highly bound to serum proteins
-Extensively metabolized by glucuronide conjugation and cytp450 oxidation -Has many active metabolites -Inhibits cytp450 metabolism: Increases the levels of Lamotrigine (and increases risk of rash) -Also inhibits the metabolism of the primary metabolite of Carbamazepine and increases Carbamazepine levels -Carbamazepine induces valproate metabolism and reduces valproate levels |
|
|
Side effects of sodium valproate
|
-nausea/vomiting
-dizziness -somnolence -tremor -increased accidents -Increased liver function tests and hepatic failure -hair loss -benign thrombocytopenia -pancreatitis |
|
|
Should valproate be used during pregnancy?
|
No-it's an teratogen that causes spinabifida
|
|
|
Carbamazepine indications
|
-Second line agent used when bipolar patient cannot tolerate or does not respond to Li
-Used for acute mania -Maintenance/prevnetion of mania (but may lose its efficacy over time) -Also DOC for partial seizures -Also used for generalized tonic-clonic seizure -Also used for trigeminal neuralgia |
|
|
Carbamazepine MOA
|
-Inhibits kindling, a process in which repeated biochemical or psychological stressors are thought to result in abnormal excitability of neurons
|
|
|
Carbamazepine metabolism
|
-Highly bound to plasma proteins
-Induces cytP450 system: -Increases its own clearance after chronic usage -Increases the metabolism of primidone, phenytoin, ethosuximide, and clonazepine -Increases the metabolism of atypical antipsychotics -Increase the metabolism of Lamotrigine -Increase the metabolism of Valproate -Valproate inhibits Carbamazepine metabolism |
|
|
Adverse effects of Carbamazepine
|
-Skin rash (does not require drug discontinuation)
-Impaired coordination, drowsiness, dizziness, slurred speech, ataxia -Inappropriate secretion of ADH and hyponatremia (water intoxication) -Leukopenia -Rare: aplastic anemia and agranulocytosis, esp. in elderly patients with trigeminal neuralgia |
|
|
Carbamazepine toxicity
|
-Drowsiness
-Ataxia -Coma -Cardiac toxicity -Treat with gastric lavage or charcoal |
|
|
Can Carbamazepine be used with Lithium?
|
-Can cause adverse CNS effects with Lithium regardless of drug levels
|
|
|
Lamotrigine indications
|
-Maintenance of bipolar disorder
-Better efficacy for prevention of relapse into depressive episodes than into manic episodes -Can be used for mild acute depressive episode |
|
|
Lamotrigine MOA
|
-Voltage and use dependent inactivation of sodium channels
-This inhibits the release of presynaptic glutamate and aspartate |
|
|
Lamotrigine metabolism
|
-Moderate protein binding
-Half-life=24 hours -Valproate increases the half life of lamotrigine (increases risk of rash) -Carbamazepine decreases the half life of lamotrigine |
|
|
Adverse effects of Lamotrigine
|
-deadly rash that can lead to toxic epidermial necrolysis or Stevens Johnson Syndrome
-risk of deadly rash greatest in pediatric patients -dizziness -headache -Diploplia -Somnolence |
|
|
How are atypical antipsychotics used for the treatment of bipolar disorder?
|
-May be used alone or with Lithium for acute main
-Olanzapine and aripiprazole are approved for maintenace of bipolar disorder |
|
|
What are the indications of Olanzapine-Fluoxetine and Quetipaine for bipolar disorder?
|
-Used for severe, acute depressive episodes of bipolar disorder
|
|
|
How long does it take Lithium to have a therapeutic effect?
|
1-3 weeks
|
|
|
Antipsychotics enhance the effects of which substances?
|
-sedatives
-alcohol -anti-hypertensive medications |
|
|
Which atypical antipsychotics caused the most weight gain and metabolic syndrome?
|
-olanzapine>Risperidone and Quetiapine
-Ziprasidone and Aripiprazole less likely |
|
|
Which atypical antipsychotic is most likely to increase Prolactin levels?
|
-Risperidone
|
|
|
Classes of drugs used to treat Generalized Anxiety Disorder
|
-Benzodiazepines
-SSRIs -SNRIs (Velafaxine and Duloxetine) -Azapirones (Buspirone) |
|
|
Classres of drugs used to treat OCD
|
-SSRIs
-SNRIs (Venlafaxine SSRI only at lower doses) -Chlorimipramine (TCA that inhibits 5HT reuptake more specifically) -Benzodiazapenes for anxiety |
|
|
Classes of drugs used to treat panic disorder
|
-Primarily SSRIs
-SNRIs -Imipramine (TCAs) -Phenelzine (MAOIs) -Alprazolam (Xanax, benzodiazapene) at 2-10 times higher dosages than used for generalized anxiety |
|
|
Meprobamate
|
-Propanediol derivative of carbamate that has similar properties and side effects as barbituates
-Not used for generalized anxiety disorder as much anymore because has been replaced by benzodiazapines -Have increased risk of developing seizure if stop abruptly |
|
|
Hydroxyzine
|
-First generation anti-histamine (H1) with strong sedative and anxiolytic properties (derivative of Piperazine)
-Not used for generalized anxiety anymore |
|
|
Buspirone
|
-non-sedating, non-benzodiazapine anxiolytic used for generalized anxiety disorder only
|
|
|
What is the difference between a sedative, a hypnotic, and an anxiolytic drug?
|
-sedative=generally decreases CNS output, but doesn't induce sleep
-hypnotic=induces sleep -Many sedatives can become hypnotics at higher doses, whereas many hypnotics can be used as sedatives at lower doses -anxiolytic=decreases CNS activity without causes sedation, i.e. doesn't cause memory loss, lethargy, etc. |
|
|
Buspirone
-MOA |
-agonist at 5HT1A receptors and blocks DA2 receptors
|
|
|
What are the differences between azopirones (Buspirone) and benzodiazapines?
|
Buspirone:
-causes less sedation -does not potentiate the depressant effects of alcohol alcohol -Has a therapeutic lag time of days to weeks, with maximum effect not occuring for 2-4 weeks -Buspirone is used for generalized anxiety only |
|
|
Buspirone pharmacokinetics
|
-Highly bound to plasma proteins
-Metabolized by cytP450 oxidation to an active compound -Parent and metabolites excreted in urine |
|
|
What are the therapeutic uses of Benzodiazapines?
|
1. Hypnotic agents for sleep induction
2. Adjunctive agents used in surgical anesthesia, or as the primary amnestic/sedative agents in non-surgical procedures 3. Anticonvulsants 4. Muscle relaxants in treating spasticity (diazepam) 5. Controlled replacement drugs (esp. in patients withdrawing from alcohol toxicity) |
|
|
What is Midazolam primarily used for?
|
-a short-acting benzodiazapene used with an analgesic for short procedures, such as colonscopy
-causes anterograde amnesia |
|
|
What kind of receptors are GABA-A, GABA-B, and GABA-C receptors?
|
-GABA-B is a GPCR
-GABA-C and GABA-A are ionotropic receptors (GABA-A=chloride channel) |
|
|
What is the MOA of benzodiazepines
|
-Benzos are allosoteric modulators that bind to a site on the GABA-A receptor separate from GABA to increase the receptors affinity for GABA
-Increase the frequency of channel openings produced by GABA, but do not increase GABA efficacy |
|
|
Flumazenil
|
-Benzodiazapine antagonist
-Binds at the Benzo receptor site without effecting the activity of GABA -Can be used to treat Benzo overdose |
|
|
MOA of barbituates
|
-Bind to a site on the GABA-A receptor different from the Benzo binding site and GABA binding site
-Barbituates modulate the actions of GABA by prolonging the duration of channel opening -At high concentrations, barbituates directly open the GABA-A receptor by themselves -This makes them more dangerous than Benzos |
|
|
What conditions can increase Benzodiazapine levels?
|
-Benzos are highly bound to plasma proteins, so individuals with low albumin (old age) can have increased half lives
-Hepatic damage from chronic ethanol abuse or hepatitis can reduce the rate of cytP450 oxidative biotransformation and/or glucuronidation of BZDs -Drugs that inhibit cytP450 enzymes (ex. Cimetidine) can reduce the rate of oxidative biotransformation of BZDs |
|
|
How does tolerance develop against benzodiazapines?
|
-Tolerance develops to the sedative and anticonvulsant actions of BZDs
-Little tolerance develops against the anxiolytic effect -The initial sedation is dose related |
|
|
What are the symptoms of BZD withdrawal?
|
-Symptoms may occur many days after discontinuing drugs that have active metabolites with long half lives, and in this case, anxiety and insomnia may be mild
-Rebound anxiety and rebound insomnia tends to occur following initial doses of benzos with short half lives -Abrupt discontinuation of BZDs after long-term administration at high doses can lead to major seizures, esp. if the BZD is short acting with no active metabolites - |
|
|
What is the safety profile of benzodiazapines?
|
-Have a large therapeutic safety index by themselves
-Can potentiate the effects of alcohol and barbituates, leading to respiratory and cardiac depression |
|
|
Diazepam
|
-fast absorption rate
-active metabolites via p450 metabolism - metabolites have half lives of up to 4 days before glucuronidation and excretion |
|
|
Chlordiazepoxide
|
-Intermediate absorption rate
-Have active metabolites via P450 metabolism -Metabolites have half lives of up to 4 days before glucuronidation and excretion |
|
|
Flurazepam
|
-Intermediate absorption
-Converted to active metabolites almost immediately by P450 enzymes -Metabolites have half lives of up to 6 days before glucuronidation and excretion |
|
|
Clonazepam
|
-Has intermediate absorption rate
-Has P450 metabolites of unknown significance -Parent drug has a half life of 1-2 days before glucuronidation and excretion |
|
|
Alprazolam
|
-Fast absorption rate
-Has active P450 metabolites of unknown significance -Has a half life of 11-19 hours before glucuronidation and excretion |
|
|
Temazepam
|
-has slow absorption rate
-Has active metabolites of unlikely clinical significance -Has half life of 8-12 hours before glucuronidation and excretion |
|
|
Lorazepam
|
-Has intermediate rate of absorption
-Does not have active metabolites -Has half life of 10-18 hours before glucuronidation and excretion |
|
|
Oxazepam
|
-has slow rate of absorption
-Does not have active metabolites -Has half life of 8-12 hours before glucuronidation and excretion |
|
|
Barbituates
-chemical properties |
-weak acids (like NSAIDs)
-require low pH in urine for excretion -absorbed more in acidic environment of stomach and duodenum; less absorption in lower GI tract |
|
|
Phenobarbital
-Induction time -Duration of action -used as a hypnotic? |
--20 min. onset
-long duration of action (6-12 hours) -not used as a hypnotic [because onset too long and long duration of action causes too many residual effects when you wake up] |
|
|
Pentobarbital
-induction time -duration of action -used as a hypnotic? |
-3 minute onset
-4-6 hours duration -used as hypnotic |
|
|
Amobarbital
-induction time -duration of action -used as a hypnotic? |
-3 minute onset
-4-6 hours duration -used as hypnotic |
|
|
Secobarbital
-induction time -duration of action -used as hypnotic? |
-2 minute onset
-intermediate/short duration (4-6 hours) -#1 hypnotic barbituate |
|
|
Thiopental
-induction time -duration of action -used as hypnotic? |
-onset in few seconds
-ultrashort duration (15-30 min) -used as hypnotic with general anesthesia as induction agent |
|
|
On what part of the brain do barbituates have their hypnotic effect?
|
-Depress the RAS in the midbrain to cause sleep
(bind to barbituate site on GABA-A receptor to increase duration of channel opening and chloride conductance; they open GABA-A channels by themselves at high enough concentrations) |
|
|
Thiopental
-administration -distribution |
-Given IV only
-highly lipid soluble -Redistribution: initially goes to brain because the brain has the highest CO; then leaves CNS and goes into muscle; then leaves the muscle and goes into adipose tissue |
|
|
Phenobarbital
-administration -metabolism |
-oral
-Metabolized by p450 system and excreted out of urine -INDUCES P450 system (drug interactions) |
|
|
Pentabarbital
-administration -metabolism |
-Oral, IM, IV
-Does not induce P450 -metabolites excreted in urine |
|
|
Secobarbital
-administration -metabolism |
-oral, IM, IV
-insignificant inducer of P450 -Metabolites excreted into urine |
|
|
What are the CNS effects of barbituates?
|
Sedative>Hypnotic> Anesthesia>coma> respiratory arrest
-stage is proportional to dose |
|
|
What are the other uses of Barbituates?
|
-Anticonvulsants-stop convulsions in progress if given substantial dose IV
-Antiepileptic-given in modest, oral doses to prevent seizures |
|
|
How do you save someone who is overdosing in Barbituates?
|
-Give artifical respiration early enough because the heart is not effected until it is anoxic
(HR will be elevated and BP may be normal; only effects respiration) |
|
|
Adverse effects of barbituates
|
-Most common=allergic rash
-allergy (blisters) and dermatitis -Leukopenia -Thrombocytopenia |
|
|
How do barbituates effect REM sleep?
|
-They suppress REM sleep
-Discontinuing barbituates causes a rebound effect, where you can only get REM sleep -Since REM sleep is the most active period of sleep, rebound REM sleep causes insomnia |
|
|
How do people accidentally overdose on barbituates?
|
-Take secobarbital to go to sleep, then wake up and don't remember taking it
-So take it again, and repeat until have accidental oversdose |
|
|
Chronic toxicity of barbituates
|
-Abuse
-Tolerance (pharmacokinetic and pharmacodynamic) -Dependency (psychological and physical) |
|
|
Barbituate withdrawal
|
-Discontinuation causes excitatory withdrawal with tremors, convulsions, violent thrashing
-Withdrawal from barbituates is deadly |
|
|
What are the advantages of using benzodiazepines as hypnotics over barbituates?
|
-Have longer effectiveness than barbituates, because it takes 6-8 weeks for tolerance to devlop vs. 2 weeks for barbituate tolerance
-Lower physical dependency -Less suppression of REM sleep and less rebound insomnia -Less likely to cause respiratory depression (higher margin of saftey and therapeutic index) -Do not inuduce P450 like phenobarbital |
|
|
What is the down side of using Flurazepam (or Quazepam) as a hypnotic?
|
Flurazepam is a prodrug with very long acting active metabolites
-Has a lot of residual drug effects |
|
|
What is the down side of using Temazepam or Estazolam as hypnotics?
|
-Temazepam and Estazolam have an intermediate duration with no active metabolites
-Early morning awakenings occur if you take them for insomnia because their max effect lasts 2-3 hours -Also get rebound insomnia if discontinue after chronic use |
|
|
What is the most popular benzodiazepine used for hypnosis?
|
-Triazolam
-Has immediate onset and lasts for 2-3 hours -If discontinue abruptly, get rebound insomnia; need to titrate patient off Triazolam slowly |
|
|
Zolipidem (Ambien) MOA
|
-non-benzodiazepine that binds to benzodiazepine receptor and has similar actions
|
|
|
Why is Zolipdem superior to benzodiazapines and barbituates for hypnosis?
|
-No effect on REM sleep (no rebound insomnia)
-Does not induce CYP450 like phenobarbital -Less likely to cause respiratory depression -No tolerance dependency problems or addiction -Onset in 30 minutes to an hour -only side effect is strange behavior in first couple of days of taking drug |
|
|
Chloral hydrate
-drug classification |
-hypnotic related to alcohol
-Prodrug converted by alcohol dehydrogenase to trichloroethanal |
|
|
What are some advantages of using chloral hydrate over barbituates as a hypnotic?
|
-Addictive, but less than barbituates
-Weak acting, requires more than one capsue -Has less respiratory effects than barbituates -But has a long onset: 2-3 hours |
|
|
Paraldehyde
-drug classifacation |
-Hypnotic
-Trimer of acetaldehyde broken down into acetate -outdated, has horrible smell |
|
|
Absorption and Distribution of Ethanol
|
-rapidly absorbed by passive diffusion; rate infulenced by fod content
-rapid distribution, with tissue levels approaching those of the blood -distribution is proportional to blood flow, with the brain receiving the highest blood flow -placenta is permeable to alcohol |
|
|
Ethanol metabolism
|
-Extensive first pass metabolism
-Metabolized in liver by alcohol dehydrogenase at zero order kinetics (eliminated at a constant rate due to depletion of NAD) -Small portion excreted by the lungs -Portion metabolized by alcohol dehydrogenase in GI tract |
|
|
Why do women have higher BACs than men?
|
-Women have less alcohol dehydrogenase in their GI tract
-Women have a lower body water content than men, making the concentration of alcohol in their blood higher -Women tend to be smaller and lighter than men |
|
|
What is the biochemical pathway of alcohol metabolism in the liver?
|
1. Ethanol is converted to acetaldehyde by alcohol dehydrogenase in the hepatic cytosol. This reaction converts NAD+ is converted to NADH. This NADH is then utilized to converted pyruvate to lactic acid, thus regenerating NAD+
2. Acetaldehyde is converted to acetic acid by aldehyde dehydrogenase in hepatic mitochondria. This reaction converts NAD+ to NADH. The electron transport chain then uses the NADH to regenerate NAD+ 3. The acetic acid is then used to form acetyl coA |
|
|
Why should people who have gout avoid alcohol?
|
-The metabolism of alcohol converts a lot of NAD+ to NADH
-When pyruvate is converted to lactic acid in order to regenerate NADH, this produces lactic acidosis -the lactic acid competes with uric acid for elimination, thus increasing uric acid levels |
|
|
What is a consequence of the altered NADH/NAD+ ratio from alcohol metabolism?
|
-The increase in NADH/NAD+ ratio and decrease in pyruvate inhibits gluconeogenesis
-If an alcoholic is not eating, then the lack of gluconeogensis will form him to use up all of his glycogen stores -The lack of gluconeogenesis and glycogen stores causes hypglycemia -The body elicits a startvation response, leading to an increase in glucagon and the utilization of fatty acids as a source of energy -Ketoacidosis, along with the increase in lactic acid production, causes metabolic acidosis |
|
|
How does alcohol effect the cytochrome p450 system?
|
-Chronic ingestion of ethanol induces the microsomal ethanol oxidizing system (MEOS)
-MEOS has a higher Km than alcohol dehydrogenase, so it plays a role in metabolism when blood levels are high or when alcohol metabolism has depleted NAD+ |
|
|
What are some racial differences in the metabolism of alcohol?
|
-Different races have different subunit combinations of alcohol dehydrogenase
-Aldehyde dehydrogenase genetic variation exists, including an inactive aldehyde dehydrogenase in Asians (this increases acetaldehyde amounts, leading to a flushing reaction) |
|
|
What is the MOA of ethanol?
|
-Enhances GABA-A receptor transmission
-Inhibits Glutamate NDMA calcium channels; glutamate usually exerts tonic inhibition of DA release in the nucleus accumbens -Enhances the actions of 5HT-3 receptors, which activate inhibitory interneurons |
|
|
Ethanol enhances the effects of which drug classes?
|
-Sedative hypnotics
-anti-depressants -neuroleptics -sedating antihistamines -narcotics |
|
|
How does alcohol effect the metabolism of other drugs?
|
-Acutely, alcohol can compete with drugs that are metabolized by the cytP450 system, such as Phenytoin
-Chronically, through induction of the cytP450 system, alcohol can enhance the clearance of many drugs, including phenytoin and oral hypoglycemic agents |
|
|
What are the drug interactions between alcohol and Acetiminophen?
|
-Chronic use of alcohol lowers the threshold for Acetiminophen liver toxicity
-IUsually acetiminophen is excreted via conjugation, but the nduction of cytochrome p450 systems leads to more oxidative metabolism and produces toxic intermediates -In addition, alcoholics have depleted stores of GSH and an already damaged liver |
|
|
Which drugs inhibit aldehyde dehydrogenase and cause a disulfuram-like reaction when alcohol is ingested while taking these drugs?
|
-Metronidazole
-Cephalosporins -Oral hypoglycemic agents |
|
|
What are the acute effects of alcohol on CNS activity?
|
-At lower concentrations, alcohol inhibits inhibitor neurons, leading to behavioral stimulation (talkativeness and mild euphoria)
-At higher concentrations, neuronal activity is decreased, leading to cereballar dysfunction and eventual respiratory depression |
|
|
What are the chronic effects of alcohol on the nervous system?
|
-tolerance (although the lethal dose does not change)
-physical dependence -memory loss -brain damage -increased risk of seizures -Peripheral neuropathy (tingling in hands and feet) -Wernicke encephalopathy: Truncal ataxia and opthalmoplegia (from thiamine deficiency) -Korsakoff's psychosis: persistent learning and memory problems (from thiamine deficiency) |
|
|
What are the acute and chronic effects of alcohol on the cardiovascular system?
|
Acute:
-Causes generalized vasodilation and hypothermia -Depresses contractility -Causes constriction of cardiac vessels, worsening stable angina Chronic: -causes reversible cardiomyopathy and hypertension |
|
|
What are the acute and chronic effects of alcohol on the GI system?
|
-Causes increase in gastric acid release (people with peptic ulcers should not drink alcohol)
-High concentrations directly irritate GI mucosa and can cause erosive gastritis -Enhances the damage caused by Aspirin -Chronic use leads to constipation and diarrhea -May also cause pancreatitis |
|
|
What are the effects of alcohol on the liver?
|
-Excess NADH accumulation inhibits oxidation of fatty acids, leading to a fatty changes
-Fatty liver can progress to alcoholic hepatitis, then cirrhosis, and ultimately leading to hepatic encephalopathy -The acetaldehyde formed is toxic and reactive -Acetiminophen liver toxicity is enhanced due to enzyme induction and depletion of GSH |
|
|
What are the effects of alcohol on the kidney?
|
-Alcohol inhibits the release of ADH, causing frequent urination
|
|
|
What are the hematological effects of alcohol?
|
-Macrocytosis (increased blood volume)
-Megaloblastic anemia from folate deficiency -Iron deficiency from GI bleeding -Anemia -Thrnombocytopenia -Pancytopenia in chronic users with hepatic cirrhosis |
|
|
What are the effects of alcohol on the fetus?
|
-causes fetal alcohol syndrome: Microcephaly, lowered IQ, facial abnormalities
|
|
|
What are the effects of alcohol on estrogen levels in women?
|
-In pre-menopausal women, alcohol decreases the release of estrogen, leading to ovarian atrophy, loss of breast and pelvic fat, infertility
-In post-menopausal women, alcohol activtes peripheral aromatase, thus increasing the conversion of androgenic precursors to estrogen. This increases the risk of breast cancer |
|
|
What are the effects of alcohol on testosterone levels in men?
|
-Alcohol causes a rapid fall in testosterone because of an acute toxic effect on the testes
-The decrease in testosterone and the induction of peripheral aromatase may lead to feminiazation: loss in body hair, palmar erythema, spider aniomata (red blood vessels radiating like a spider), gynecomastia -Feminization can be worsened by liver damage and decreased metabolism of androgenic precursors |
|
|
What are the signs of minor alcohol withdrawal?
|
-tremulousness
-hallucination -seizure |
|
|
What are the signs of major/late alcohol withdrawal?
|
-Occur 1-6 days after cessation of drinking
-Profound agitation -Insomnia -Hallucinations -Tremor -Hypertension -Tachycardia -Hyperthermia |
|
|
How do you treat alcohol withdrawal?
|
1. Benzodiazapines are the drug of choice: similar MOA as alcohol, wide therapeutic index, prevent seizures and convulsions
2. Oxazepam and Lorazepam are short-acting benzodiazapines metabolized by conjugation, and are used if patient has severe liver damage 3. Haloperidol for hallucinations 4. Beta blockers and clonidine may reduce adrenergic manifestations |
|
|
MOA of Disulfiram
|
-Inhibits aldehyde dehydrogenase by chelating metal ions essential for its activity
-If drink ethanol, causes acetaldehyde syndrome: Facial flushing, headache, hypotension, marked uneasiness, confusion, and vomiting |
|
|
Side effects of Disulfiram
|
-Also inhibits DA hydroxylase, resulting in imapired cardiovascular reflexes and hypotension
|
|
|
What are other drugs used to treat alcoholism?
|
-Naltrexone (opioid antagonist), may block positive reinforcing affects of alcohol
-Acamprosate (inhibits NDMA receptors), may prevent conditioned responses to alcohol withdrawal and craving -Rimonobat (CB-1 receptor antagonist), also used to treat obesity and nicotine addiction |
|
|
Why is ingestion of methanol toxic?
|
-Methanol is metabolized by alcohol dehydrogenase to formaldehyde and then formic acid
-Causes metabolic acidosis -The most characteristic symptom of methanol poisoning is visual disturance |
|
|
Why is the ingestion of ethylene glycol toxic?
|
-Ethylene glycol is converted by alcohol dehydrogenase to toxic aldehydes and oxalate
-Causes metabolic acidosis -Causes renal insufficiency due to deposition of oxalate crystals |
|
|
How do you treat methanol or ethylene glycol toxicity?
|
-FOMEPAZOLE: Inhibits alcohol dehydrogenase, will prevent conversion to toxic products
-Saturate ADH with ethanol -Dialysis |
|
|
What are the indications for anti-retroviral initation in asymptomatic HIV patients?
|
-If CD4 count less than 200, initiate treatment
-If CD4 count between 200-350, treatment is highly recommended -If CD4 count is greater than 350, but viral load is greater than 100,000, 3 year risk of developing AIDS is over 30% and treatment is recommended -If CD4 count greater than 350 and viral load is less than 100,000, treatment should be deferred and observation continued (3 year risk of AIDs less than 15%) |
|
|
Why is patient adherence to HIV regiments so imporant?
|
-Taking sub-therapeutic levels of drugs permits viral replication and leads to resistance
-The medications put a new selective pressure on both mutant and wild type viruses -Now mutants that are most resistant to medication will prevail over the wild type virus |
|
|
How do you know if an HIV drug regiment is not working?
|
-If HIV viral load is greater than 400 by week 24 or greater than 50 by week 28
|
|
|
Maraviroc
-MOA |
-Inibits HIV gp120 protein from binding to the co-receptor CCR5 on host cells
|
|
|
Maraviroc
-Uses |
-Only works on HIV strains that are CCR5 tropic (do Trofile study to determine virus tropism and eligibility)
-Only used if patient is resistant to other medications |
|
|
Maraviroc
-Adverse effects |
-Black box warning: Hepatoxicity and increase in heart attacks
-Constipation -Fever -Upper respiratory infection -Cough -Insomnia -Postural dizziness -Musculoskeltal symptoms -Herpes? |
|
|
Maraviroc
-administration -metabolism |
-Taken orally
-Metabolized by CYP3A, and reauires dosage adjustment if taking other drugs effecting CYP450 system |
|
|
Fuzeon/Enfuviritide (T-20)
-MOA |
-Fusion inhibitors: Inhibit gp41 mediated HIV fusion with host cell membrane
|
|
|
Fuzeon/Enfuviritide
-Adminsitration |
-Subcutaneous injection, twice a day
-only used if resistant to other meds |
|
|
Fuzeon/Enfuviritide
-Adverse effects |
-Local injection site reaction
-Increased rate of bacterial pneumonia -Hypersensitivity reaction (because foreign protein) |
|
|
What enzymatic reactions are carried out by reverse transcriptase?
|
-RNA-dependent DNA synthesis (uses viral RNA to make ssDNA)
-DNA-dependent DNA synthesis (uses ssDNA to make dsDNA) |
|
|
Zidovudine (AZT)
-MOA |
-Nucleoside RT inhibitor
-2,3 dideoxy DNA analog that is first phosphorylated by host enzymes, and then inhibits elongation of DNA synthesis |
|
|
Lamivudine (3TC)
-MOA |
-Nucleoside RT inhibitor
-2,3 dideoxy DNA analog that is first phosphorylated by host enzymes, and then inhibits elongation of DNA synthesis |
|
|
Emtricitabine
-MOA |
-Nucleoside RT inhibitor
-2,3 dideoxy DNA analog that is first phosphorylated by host enzymes, and then inhibits elongation of DNA synthesis |
|
|
Abacavir (ABC)
-MOA |
-Nucleoside RT inhibitor
-2,3 dideoxy DNA analog that is first phosphorylated by host enzymes, and then inhibits elongation of DNA synthesis |
|
|
Stavudine
-MOA |
-Nucleoside RT inhibitor
-2,3 dideoxy DNA analog that is first phosphorylated by host enzymes, and then inhibits elongation of DNA synthesis |
|
|
Tenofovir
-MOA |
-Nucleotide RT inhibitor
-2,3 dideoxy DNA analog that inhibits elongation of DNA synthesis but does not require phosphorylation by host enzymes |
|
|
Efavirenz
-MOA |
-Non-Nucleoside RT Inhibitor
-Inhibits RT by binding to allosoteric site separate from active site |
|
|
Delavirdine
-MOA |
-Non-Nucleoside RT Inhibitor
-Inhibits RT by binding to allosoteric site separate from active site |
|
|
Nevirapine
-MOA |
-Non-Nucleoside RT Inhibitor
-Inhibits RT by binding to allosoteric site separate from active site |
|
|
What are the recommended combinations of NRTIs and NNRTIs?
|
Efavirenz (NNRTI) + [Tenofovir/Emtricitabine or Zidovudine/lamivudine]
|
|
|
How do NRTIs cause so many adverse reactions?
|
-They inhibit mitochondrial DNA polymerase gamma
-This causes impaired synthesis of mitochondrial proteins necessary for oxidative phosphorylation -Defective ox. phosph. leads to increased lactate production and lactic acidemia |
|
|
What are the adverse effects of NRTIs?
|
-lactic acidemia, nausea, abdominal pain, fatigue, and weight loss are common
-Myopathy and peripheral neuropathy -dilated cardiomyopathy, hepatic steatosis, and pancreatitis -Causes proximal muscle wasting and lipid dystrophy -Zidovudine-induced anemia and neutropenia -Rare: lactic acidosis |
|
|
What are the adverse effects unique to Abacavir?
|
-Possibly fatal hypersensitivity reaction: Fever, rash, nausea, malaise, and respiratory symptoms
|
|
|
Drug interactions of NRTIs
|
-using combinations of NRTIs produces overlapping drug toxicities
-Excreted by the kidney, and require dosage adjustment for renal impairment -Stavudine and Zidovudine cannot be combined because they compete for the same activation pathways -Lamivudine and Emtricitabine should not be combined because they are basically the same drug |
|
|
What are the side effects of Tenofovir?
|
-Weakness, headache, and diarrhea not related to mitochondrial toxicity
-Possible renal toxicity if have pre-existing kidney problems |
|
|
What is a major problem associated with NNRTIs?
|
-Have significant interactions with CYP450 system
-Ex. Efivirenz and Nevirapine are enzyme inducers, and may decrease the levels of other agents |
|
|
Efavirenz
-adverse effects |
-dizziness
-vivid dreams -depression (avoid use if patient has serious mental illness) -Rash (mild) -Increased transaminase levels and hepatitis -Do not use in pregnant women because teratogenic in monkeys -Mixed inducer/inhibitor of CYP3A |
|
|
Adverse effects of Nevirapine
|
-Causes rash that may progress to Steven Johnson Syndrome and requires frequent monitoring
-Most likely NNRTI to cause hepatitis quickly after start of treatment (women co-infected with HepC, women with CD4 counts greater than 250, and men with CD4 counts greater than 400 most at risk for hepatotoxicity) -Induces CYP3A |
|
|
Adverse effects of Delavirdine
|
-Rash similar to Nevirapine
-Increased transaminase levels -Inhibits CYP3A |
|
|
Raltegravir
-MOA |
-Inhibits viral integrase, which incorporates HIV's DNA with the host DNA
|
|
|
Raltegravir
-adverse effects |
-minor: diarrhea, nausea, headache
-only used in patients who are resistant to other drugs |
|
|
Atazanavir
-MOA |
-Protease inhibitor
-Inhibits the protease that chops up large precurosr proteins into smaller proteins necessary for viral assembly |
|
|
Ritonavir
-MOA |
-Protease inhibitor
-Inhibits the protease that chops up large precurosr proteins into smaller proteins necessary for viral assembly |
|
|
Fosamprenavir
-MOA |
-Protease inhibitor
-Inhibits the protease that chops up large precurosr proteins into smaller proteins necessary for viral assembly |
|
|
Lopinavir
-MOA |
-Protease inhibitor
-Inhibits the protease that chops up large precurosr proteins into smaller proteins necessary for viral assembly |
|
|
Amprenavir
-MOA |
-Protease inhibitor
-Inhibits the protease that chops up large precurosr proteins into smaller proteins necessary for viral assembly |
|
|
What are the recommended regiments that include protease inhibitors?
|
[Atazanavir/Ritonavir or Fosamprenavir/Ritonavir or Lopinavir/Ritonavir] + [Tenofovir/emtricitabine or Zidovudine/Lamivudine]
|
|
|
What are the GI side effects of protease inhibitors?
|
-Diarrhea, nausea, vomiting
|
|
|
How do protease inhibitors effect the liver?
|
-Cuase hepatotoxicity and increased transaminase levels
-Can occur at any time during treatment, unlike the early onset with Nevirapine -Ritonavir most likely to cause hepatotoxicity |
|
|
How do protease inhibitors effect blood sugar and lipid levels?
|
-decrease glucose tolerance, cause new onset diabetes, and diabetic ketoacidosis (polydypsia, polyphagia, polyuria)
-Causes elevation of total cholesteral, LDL, and fasting TGs (esp. Ritonavir) -This causes fat maldistribution/lipodystrophy, with the development of central obesity and Cushingoid appearance |
|
|
What are the hematological and bone mineral effects of protease inhibitors?
|
-Increase bleeding episodes among patients with Hemophilia
-Causes osteopenia, osteoporosis, and osteonecrosis |
|
|
What are the major drug interactions associated with Protease Inhibitors?
|
-They are substrates and inhibitors of CYP450, leading to drug/drug interactions
|
|
|
What are the unique adverse effects associated with Fosamprenavir and Atazanavir?
|
-Fosamprenavir-allergy if allergic to sufla drugs
-Atazanavir interferes with proton pump inhibitors, but causes less hyperlipidemia |
|
|
What is the Antiretroviral Lipodystrophy Syndrome?
|
The combination of muscle wasting and lipoatrophy caused by NRTIs with the hyperlipidemia, insulin resistance, and central obseity caused by PIs
-Characterized by lipoatrophy in the limbs, buttocks, and face, plus central fat accumulation in the abdomen, upper back, and breasts in women |
|
|
What is PI Boosting?
|
Other PIs are "boosted" by Ritonavir, because it is a powerful cyp3A4 inhibitor and boosts their drug concentrations
|
|
|
How does Ritonavir effect Saquinivir concentrations?
|
-Ritonavir blocks CYP3A4 activity in intestinal epithelial cells and blocks its export back out into the lumen, thus increasing the amount of Saquinivir levels absorbed
|
|
|
How does Ritonavir effect Lopinavir concentrations?
|
-Ritonavir increases both the Cmax and t1/2 of Lopinavir mostly by inhibiting first pass metabolism by CYP3A4, and also by inhibiting its dispositional metabolism (CYP450 metaboism every time drug passes through the liver after first pass)
|
|
|
How does Ritonavir effect Amprenavir levels?
|
-Ritonavir increases Amprenavir's t1/2 by inhibiting its dispositional metabolism
-It does not increase its Cmax because does not inhibit its first pass metabolism |
|
|
What is Kaletra?
|
-Fixed dose PI containing Ritonavir and Lopinavir
-Lopinavir gets boosted to very high levels -Taken with food and must be refridgerated -GI side effects mild |
|
|
What are the relative disadvantages that should be kept in mind when deciding whether to combine NRTIs with either NNRTIs or PIs?
|
-Resistance to NNRTIs requires a single mutation, and there is cross resistance among the NNRTIs
-Also, NNRTIs cause rash and hepatotoxicity -Both classes have potential drug interactions (CYP450), but there is a much greater potenential for interactions with PIs, esp. Ritonavir -PIs also cause fat maldistribution and metabolic complications |
|
|
What receptors does Glutamate bind to?
|
-AMPA, NDMA, Kainate: Gated, non-specific cation channels
-Metabotropic Glutamate receptors |
|
|
Why are Ketamine, Phencyclidine, and Dizocilpine not used to treat seizures?
|
-Although they are direct NMDA antagonists, they have dissociated and hallucinogenic properties
|
|
|
What are the general pharmacokinetic properties of anti-epileptic drugs?
|
-Good oral absorption
-Most are metabolized by the P450 system in the liver, and then excreted in the kidney (except Gabapentin, which is excreted by the kidneys unchanged) |
|
|
Felbamate
-MOA |
-Blocks the glycine site on NDMA receptors (Glycine=NDMA co-agonist)
-Blocks Na+ channels |
|
|
Felbamate
-Adverse effects |
-Black box warning: can caused fatal aplastic anemia
-Hepatotoxic, can cause hepatic failure -Weight gain -Behavioral effects -Mixed inducer/inhibitor: Inducor of CYP3A, effecting oral contraceptive efficacy, decreasing Vit D, etc.; also inhibits CYP2C19, which increases Phenytoin, VPA, and Phenobarbital concentrations -Lacks sedative side effects, but use has fallen out of favor |
|
|
Topirimate
-MOA -Uses |
-Blocks Glutamate binding site on AMPA receptors
-Blocks Kainate receptors -Blocks Na+ channels -Enhances GABA currents (Highly Pleiotropic) -Used for Generalized seizures: Absence and Tonic Clonic -Used for partial seizures |
|
|
Topirimate
-adverse effects |
-Mixed inducer/inhibitor: Inducor of CYP3A, effecting oral contraceptive efficacy, decreasing Vit D, etc.; also inhibits CYP2C19, which increases Phenytoin, VPA, and Phenobarbital concentrations
-Causes cognitive difficulties: patient feels "dopey" and can't find the right word -Causes CaPO4 renal calculi by inhibiting Carbonic anhydrase -Causes metabolic acidosis, with tingling in hands and feet -Causes weight loss -Increases intraocular pressure and acute angle glaucoma |
|
|
What are the anti-epileptic uses of Lorazapam and Diazepam?
|
-Fast acting benzos given IV to stop Status Epilepticus
-Diazepam also comes in rectal formulation |
|
|
What are the anti-epileptic uses of Clonazapam?
|
-Benzo used as adjunctive therapy for absence seizures
-Most specifically enhances GABA-A channels in the reticular formation, which then leads to the inactivation of the t-type Ca2+ channels involved in absence seizures -Can also be used as adjunct in myoclonic seizures |
|
|
What are the anti-epileptic uses of Phenobarbital?
|
-Used for partial seizures, especially in neonates
|
|
|
-What are the adverse effects of Phenobarbital?
|
-Inducer of P450 system
-Tolerance and dependence -Strong sedation -Cognitive impairment -Behavioral changes -Long half life, approximately 5 days |
|
|
Primidone
|
-Barbituate that is metabolized to Phenobarbital
|
|
|
Tiagabine
-MOA |
-Inhibits GABA reuptake
|
|
|
Tiagabine
-Uses |
-Used as adjunct for partial seizures
-Short half life, sedating |
|
|
Phenytoin
-MOA |
-Blocks Na+ channels in used dependent manner
|
|
|
Phenytoin
-uses |
-First line for partial siezures
-Used for status epliepticus following stabilization with Diazepam or Lorazepam -Some use for Tonic-clonic seizures |
|
|
Phenytoin
-adverse effects |
-Short term: CNS sedation (drowsiness, ataxia, insomnia, nystagmus, etc.)
-Long term: Gum hyperplasia, hirsutism, thickening of facial features -Folic acid deficiency -Inducer of P450 -Alcohol, diazepam, and methylphenidate increases its metabolism |
|
|
Fosphenytoin
|
-Prodrug of phenytoin
-Given IV, IM, or IP following inital stabilization with Lorazepam or Diazepam for status epilepticus |
|
|
Carbamazapine
-MOA |
-Tricyclic antidepressant that blocks Na+ channels in use dependent manner
|
|
|
Carbamazapine
-uses |
-Used for parital seizures
-Some use for tonic-clonic seizures |
|
|
Carbamazapine
-Adverse effects |
-Causes SIADH and hyponatremia, especially in the elderly
-Inducer of P450 -Agranulocytosis and aplastic anemia, esp. in the elderly -causes leukopenia in a large percentage of patients -Weight gain -Nausea -Visual disturbances -Sedation |
|
|
Oxcarbazapine
-MOA |
-Closely related to Carbamazapine, blocks Na+ channels in use dependent manner
-Augments hyperpolarizing K+ channels |
|
|
Oxcarbazapine
-uses |
-Partial seizures
|
|
|
Oxcarbazapine
-adverse effects |
-Mixed inducer/inhibitor: Inducor of CYP3A, effecting oral contraceptive efficacy, decreasing Vit D, etc.; also inhibits CYP2C19, which increases Phenytoin, VPA, and Phenobarbital concentrations
-Causes SIADH and hyponatremia, esp. in the elderly -Sedation -Less toxic than oxcarbazapine |
|
|
Zonisamide
-MoA |
-Blocks Na+ channels in use-dependent manner
-Also blocks t-type Ca2+ channels |
|
|
Zonisamide
-uses |
-Used for generalized seizures, including Absence seizures
-Used for parital seizures |
|
|
Zonisamide
-Adverse effects |
-Causes weight loss
-Very long half life (1-3 days) -No effect on P450 |
|
|
Lamotrigine
-MOA |
-Blocks Na+ channels in use dependent manner
-Inhibits Glutamate release -Inhibits Ca2+ channels -Pleiotropic |
|
|
Lamotrigine
-uses |
-Used for Generalized seizures
-Used for partial seizures |
|
|
Lamotrigine
-adverse effects |
-Causes severe dermatitis (Stevens Johnson Syndrome), esp. in pediatric patients
-Metabolism is incresed by valproic acid -Metabolism is decreased by phenobarbital, phenytoin, and carbamazapine -Has no effect on P450 system itself |
|
|
Ethosuximide
-MOA -use |
-Inhibits t-type Ca2+ channels in the thalamus, which are critical in generating the thalamocortical rhythms underlying absence seizures
-Used specifically for absence seizures |
|
|
Ethosuximide
-Adverse effects |
-Long half life (~2 days)
-GI distburbances -But less sedating than the rest of the older anti-epileptics |
|
|
Gabapentin
-MOA |
-Specifically acts on alpha-2-delta subunits on Ca2+ channels, although the consequences of which are unknown
|
|
|
Gabapentin
-uses |
-Used for partial seizures
-Also tonic-clonic seizures |
|
|
Gabapentin
-Adverse effects |
-causes weight gain
-no effect on P450 system -Less sedating than other anti-epileptic drugs |
|
|
Pregabalin
-MOA |
-Derivative of Gabapentin
-Specifically acts on alpha-2-delta subunits on Ca2+ channels, although the consequences of which are unknown |
|
|
Pregabalin
-uses |
-Used for partial seizures
-Also tonic-clonic seizures |
|
|
Pregabalin
-adverse effects |
-causes weight gain
-no effect on P450 system -Less sedating than other anti-epileptic drugs |
|
|
Valproic acid
-MOA |
-Augments hyperpolarizing K+ currents
-Blocks Na+ channels -Enhances GABA transmission -Highly pleiotropic |
|
|
Valproic acid
-Uses |
-Used for generalized seizures
-Effective in Absence seizures that progress to tonic-clonic -Used for partial seizures |
|
|
Valproic acid
-Adverse effects |
-Inhibits P450 system
-increases Lamotrigine levels -Gi disturbances -hair loss -weight gain: insulin resistance, water retention, increased appetite -Teratogenic: increases NTDs and malformations, lowers IQ -decreases fertility; can cause polycystic ovarian syndrome |
|
|
Levetiracetam
-MOA |
-Binds to synaptic vesicle protein SV2A, which modulates neurotransmitter release
|
|
|
Levetiracetam
-Uses |
-Used for generalized seizures, including Absence seizures
-used for parital seizures |
|
|
levetiracetam
-adverse effects |
-Sedation
-Irritability -short half life, 6-8 hrs (not metabolized by the liver) |
|
|
What are the pleiotropic anti-epileptics?
(good for refractory epilepsy) |
-Felbamate
-Lamotrigine -Topiramate -Valproic acid |
|
|
Which anti-eplipetics are used for partial seizures (with or without further generalization)?
|
-Phenytoin
-Carbamazapine -Oxcarbazapine -Gabapentin -Pregabalin -Phenobarbital -Tiagabine=used as adjunct |
|
|
Which anti-epileptics are used for both partial AND generalized seizures?
|
-valproic acid
-Lamotrigine -Topiramate -Levetiracetam -Zonisamide |
|
|
Which anti-epileptics are used for Absence/petit mal seizures?
|
-Ethosuximide
-Lamotrigine -Topiramate -Leviteracetam -Zonisamide -Clonazepam=adjunct -Valproic acid=absence seizures that progress to tonic-clonic |
|
|
Which anti-epileptics are inducers of the P450 system?
|
-Phenobarbitial/Primidone
-Phenytoin -Carbamazapine -Topiramate (CYP3A) -Oxcarbazepine (CYP3A) -Felbamate (CYP3A) |
|
|
What are the major side effects of the anti-epileptics that induce P450 enzymes?
|
-Decrease oral contraceptive levels and their efficacy
-Decreases Vitamin D levels, leading to osteoporosis and fractures -Decreases the levels of chemotherapy -Decreases the levels of corticosteroids -Decreases the levels of Warfarin -Eventually increase their own metabolism and lead to a decrease in their levels |
|
|
Which anti-epileptics inhibit P450 enzymes?
|
-Valproic acid [increases Lamotrigine levels]
-Topiramate (CYP2C19) -Oxcarbazepine (CYP2C19) -Felbabamte (CYP2C19) [Increase levels of phenytoin, VPA, and phenobarbital] |
|
|
Which anti-epileptics inhibit P450 enzymes?
|
-Valproic acid [increases Lamotrigine levels]
-Topiramate (CYP2C19) -Oxcarbazepine (CYP2C19) -Felbabamte (CYP2C19) [Increase levels of phenytoin, VPA, and phenobarbital] |
|
|
Which anti-epileptics have no effect on P450 enzymes?
|
-Lamotrigine
-Tiagabine -Levetiracetam -Zonisamide -Gabapentin |
|
|
How do you treat status epilepticus?
|
First, use IV (or rectal) Diazepam or IV Lorazepam
Second, use longer lasting anti-epileptics, such as: -Fosphenytoin (IM or IP) -Phenytoin -Phenobarbital |
|
|
What is an opioid?
|
-Any compound regardless of chemical structure that binds to opioid receptors
|
|
|
What is an opiate?
|
-An opioid containing the fundamental morphine or thebaine structure
|
|
|
What is a narcotic?
|
-Drug that has both analgesic and sedative properties
|
|
|
What are the natural opiates?
|
-Found in opium; include morphine, codeine, and thebaine
|
|
|
What are semi-synthetic opiates?
|
Synthesized by functional modification of morphine
|
|
|
What are synthetic opioids?
|
-Opioids synthesized without using morphine or derivatives
|
|
|
What are the naturally occuring opioid compounds in humans?
|
-Leu- and met-enkephalin
-Endorphins -Dynorphin A and Dynorphin B -Endomorphin1 and Endophorphin 2 |
|
|
What are the opioid receptors?
|
-mu, kappa, and delta
-mu receptor is primarily responsible for the analgesic effects of opioids -mu binds endorphins>enkephalinw>dynorphins -delta binds enkephalins>>>endorphins and dynorphins -kappa binds dynorphins>>>endorphins and enkephalins |
|
|
Full agonists have similar ________ but may have different ___________.
|
full agonists have similar efficacies (maximum response) but may have different potencies (how much drug is needed to achieve max response)
|
|
|
What is a partial agonist?
|
-Has a lower efficacy than a full agonist (achieves a lower maximum response)
-also can act as an antagonist by displacing full agonists from their receptor -ex. codeine is a partial agonist with less than maximal effect despite its high affinity for the mu receptor |
|
|
What is a mixed agonist/antagonist?
|
-agonist at one receptor, antagonist at another
ex. Butorphano is an agonist at the kappa opioid receptor and an antagonist at mu receptors |
|
|
What are the therapeutic uses of opioids?
|
Analgesia:
-terminal illness, esp. cancer -pre and post operative -obstetrical (epidural) Acute pulmonary edema (dyspnea) Antidiarrheal Antitussive |
|
|
How do opioids effect pain sensation?
|
-Reduce both sensory and affective (emotional) components of pain, but esp. reduce the affective component
-Most effective in reducing severe, constant pain, and not sharp, intermittent pain (if taking morphine for chronic pain, can still feel a pinprick) -selectively act on pain sensation via the mu receptor, allowing other sensory and motor modalities to remain intact |
|
|
What are the spinal sites of action of the opioids?
|
-Decrease substance P and glutamate release from presynaptic primary afferent nociceptors
-Cause hyperpolarization of neurons in the substantia gelatinosa |
|
|
What are the supraspinal sites of action of the opioids effecting descending modulatory pathways?
|
-Periaqueductal gray
-Locus coeruleus -medullary nuclei (mainly nucleus raphe magnus) -Inhibit interneurons that tonically inhibit descending neurons that inhibit pain, i.e. disinhibit inhibitory neurons |
|
|
What are the other central effects of opioids on emotion and cognitive function?
|
-Cause euphoria: anxiolytic, floating sensation; feel a rush of intense sensation of warmth and thrill, followed by detachment, tranquility, mood elevation (individuals not in pain may experience dysphoria)
-Sedation, with minimal amnesia and no loss of consciousness, but may produce sleep from which the patient is easily awakened |
|
|
How do opioids effect respiration?
|
-Cause significant respiratory depression by inhibiting respiratory centers in the NTS
-Opioid respiratory depression is characteriaed by a reduced response to carbon dioxide challenge -Sensory stimulation, like talking to the person, can help overcome the respiratory depression -Dose related; tolerance develops -Not tolerated in patients with asthma, COPD, or with prior respiratory difficulty -Opioids also suppress the cough reflex via mu receptors in the medulla, which allows codeine and dextromothorphan to be used as cough suppresants |
|
|
What are the GI effects of opioids?
|
-Stimulate the brain stem chemoreceptor trigger zone and cause nausea and vomitting
-Vestibular component of nausea and vomitting may be present, for it gets worse when you move around -Causes decreased stomach motility, decreases gastric acid secretion, increases GI tone, -Decreass large intestinal motility, increases tone, and leads to delayed fecal passage with increased water absorption -This causes constipation, and is the basis for the use of opioids as anti-diarrheals -Tolerance does not develop to constipation |
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What is a good way to diagnose an opioid overdose?
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-Opioids cause miosis (pinpoint pupils)
-This is caused by the mu and kappa receptor mediated activation of the parasympathetic nervous system -Can be blocked by opioid antagonists and atropine -Tolerance does not develop to the miotic effects |
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Are opioids effective for peripheral inflammatory pain?
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Yes, opioids reduce inflammatory mediated pain in the periphery, which is probably related to the finding that endomorphin-2 is localized within nociceptors and may autoregulate primary sensory neurons
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What are the cardiovascular effects of opioids?
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-Cause generalized vasodilation, which decreases blood pressure
-Hypotension is worsend by hypovolemia and nitroglycerin -Peripheral vasodilation causes cutaneous flushing, sweating, and postural hypotension -Opioids are contraindicated in patients with increased intracranial pressure (because of vasodilation) |
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How do opioids effect muscle tone?
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-Opioids Increase large trunk muscle tone (supraspinal action)
-this decreases thoracic compliance and interferes with breathing -This is most often seen with highly lipophilic opiods with rapid IV administration, like fentanyl and its derivatives -Can be reversed with opioid antogonists concurrently with NMJ blockers |
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How do opioids effect the Biliary tract, genitourinary tract, and the uterus?
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-Biliary tract: causes smooth muscle constriction and biliary colic
-Renal function: decreases renal plasma flow, causes increased bladder and ureteral tone, thus causing urinary retention -Uterus: reduces the tone of the uterus, and thus prolongs labor |
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How do opioids effect hormone levels?
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-Promote the realse of: ADH, PRL, and GH
-Inhibit the release of LH |
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What are the other effects of opioids?
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-Causes release of histamine, inducing flushing, sweating, and itching
-Causes immunosupression by inhibting lymphocyte proliferation, chemotaxis, and antibody production |
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What effects of opioids can you develop tolerance to, and what effects of opioids do you never develop tolerance to?
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-Develop tolerance to nausea, analgesia, sedation, respiratory depression, cardiovascular effects, and euphoric effects within 2-3 weeks of frequent administration
-Also develop cross tolerance to other opioids -Do not develop tolerance to miosis or constipation |
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What are the symptoms of opioid withdrawal?
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-rhinorrhea
-lacrimation -chills -hyperventilation -muscular aches -vomiting -diarrhea -anxiety -hostility -piloerection -yawning - |
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What are the signs of opioid toxicity?
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-respiratory depression
-miosis/pinpoint pupils -coma |
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What are the contraindications of opioid use?
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-People with decreased pulmonary ventilation: COPD, asthma, elderly patients, CHF and other cardiopulmonary conditions
-Patients with head injuries: the vasodilator effects of opioids can increase intracranial pressure -Patients with decreased renal function: for example, the active metabolite of morphine, morphine-6-glucuronide, will accumulate in patients with renal dysfunction -patients with liver dysfunction or pre-hepatic coma -Can induce seizures in seizure-prone patients, especially children -Patients with endocrine disorder: adrenal insufficiency (Addison's), hypothyroidism (myxedema); will have prolonged opioid responses |
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What are the effects of opioid usage during pregnancy on the fetus?
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-chronic use can induce fetal ependence
-also can cause respiratory depression, since fetuses lack a BBB |
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How do you treat fetal opioid withdrawal?
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-mild: manage with benzos
-severe: oral methadone or paregoric (tincture of opium) |
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How do you treat toxic opioid overdose?
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-stabilize breathing
-IV naloxone |
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What are the drug interactions of opioids?
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-With phenothiazines (i.e. chlorpromazine): enhanced CNS depression and other opioid actions, including respiratory depression
-Tricyclic antidepressants: Can produce increased hypotension -Meperidine and MAO inhibitors: Results in severe and immediate excitation, rigidity, hypertension, severe respiratory depression (seratonin syndrome) -Amphetamines enhance the analgesic side effects of opioids -Opioids can increase the clearance of barbituates |
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Morphine
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-naturally occuring opiate
-strong agonist |
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Morphine metabolism
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-t1/2=3 hrs; 10 mg dose lasts 4-5 hours
-does not persist in body tissues -Conjugated with glucuronic acid into morphine-3-glucuride (main metabolite, less active) and morphine-6-glucuronide (minor metabolite, more potent than morphine) -metabolites excreted by the kidney |
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morphine administration
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-oral, IV, epidural, IV
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Heroin
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-semisynthetic opiate derived from morphine
-strong opioid agonist |
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Heroin metabolism and addiction
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-Greater BBB permeability and more addictive
-Metabolized to morphine in the brain -3-4 times greater analgesic potency than morphine |
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Signs of heroin withdrawal
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-More intense than morphine withdrawal
-Miosis (pinpoint pupils) -vasoconstriction -diarrhea -dysphoria -not fatal, but death can occur in newborns |
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Hydromorphone
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-strong opioid agonist
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How does hydromorphone compare to morphine?
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-9 times more potent than morphine
-more sedation than morphine less euphoric feeling, -less constipation -does not produce miosis -same respiratory depression |
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Methadone
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-synthetic opioid agonist
-long duration of activity: 16-20 hours -Absorbed well orally -bound to plasma proteins |
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What is a major use of methadone?
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-Has more positive effects than other drugs used for heroin addiction, so you have more motivastion to take it
-can be taken once a day -no high -decreases craving -diminishes the euphoric effects of heroin because of cross tolerance |
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Fentanyl
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-synthetic opioid
-80 to 100 times more potent than morphine -onset in 5 minutes, short duration (45-90 minutes) |
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How is Fentanyl administered?
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-Epidural, IV, or transdermal patch
-used as preoperative medication, or transdermal patch is used to treat cancer pain -Need to be tolerant to opioids before usage, or can cause hypoventilation -highly abused (china white) |
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How are Fentanyl and its derivatives metabolized?
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-not glucuronidated like morphine
-hepatic oxidative metabolism; some unchanged and excreted in urine -stored in muscle and fatty tissue because highly lipophilic |
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Alfentinil
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-Fentanyl derivative
-less potent |
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Sufentanil
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-Fentanyl derivative
-more potent |
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Remifentanil
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-Fentanyl derivative
-Has unusually rapid metabolism and elimination -Administered continuously during surgery -must be administered with longer acting drug to provide post-surgical analgesia |
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Meperidine (Demoral)
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-synthetic opioid
-strong opioid agonist, less potent than morphine |
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Why has the use of Meperidine (Demoral) fallen out of favor?
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-toxic metabolite, normeperidine, causes excitotoxicity, including tremors, twitching, and seizures, esp. with renal dysfunction of chronic use
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Diphenoxylate
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(Lomotil)
-meperidine derivative used as anti-diarrheal -mild opioid agonist that does not cross the BBB |
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Codeine
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-Partial opiate agonist
-Naturally occuring opioid -used as antitussive -abosprtion is more regular than morpheine because protected from 1st pass effect |
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Dextropropoxyphene (Darvon)
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-Methadone derivative
-less potent than codeine, but has smaller therapeutic window |
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Darvocet
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-Dextropropoxyphene with acetiminophen
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Oxycodone
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-mild to moderate opioid agonist
-used for severe chronic pain, such as cancer, back pain, and fractures -less first pass metabolism, highly effective orally |
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Oxycontin
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-time released formula of oxycodone
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Percocet
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-oxycodone/acetaminophen
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Percodan
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-oxycodone/aspirin
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Loperimide
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-mild opioid agonist used as antidiarrheal, doesn't cross BBB
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Buprenorphine
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-opiate
-partial mu agonist -used as heroin addiction |
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Butorphanol
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-mixed agonist/antagonist
-kappa agonist, mu antagonist -available in nasal formula -effective analgesic in women |
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Pentazocine
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-mixed opioid agonist/antagonist
-kappa agonist, mu antagonist -precipitates withdrawal in patients taking full agonists |
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Nalaxone
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-Competetive antagonist at mu, kappa, and delta opioid receptors
-used IV to treat acute opioid toxicity (but can increase BP) -precipitates withdrawal |
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Naltrexone
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-competetive antagonist at mu, kappa, and delta receptor
-opiate -has longer duration than naloxone -in acute heroin toxicity, first stabilize with naloxone, then give longer lasting naltrexone -Used to treat heroin addiction-blocks the effects of heroin for 24 hours -used to treat alcohol dependence |
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What is the MOA of cocaine?
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-blocks DA reuptake by inhibiting DAT
-also blocks some NE reuptake |
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What is the MOA of amphetamines?
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-cause release of DA from non-vesicular stores
-also causes some NE release from non-vesicular stores |
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What is the MOA of LSD, dimethyltriptamine (DMT), and Psilocybin?
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-Partial agonists at 5-HT2A and 5-HT2C receptors
-Members of indoleamine family of hallucinogens |
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What is the MOA of mescaline, dimethoxy-4-methylamphetamine (DOM), and methylenedioxymethamphetamine (MDMA)?
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-Partial agonists at 5-HT2A and 5-HT2C receptors
-Members of phenethylamine family of hallucinogens -Have more sympathomimetic effects than indoleamines |
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What is the MOA of phencyclidine (PCP)?
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-Non-competetive Ca2+ channel blocker at the NDMA receptor
-Dissociative anesthetic |
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What is the MOA of ketamine?
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-Non-competetive Ca2+ channel blocker at the NDMA receptor
-Dissociative anesthetic |
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What is the MOA of dizocilpine?
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-Non-competetive Ca2+ channel blocker at the NDMA receptor
-Dissociative anesthetic |
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What is the MOA of phencyclidine (PCP)?
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-Non-competetive Ca2+ channel blocker at the NDMA receptor
-Dissociative anesthetic |
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What is the MOA of ketamine?
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-Non-competetive Ca2+ channel blocker at the NDMA receptor
-Dissociative anesthetic |
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What is the MOA of dizocilpine?
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-Non-competetive Ca2+ channel blocker at the NDMA receptor
-Dissociative anesthetic |
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How do you treat withdrawal from the dissociative anesthetics?
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-Diazepam or Haloperidol
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What is the MOA of tetrahydrocannabinol (THC)?
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-Agonist at CB1 receptors in the brain
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What is the endogenous ligand of CB1 receptors in the brain and CB2 receptors in the periphery?
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-anandamide (arachinoylethanolamide)
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Flumazenil
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-Benzodiazapine antagonist thast can be used for acute toxic overdose of benzos
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Methylphenidate MOA
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-Blocks reuptake of dopamine, NE to lesser extent, mainly in prefrontal cortex
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Dexmethylphenidate MOA
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-more active isomer of methylphenidate
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Methylphenidate
-duration -why have longer lasting formulations been developed? |
-last 3-4 hours, dosing twice a day
-Effects may end too abruptly, and may get rebound mood effects (more irritable, more crying, aggressive)? |
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What is the active ingredient in Ritalin, Methylin, Concerta, Metadate, and Daytrana?
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-methylphenidate
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What are the pharmacokinetics of Ritalin SR, Metadate ER, and Methylin ER?
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-methylphenidate slow release formulations
-constant slow release with no peaks; duration 6-8 hours |
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What are the pharmacokinetics of Metadate CD and Ritalin LA?
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-Have biphasic release
-first peak at 1.5 hours, second peak at 6 hours -duration for 8 hours -Have immediate:Extended release, so that a percentage of the drug is release initially and the rest is delivered through out the day |
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What are the pharmacokinetics of Concerta?
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-osmotic release (water enters the pill and pushes the drug out through a laser drilled hole)
-Triphasic: stimulates 3 times a day dosing, with 3 peaks throughout the day -Duration=10-12 hours |
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How is Daytrana delivered?
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-Daytrana is a methylphenidate patch
-meant to be placed for 9 hours, and effects are still presents 3 hours after removing patch -allows more flexibility with timing and dosing |
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What are the pharmacokinetics of dexmethylphenidate (Focalin)?
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-more active isomer of methylphenidate
-immediate release lasts 6 hours -also comes in bimodal release |
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What are the side effects of methylphenidate?
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-Anorexia (should eat larger meal in the morning)
-Insomnia (avoid night time administration) -Nervousness (increased OCD, anxiety, and panic attack symptoms) -GI distress -Irritability or increased crying -Tachycardia/Increase BP (should be minimal if have no cardiac history) -Very minor growth suppression -Increased motor and vocal tics |
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Which has more cardiovascular effects, amphetamines or methylphenidate?
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-amphetamines cause more peripheral cardiovascular effects, such as tachycardia and increased bp
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Dextroamphetamine (Dexedrine)
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-isomer of amphetamine
-duration: 4-6 hours, but also in slow release once a day formulation -approved for children 3 years and older |
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Lisdexamfetamine (Vyvanse)
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-amphetamine prodrug
-less potential for abuse, because only can he broken down in the gut and has slower absorption -once a day dosing, lasts 8-12 hours |
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What is the active ingredient in Adderal?
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-mixed amphetamine salts
-comes in immediate release (4-6 hours) or biphasic extended release (10-12 hours) |
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Why is there a black box warning on Adderal?
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-Increased incidence of sudden deaths
-black box: do not use in children with cardiac abnormalites |
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What are the contraindications of using amphetamines or methylphenidate derivaties for ADHD?
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-Anxiety disorder
-Tics -Cardiac abnormalities -Glaucoma (increased NE) -History of drug abuse -History of psychosis (increased DA) -Seizure disorders or EEG abnormalities (lowers seizure threshold) -Do not use with MAOI inhibitors, can cause hypertensive crisis -History of drug abuse |
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Atomoxetine
-MOA |
-Norepinephrine inhibitor
-Non-stimulant used as 2nd line drug for ADHD |
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Atomoxetine
-Pharmacokinetics |
-Once daily dosing
-May take 1-2 weeks to see effects |
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Atomoxetine
-side effects |
-Black box: Causes hepatoxicity; monitor at least once/year
-Nausea -Anorexia -Increased pulse rate and BP -Constipation |
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Clonidine
-MOA |
-Central alpha-2 adrenergic agonist
-in the treatment of hypertension, it works pre-synaptically to block NE release -in the treatment of ADHD, it works post-synaptically to activate receptors in the prefrontal cortex |
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Guanfacine
-MOA |
-Central alpha-2 adrenergic agonist
-in the treatment of hypertension, it works pre-synaptically to block NE release -in the treatment of ADHD, it works post-synaptically to activate receptors in the prefrontal cortex |
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Uses of Clonidine/Guanfacine in treating ADHD
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-More effective for impulsivity and hyperactivity than inattentiveness
-used off label, may cautiously be used with stimulant -May improve tics -Good for night time and sleep |
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What are the side effects of Clonidine and Guanfacine?
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-Sedation (more common with Guanfacine)
-Orthostatic hypotension -dry mouth |
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Administration of Clonidine and Guanfacine
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-2-3 times per day
-Clonidine also in patch form |
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Bupropion
-uses in ADHD |
-used off label for ADHD
-improvement in hyperactivity, hostility, sleep, and behavioral problems -but takes weeks to see effects |
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Bupropion
-contraindicastions |
Do not use if have:
-Bulimia/Anorexia Nervosa -Seizure disorder (lowers seizure threshold) -History of alcohol or sedative abuse, or current withdrawal -Head trauma |
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Modafinil (Provigil)
-uses |
-FDA approved for narcolepsy
-studies show improvement in hyperactivity/inattentive symptoms of ADHD -Also used to treat fatigue associated with Parkinsons, depression, and sleep apnea) |
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Modafinil
-MOA |
-may increase glutamine activity in the hippocampus and thalamus (does not effect DA or NE)
-lower abuse potention and not many peripheral effects |
