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167 Cards in this Set
- Front
- Back
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What is the mechanism of action for aspirin?
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Inhibit COX-1 and COX-2 by covalently binding.
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What does aspirin do?
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Decreases thromboxane (↑platelet aggregation), prostaglandins (↓vascular tone), and prostacyclin (↓platelet aggregation, uterine tone).
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What are the major side effects associated with aspirin?
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GI bleeding, acute renal failure, interstitial nephritis, and salicylism (neurological), Reye's syndrome (viral, hepatitis and cerebral edema).
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Why do we use acetaminophen in children rather than aspirin?
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Risk for Reye's syndrome in children with viral infection.
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What is the balance that NSAIDs strike up in inflammatory responses?
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Inhibition of prostaglandins decrease inflammation, but shunting AA towards leukotrienes increase inflammation/hypersensitivity.
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Provide an example of a COX-2 specific inhibitor.
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Celecoxib.
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What is the major benefit to using celecoxib?
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It does not have GI disturbances b/c it doesn't block COX-1.
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List several common NSAIDs.
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Ibuprofen, naproxen, indomethacin, and ketorolac.
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What is the major benefit of naproxen?
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Much longer half life.
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What do NSAIDs do?
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Reversibly inhibit COX-1 and -2. Decrease prostaglandin synthesis.
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What is indomethacin used for?
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2nd choice for arthritis. ENDs patency of PDA.
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What are major toxicities associated wtih NSAIDs?
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Renal damage, fluid retention, aplastic anemia, GI distress, ulcers.
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What two main pathways may arachidonic acid enter?
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Lipoxygenase (Leukotriene) and Cyclooxygenase (prostacyclin, prostaglandin, thromboxane).
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What is the major function of LTB4?
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This leukotriene induces neutrophil chemotaxis (neutrophils arrive B4 others).
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What do other leukotrienes do?
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Induce bronchoconstriction.
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What is PGI2?
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A prostacyclin: Platelet Gathering Inhibitor.
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What is amantadine?
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It is an antiviral drug effective for treating influenza but has anti-parkinson actions.
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What is amantadine used for?
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It is similar to L-DOPA but less effective.
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What is atropine used for?
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It is an muscarinic receptor antagonist that may be used to treat some of the symptoms of parkinson's.
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What is benztropine used for?
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It is an muscarinic receptor antagonist that may be used to treat some of the symptoms of parkinson's.
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What is bromocryptine?
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A D2 agonist and D1 partial agonist.
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What is the advantage to Bromocryptine relative to L-DOPA/carbidopa alone?
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It is less effective than L-DOPA, but when used in combination with L-DOPA, less "on-off"" phenomenon. Lower doses of L-DOPA required.
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What does Carbidopa do?
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It is a DOPA decarboxylase inhibitor. It decreases the peripheral side effects associated with dopamine.
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What is carbidopa used for?
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In combination with L-DOPA, it is used to treat Parkinson's disease.
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What is the principle problem occurring in parkinson's disease?
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Decreased DA synthesis.
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What are the two major categories for treatment of Parkinson's?
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1. Affect dopamine levels
2. Curb excess cholinergic activity. |
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What are three ways to improve dopamine levels in Parkinson's and provide an example of drugs in each class.
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1. Agonize dopamine receptors (Bromocriptine).
2. ↑ dopamine levels (amantadine, L-DOPA) 3. Prevent dopamine breakdown (Selegiline) |
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What are the specific abnormalities in the brain in Parkinson's?
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1. Loss of D1 diminishes activation of inhibitory (direct) pathway.
2. Loss of D2 diminishes inhibition of excitatory (indirect) pathway. |
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What neurons are damaged in Parkinson's?
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Degeneration of dopaminergic neurons in substantia nigra.
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What is the principle problem in Huntington's disease?
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Caudate loses ACh and GABA.
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What is Levodopa used to treat?
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It is a precursor of dopamine that can pass over the BBB and then is converted to dopamine. It is used in combination with carbidopa to treat Parkinson's disease.
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What is Procyclidine?
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A muscarinic receptor antagonist used to treat Parkonson's disease.
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What is reserpine?
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An amine depleting agent which is used to treat Huntington's disease by decreasing dopamine levels.
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What is selegiline?
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A MAO(B) inhibitor that prevents degradation of dopamine selectively in the brain. Used to treat Parkinson's disease.
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What is alpha-methyldopa hydrazine?
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Carbidopa, used to inhibit peripheral metabolism of L-DOPA. It inhibits peripheral decarboxylase.
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What is entacopone?
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A peripheral inhibitor of catechol-O-methyl transferase
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What do neuroleptics do?
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They antagonize dopaminergic receptors.
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What does alpha-methyltyrosine do?
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It inhibits tyrosine hydroxylase that is involved in dopamine, NE, and Epi synthesis. Therefore it decreases peripheral and central catecholamine synthesis.
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In schizophrenia, what is the current hypothesis of chemical-induced problems?
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It is thought that hyperactivity of the dopaminergic system is associated with schizophrenia.
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Provide three basic examples that provide support for the hypothesis that DA hyperactivity contributes to schizophrenia.
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1. Amphetamines and Cocaine induce schizophrenic symptoms and is reversed by DA receptor blockers.
2. Reserpine decreases DA stores and alleviates symptoms in schizophrenic patients. 3. Phenothiazines antagonize DA receptors and alleviate symptoms of schizophrenic patients. |
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What does amphetamine do?
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It promotes release of DA from neurons.
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What does reserpine do?
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It inhibits vesicular monoamine transporters leading to a long-term depletion of DA.
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What is the major side effect of reserpine?
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It causes hypotension.
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What do D1 like receptors do?
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They activate adenylate cyclase, increasing cAMP levels. D1, D5
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What do D2-like receptors do?
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They inhibit adenylate cylcase, decreasing cAMP levels. D2, D3, D4.
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What does apomorphine do?
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It agonizes pre- and post-synaptic D2 receptors.
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What does chlorpromazine do?
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It antagonizes D1 and D2 receptors.
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What does haloperidol do?
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It is a high affinity antagonist for D2 receptors.
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What are the two principle enzymes involved in dopamine catabolism?
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Catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO).
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What are the two historical groups of anti-psychotics?
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Minor tranquilizers and major tranquilizers.
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What classes of drugs are included as major tranquilizers?
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antipsychotics and neuroleptics
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What is diazepam?
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A minor tranquilizer used to treat anxiety and promote sedation.
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What is haloperidol?
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An anti-psychotic D2 antagonist.
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What are the primary extrapyramidal effects of anti-psychotics?
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1. Drug-induced parkinsonism.
2. Akathisia 3. Tardive dyskinesia (stereotyped involuntary movements) |
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What is the working hypothesis for how tardive dyskinesia develops?
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It reflects supersensitivity of dopamine receptors in the striatum.
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What is gout?
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The deposition of urate crystals in tissue at physiologic pH. It is made worse by cold temp, inflammation, and matrix proteins.
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What is gout typically associated with?
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Hyperuricemia (>7mg% uric acid)
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What is colchicine?
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It binds to tubulin and blocks polymerization of microtubules. This leads to decreased leukocyte migration and decreased LTB4 production.
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What is allopurinol?
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An inhibitor of xanthine oxidase which is important for uric acid production. Therefore, this drug is useful for treating gout.
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What drugs are useful for treating gout?
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NSAIDs, glucocorticoids, uricosurics, colchicine, allopurinol.
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What NSAIDs are used in gout?
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Indomethacin and naproxen.
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Is aspirin used in treating gout?
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NO!!
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What is probenecid?
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A uricosuric that inhibits renal absorption of uric acid.
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What glucocorticoid is used to treat gout?
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Prednisone.
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What is the major problem in depression?
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Decreased norepinephrine and serotonin (5HT).
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What drug causes depression and was used to prove the monoamine hypothesis of depression?
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Reserpine (blocks monoamine vesicle transporter).
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What are the principle drug classes for treating depression?
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1. Tricyclic antidepressants (re-uptake inhibitors)
2. Heterocyclics (re-uptake inhibitors) 3. Selective serotonin reuptake inhibitors (SSRI) |
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What is fluoxetine?
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A SSRI, preferable to use.
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What is tranylcypromine?
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MAO inhibitor used for treating depression.
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What are the two MAO inhibitors used to treat depression?
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Tranylcypromine (irreversible) and phenelzine (reversible).
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What are the three major classes of drugs for depression treatment?
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1. Tricyclics (prevent amine reuptake).
2. MAO inhibitors (block catecholamine degradation). 3. SSRIs (selectively block reuptake of serotonin). |
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Which receptor is most important for the serotonin effect on depression?
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5-HT(1A) receptors.
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What is the side-effects of tricyclics based upon?
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antagonistic activity of alpha1/2 and histamine receptors.
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What is an important drug interaction of tricyclics?
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MAO inhibitors, must wait 2-3 week period when switching from MAO to tricyclics because of residual intracellular signaling. This serotonin syndrome also occurs with SSRIs.
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What is the first line for depression?
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SSRI, then tricyclics, and finally MAOi's.
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What is a major food interaction with MAOi's?
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Tyramine found in aged cheese, chicken liver, beer, red wines. This sympathomimetic compound is usually metabolized in the gut by MAO(A).
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What is bipolar disorder?
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Mood swings between mania and depression.
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What is the most common treatment for bipolar disorder?
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Lithium, don't know how it works.
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What is the best defined action of lithium?
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It inhibits the conversion of IP2 and IP1 to inositol which limits phosphatidylinositol-4,5-bisphosphate (PIP2 level in the membrane.
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What is diazepam?
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It is a benzodiazepine that agonizes GABA(A) receptors, hyperpolarizing neurons away from threshold and used to treat anxiety disorders.
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If a patient experiences abnormal responses to diazepam, what can be used?
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Flumazenil, which is a benzodiazepine antagonist.
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What is flurazepam?
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Otherwise known as dalmane, it is a long-acting benzodiazepine used to treat anxiety.
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What is triazolam?
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A short-acting benzodiazepine used to treat anxiety. It has relatively more withdrawal symptoms than other benzodiazepines.
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What is phenobarbital?
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It is a medium-long acting barbituate sedative for anxiety, seizures, and insomnia.
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What do barbituates do?
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BarbiDURATEs increase duration of GABA(A) Cl- channel opening.
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What are some major toxicities associated with barbituates?
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Dependence, induction of P450, depression of respiratory functions.
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Are there antidotes for barbituates?
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No.
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Why are benzodiazepines preferable to barbituates in the treatment of anxiety?
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Tolerance, dependence, potential coma, withdrawal.
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What is a side effect of lithium and how can it be treated?
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Essential tremor can be treated with beta-blockers (propranolol).
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study
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study
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What is the common precursor for prostaglandins, leukotrienes, prostacyclins, and thromboxanes?
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Arachidonic acid
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What are the major advantages to COX-2 selective antagonists over non-selective antagonists?
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They do not inhibit platelet function or cause gastric ulceration and intolerance.
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What is ibuprofen?
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It is a proprionic acid derivative that non-selectively inhibits COX-1 and COX-2.
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What is naproxen?
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It is a proprionic acid derivative that non-selectively inhibits COX-1 and COX-2 and has a much longer t1/2 life than ibuprofen.
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What is indomethacin?
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An indoleacetic acid derivative that non-selectively inhibits COX-1 and COX-2. More potent than aspirin, so used to treat arthritis when patients can't tolerate it.
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What are some of the clinical uses for Indomethacin.
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Treating the I (eye), acute gouty arthritis, ankylosing spondylitis, osteoarthritis of the hip.
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What are the major adverse effects associated with indomethacin?
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Severe headaches and GI side effects.
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What is diclofenac?
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An acetic acid derivative that is a non-selective COX inhibitor. It is more potent than indomethacin and naproxen and is used for treating arthrititis.
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What is piroxican?
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An oxicam derivative that is a non-selective COX inhibitor. It is used to treat arthrititis and it has a very long half life (1 dose/day).
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What is celecoxib?
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A selective COX-2 inhibitor used to treat arthrititis.
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What is the major advantage to celecoxib relative to other NSAIDs?
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GI side effects are reduced and there is no effect on platelet aggregation or bleeding time.
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What is penacillamine?
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A metabolite of penicillin which may be used in rheumatoid arthritis as a last resort.
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What is the first choice for treatment of rheumatoid arthritis?
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Aspirin, but it has bad GI toxicities.
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List the important prostaglandins and how they are related biosynthetically.
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Arachidonic acid→PGG2→PGH2→→PGE2 or PGF2
First two reactions catalyzed by COX1/2 |
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What effect do COX inhibitors have on thromboxane?
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They reduce TXA2 levels because TXA2 is synthesized from arachidonic acid via COX1/2 enzymes. This decreases platelet aggregation.
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What is alprostadil?
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PGE1, it relaxes smooth muscle and is used to treat erectile dysfunction.
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What is aspirin?
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A salicylate that irreversibly inhibits COX-1/2. It reduces pain, fever, and prolongs bleeding time.
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What is dinoprostone?
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A synthetic PGE2 that causes contraction of the uterus and is used in first/second trimester abortion or inducing labor.
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What is misoprostol?
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A derivative of PGE1 that is used to treat gastric ulcers.
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What are prostacyclins?
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They are synthesized via COX1/2, and are potent vasodilators and platelet gathering inhibitors (PGI). They generally have opposite actions to tromboxanes.
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What do thromboxanes do?
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TXA2 causes vasoconstriction and increased platelet aggregation.
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What is zileuton?
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An inhibitor of lipoxygenase that causes decreased leukotriene synthesis and therefore less acute inflammation.
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What are the most common chemically-related deaths?
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Analgesics, sedatives/antidepressants, alcohols, CO
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What toxicity rating system is used to categorize toxins?
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The gleason toxicity rating system. 1: a quart; 6: a taste
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What are the two most important things to do when a patient presents with intoxication?
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First, treat the patient for immediate signs of distress, then ensure that the exposure is stopped.
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When a toxic compound is ingested, what are the principle ways that exposure can be limited?
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1. Emesis
2. Limit GI absorption 3. Hasten elimination 4. Apply systemic antidotes |
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What is the syrup of ipecac used for?
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It is used to induce emesis by acting on the gastric mucosa and the chemoreceptor trigger zone (takes 30 minutes to act).
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What is apomorphine used for?
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It is an emetic agent that acts directly on the chemoreceptor trigger zone and acts within 5 minutes. Importantly, it is a respiratory depressant and is contraindicated if poison is a CNS depressant.
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What are some reasons why you may not want to induce emesis?
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Aspiration, repeat exposure of esophageal mucosa, CNS toxicant (apomorphine interaction), cardiac (ipecac interaction), stress of vomiting.
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What is another way of clearing the stomach without inducing emesis?
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Gastric lavage with a french tube.
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What are three approaches for limiting GI absorption?
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Activated charcoal, cathartics, and whole bowel irrigation.
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What are some approaches to hasten elimination?
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Forced diuresis, alter urine pH, dialysis.
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What two diuretics are commonly used during intoxication?
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Furosemide (K sparing) and mannitol (osmotic agent).
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List compounds that can be used to either increase or decrease urine pH.
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Sodium bicarbonate IV (increase pH) and ammonium chloride gavage (decrease pH).
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When would you choose dialysis as a treatment?
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If the Vd is very low for a compound.
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How would you treat an aspirin overdose?
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emesis/lavage, alkaline diuresis, IV bicarbonate, hydration, glucose, potassium.
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What is N-acetyl cysteine used for?
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It is used to augment the glutathione reserves in the body during acetaminophen overdose.
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What is the best therapy for CO intoxication?
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Use hyperbaric oxygen to displace CO from hemoglobin.
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What is the mechanism by which acetaminophen causes renal and liver toxicity?
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During its metabolism, it is conjugated with glutathione. Depletion of glutathione causes cells to be sensitive to oxidative damage.
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When do the major symptoms of acetaminophen toxicity occur?
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3-5 days following intoxication because hepatic and renal necrosis develop. Death is due to liver failure.
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How is acetaminophen overdose treated?
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Lavage, activated charcoal, N-acetyl cysteine every 4 h for 3 days.
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What enzymes are involved in ethanol metabolism?
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Alcohol dehydrogenase and aldehyde oxidase.
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What are some major metabolic consequences of ethanol abuse?
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Fatty liver (glycerol) and smelly breath (bet-hydroxy butyrate).
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What may naltrexone (and naloxone) be used to treat?
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Decrease alcohol craving and treat problems with narcotic analgesics by competing with them at receptors.
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What is an important side effect of methanol?
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Optic nerve damage may cause blindness.
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What is the somewhat surprising treatment for methanol intoxication?
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Maintain blood ethanol at 0.1% for 5 days to prevent oxidation of methanol to toxic metabolites.
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What is malathion?
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An anticholinesterase inhibiting insecticide.
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What two chemicals may be used to counteract malathion toxicity?
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1. Atropine to counter ACh.
2. Pralidoxime to reactivate acetyl cholinesterase |
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What is deferoxamine?
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It is a bacterial siderophore which is used to treat iron overload by chelating iron. Either oral to inhibit absorption or parenterally to inhibit systemic iron.
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What is penacillamine?
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A metabolite of penicillin that is used to chelate copper in Wilson's disease and to treat mercury toxicity.
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What are the two major problems associated with lead intoxication?
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Encephalopathy, peripheral neuropathy, inhibition of heme synthesis.
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Are there any effective treatments for cadmium toxicity?
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No!!
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How can arsenic clearance be improved?
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By alkalinizing the urine with IV sodium bicarbonate.
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What drug can be used to treat methemoglobinemia?
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Methylene blue can be used as a reductant to convert ferric to ferrous iron.
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What does polyethylene glycol intoxication cause?
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Accumulation of glyoxylic acid which crystallizes in the kidney.
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What is ACTH?
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Adrenocorticotropic hormone. It is released by the pituitary gland in response to corticotropin releasing hormone and acts on the adrenal gland to promote glucocorticoid secretion.
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What are corticosteroids?
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Glucocorticoids and mineralocorticoids synthesized in the adrenal cortex (zona glomerulosa and zona fasiculata).
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What does cortisol do?
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It is BBIIG: maintains Blood pressure, decreases Bone formation, anti-Inflammatory, decreases Immune function, increases Gluconeogenesis, lipolysis, proteolysis.
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What effect do glucocorticoids have on COX-2 levels?
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They decrease COX-2 expression.
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Compare and contrast prednisone and dexamethasone.
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Prednisone has a mixture of glucocorticoid and mineralocorticoid activities, whereas dexamethasone has purely glucocorticoid activity.
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What is the overall abnormality in Cushing's syndrome?
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Increased cortisol production.
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How can Cushing's syndrome be diagnosed?
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Administering dexamethasone and then monitoring corticol levels in the blood. If the levels do not decrease, then Cushing's syndrome is diagnosed.
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What is 5-hydroxytryptamine?
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5-HT = serotonin
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What are alanine and aspartate aminotransferases?
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ALT and AST, enzymes that if circulating in the blood indicate liver damage.
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What may deferoxamine be used to treat?
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Iron or aluminum toxicity.
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What is disulfiram?
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Otherwise known as antabuse, it is an inhibitor of aldehyde oxidase. It is used to discourage alcoholism.
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What is DOPA-decarboxylase?
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An enzyme that converts L-DOPA to dopamine. It is inhibited by carbidopa to prevent peripheral side effects of L-DOPA treatment.
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What do reserpine and guanethidine do, and what drug interactions do they have?
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They inhibit transmitter release from sympathetic neurons and lead to upregulation of post-synaptic receptors. This increases the actions of direct acting sympathomimmetic drugs.
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What are isoprostanes?
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Prostaglandin-like compounds that are produced by oxidation of arachidonic acid in the absence of COX-1/2.
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What is phenoxybenzamine?
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It is an irreversible alpha-antagonist.
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What can sodium nitrate cause?
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Methemoglobinemia.
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What is the major chemical problem with depression?
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Problems with NE and 5-HT receptors.
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What are imipramine and desipramine?
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Trycyclic anti-depressants that inhibit reuptake of NE and 5-HT.
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What is fluoxetine?
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Prozac, it is a selective serotonin reuptake inhibitor (SSRI).
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What are major advantages of SSRIs over tricyclics?
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They lack the anti-muscarinic, anti-histaminic, and anti-adrenergic actions of tricyclics.
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What are phenelzine and tranylcypromine?
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Nonselective inhibitors of MAO. Phenelzine is irreversible, whereas tranylcypromine is reversible.
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What is important about SSRIs and MAO inhibitors?
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They have a 2-3 week wash out period between application because of possible "serotonin syndrome"
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