Final Exam Review for Pharmacology - March 2005, Exams of Pathophysiology

Download Final Exam Review for Pharmacology - March 2005 and more Exams Pathophysiology in PDF only on Docsity! Final Exam Review – March 2005 New Topics Since Midterm Cases Antiinflammartory Drugs Placebo Antihistamines Geriatric Pharmacology Immunosuppressive therapy Antiemetics Drug Development Renal failure Drugs Fro Movement Disorders Placental Transfer Anxiolytics/Antidepressants Alcohol Anti-Convulsants Drug Allergy Antimicrobials Migraines Chemotherapy Folate Opioids Oral Hypoglycemics Cancer Analgesia 1 1 docsity.com 2. NSAIDs inhibit COX-1. NSAIDs are designed to function as analgesics, anti-inflammatories, and anti-pyretics. Inhibition of COX-1 leads to other effects like gastric mucosal damage, nephrotoxicity, CNS effects, and platelet inhibition. * Aspirin irreversibly inhibits COX-1. Aspirin is used to inhibit thromboxane synthase in platelets. Without thromboxane synthase, TXAz levels decline, and the patient’s ability to activate and aggregate platelets is diminished, so aspirin functions as an anticoagulant (i.e. post MI or MI prophylaxis). * Other NSAIDs reversibly inhibit COX-1: o Ibuprofen, Indomethacin, Naproxen. Ibuprofen and Indomethacin have short half lives vs. naproxen has a longer half life. This is important for rapid onset or longer duration of action. Uses of these drugs include rheumatoid arthritis, osteoarthritis, gouty arthritis, dysmenorrhea, surgical pain, and other muscular pain. o = Sulfasalazine a molecule of sulfapyridine linked to 5-aminosalicylic acid. Sulfasalazine travels to intestine where it is broken down by bacteria, releasing the anti-inflammatory 5- aminosalicylic acid. Sulfasalazine is used in ulcerative colitis * NSAIDs cause gastropathic side effects by reducing levels of cytoprotective prostaglandins like PGE. Misoprostol is a PGE, analog which restores the cytoprotective effect to GI mucosa. = To avoid some of the side effects caused by COX-1 inhibition, there is a new class of drugs called coxibs or COX-2 selective inhibitors. These drugs include celecoxib and rofecoxib, which are used for rheumatoid arthritis, osteoarthritis, gouty arthritis, dysmenorrhea, surgical pain, other muscular pain, and for familial adenomatous polyposis (celecoxib). Theoretically the coxibs should decrease gastropathic side effects. However, they may have deleterious cardiovascular effects. 3. Newer methods of anti-inflammatory therapy: ati-cytokine therapies which limit TNF levels. = Etanercept: soluble TNF receptor. Used in rheumatoid arthritis as a monotherapy. = Infliximab: antt TNF IgG. Used in Crohn’s disease, and in rheumatoid arthritis in combination with methotrexate. Anti-Histamine Drugs (Dershw: 1. Hi blockers: diphenhydramine, chlorpheniramine, promethazine, terfenadine, fexofenadine. a. Used to control hypersensitivity reactions (antagonize bronchoconstriction, vasodilatation, itch), lessen rhinorrhea and coughing, causing sedation (also a general side effect). b. Anti-cholinergic side effects: xerostomia, blurred vision, urinary retention, tachycardia, mydriasis c. Terfenadine can cause arrythmias. Terfenadinds a prodrug converted into fexofenadine. 2. Hy blockers: cimetidine, ranitidine a. Used for gastric ulcers, peptic ulcers, etc. b. Cimetidine is a PASO inhibitor. c. Instead of H» blockers, can use proton pump inhibitors likeomeprazole which have a longer lasting effect (because they covalently inhibit the gastric Ht K+ ATPase. docsity.com Movement Disord rs (Standae Parkinson’s Disease involves loss of dopaminergic neurons in substantia nigra. Chief symptoms are rigidity, bradykinesia, and tremor. There are also many other classic symptoms. Parkinson’s DSEASE = ond Glutamate (abveys exe viata <——. aw Devaming (either tabiaitory °F 6ug| (or) as=* GABA (always ianibitery> Venn a pebstantia wlagre Ps ses ee Ne 2 Sot fame ends oy . erne eo ey renee sen Direct Pathwey Pharmacologic treatment of Parkinson’s involves methods to increase CNS dopamine. se oy Piet wore Smtgrt Pe nevmprortchive Pharmac! ogy "> degradation we deg redation [roteares) 4 Ft coare 2 Weer tuxtaty \e wre 5 > Lr DOrh ee ceceet “4 J ARO (ezeme cri Degerine ergo Dopaming ™ mar ger iar act on agen . i jc v omer * PeTraaggheniay) orc unteana nn io Parcs son's) (Banactadiag) « anheien 1. Restore dopamine levels in CNS: Levodopa (L-DOPA) is used because dopamine does not cross BBB. L-DOPA is converted to dopamine by DOPA decarboxylase in CNS. a. Recall how tolerance develops. Requires either elaborate dosing schemes or drug holidays (not very successful). 2. Helping to maintain levels of levodopa: a. Carbidopa: inhibits peripheral decarboxylation of DOPA i. Combination of levodopa/carbidopa = Sinemet b. Entacapone: inhibits catechol O-methyltransferase (increase t)/2) c. Selegiline: inhibits central MAO-B 3. Dopamine agonists / mimetics: Bromocriptine, Pergolide a. Trihexylphenidyl: antt muscarinic side effects b. Amantadine: also anti-viral, has anti-cholinergic effects Anti-psychotics: all antagonize dopamine receptors for psychotic illnesses and schizophrenia. As dopamine blockers, can cause Parkinsonian side extrapyramidal effects (dystonia), Two major side effects: tardive dyskinesia (choreiform disorder affecting mouth and face which persists after treatment stopped) and neuroleptic malignant syndrome (muscle rigidity, hyperthermia, increased creatinine kinase; treat with dantrolene, cool patient). docsity.com = Typical anti-psychotics: block D2 receptors but also have significant anti-cholinergic effects. These three listed in increasing order of D2 blockade and decreasing order of anti-cholinergic effect. o Chlorpromazine, Thioridazine, Haloperidol * Atypical anti-psychotics: do not block D2 receptors, but D4 and other subtypes. o Clozapine: causes agranulocytosis and requires regular blood checks o Rispderal, olazenapine, quietapine, etc. Depression (Standaert): ACHR = TEA show antredellnergic Side eMecty which are Tricyelic Antidepressants (rca) PRACT ade Dermession | 4 [Baieriptitine] Aeardiac Fox acd Torsades de “) Rauptake Pelntec) se {\— tye Th, t-pora > IN degraded, neue? J - NE Tew Top > sure anit s-ut tno _tanivitets epee cevgtaiee Depression Pharmacotherapy: based on amine hypothesis ® increase levels of dopamine, norepinephrine, serotonin = Tricyclics and heterocyclics: block reuptake of serotonin and norepinephrine. Have anti-cholinergic side effects o Amitriptiline, nortriptyline, trazodone(sedation) = SSRIs: less anticholingeric side effects, but can inhibit P450 o Fluoxetine, sertraline, citalopram, escitalopram, paroxetine = Non-selective MAOI: used for atypical depression = Buproprion: structurally similar to tricyclics, but may actually help release norepinephrine. Also used in smoking cessation. = Two major classes: benzodiazepines and barbiturates = Both bind to GABAg receptor (which regulates inhibitory transmitter GABA). Benzodiazepines increase frequency of channel opening. Barbiturates prolong duration of opening. = Benzodiazepines Used as anti-anxiety and for sedation (also anesthesia) docsity.com Differentiated based on half lives: Short: midazolam, triazolam. Medium: temazepam, lorazepam Long: diazepam, flurazepam Benzodiazepine antagonist: Flumazenit = Barbiturates Major toxicities are sedation and respiratory depression. = Tolerance and cross tolerance Chronic use of either class results in tolerance to all members of that class and cross-tolerance to other class. Both produce dependence; withdrawal may create anxiety, agitation, seizures. Anti-convulsants: Some mechanisms include blocking sodium channel conductance and increasing GABA channel conductance. far feet inechve Sires Eriwerty | Aswvery : oF apanin ae i ih [eqrearasating) (Barapa) tensor c8“9 miami Uy : ee are ae \ “ rn ee fmidersien) °°! oO “Geiss Seizures gam cpanzetionsping Iabibitor means order Kine Ferenes aia Barista Chess jurate) «tdvration of ateaiag Fee ean, (ones durat ee es ill wa v ; nen Not - (erintdone) Na Channel blockers: phenytoin, fosphenytoin, and carbamazepine Phenytoin: used for partial, tonie clonic seizures, and status epilepticus. Side effects: gingival hyperplasia, hirsutism, sedation, fetal hydantoin syndrome. Zero order kinetics. Fosphenytoin: water soluble prodrug metabolized to phenytoin in blood. Carbamazepine: used for partial and tonic-clonic seizures. Side effects include agranulocytosis and P450 inhibition. Barbiturates: Phenobarbital and Primidone: used for tonic clonic seizures Benzodiazepines: Diazepam, Lorazepam: used for status epilepticus Valproic acid and Ethosuccimide: for absence seizures. Side effects include birth defects / spina bifida and GI distress respectively. docsity.com o Increased expression of gene: resistance to methotrexate by increasing the copy number of the DHFR gene. (double minute chromosomes, and HSR) o Altered gene product: methotrexate, 5-FU, vinca alkaloids Opioids (Rosow = Mechanism: decrease adenylate cyclcase via Gi coupled receptors = Uses of opioids: analgesia. Also used for cough suppression (dextromethorphan), and as anti-diarrheal agents (loperamide, diphenoxylate). o Can combine opioids and analgesics: Oxycodone can be combined with acetaminophen > percocet = Side effects: respiratory depression (lose response to hypercapnia, hypoxia), pupillary constriction, nausea and vomiting, smooth muscle constriction, dependence, constipation, urinary retention. o Meperidine: opioid agonist that causes less smooth muscle contraction, so could be useful for analgesia in biliary colic (will not increase tone in sphincter of Oddi) = Dependence involves physical and psychological dimensions. Physical = withdrawal (vomiting, diarrhea, mydriasis, chills); psychological = need for opioid induced euphoria = Tolerance: tolerance develops to all side effects except pupillary constriction and constipation. = Opioids can directly induce histamine release without activation of IgE. Anaphylactoid reaction, but not a true allergic reaction. = Antagonists: naloxone, naltrexone Murced Agent i Aatagenists : to: (Mast aches @ p) Agonists: ( » = Maxed action @ pr-rececot prengr pring Sa } Kk agantst, p tay \/ NT + Shere duration Maca Fecegtor Kaper (receptor Synal ey cecartor , (Enxephalins) mee ee Canta sanatgesis, + analges? a shallect aah os + Pacpiratory doytersion - Gupberiad sedation + phystcal dependence + 4.6L mobtty > + pupil eaashichon + sedaiten f dy pheta + dysphario + pupil constriction Antageni st [naloxone] Other Cases and Topics: 10 docsity.com Glaucoma: engineering problem: decrease aqueous humor by 1. increasing outflow or 2. decreasing production of aqueous humor 1. Increase outflow: basically need cholinergic agonists, which acts as miotic agents and contract ciliary muscle which opens trabecular network and allows outflow. Can use direct agonists or acetylcholinesterase inhibitors. = Agonists: Pilocarpine = Acetylcholinesterase inhibitors: echothiophate 2. Decrease production = Beta blockers (beta | selective): timolol. Antagonize beta receptors which stimulate production. = Carbonic anhydrase inhibitors (acetazolamide) decrease HCO-3 levels which limits Na+/HCO-3 cotransport necessary for aqueous production. Gout: precipitation of uric acid = Colchicine: used for acute gout as anti-inflammatory agent by depolymerizing microtubules thus inhibiting Jeukocyte chemotaxis and organelle degranulation = Allopurinol: for chronic gout by inhibiting enzyme xanthine oxidase which limits production of uric acid = Probenecid: used in chronic gout. Inhibits reabsorption of uric acid from renal tubule. (Probenecid inhibits secretion of penicillin into tubule, so concentrations remain high) Drug Allergy: Both of these cause drug induced lupus Hydratazine: Procainamide: Oral Hypoglycemics: Various mechanisms: = Metformin: type of biguanide that decreases serum glucose. Side effect: lactic acidosis = Glyburide, tolbutamide: types of sulfonylurea. These agents increase K+ influx into islet cells which stimulates insulin release and hypoglycemia. Older agents like g/yburide have disulfiram like side effects. = Acarbose, miglitol: Types of alpha-glucosidase inhibitors which prevent breakdown and uptake of glucose from intestines. = Rosiglitazone: type of thiazolidinedione activate PPAR signaling pathways that increase peripheral sensitivity to insulin Lithium: used to treat mania and manic depression and SIADH. Mechanism is blocking IP3 pathway. Side effects include diabetes inspidus = polydipsia and polyuria. Migraine: Sumatriptan: Triptans are serotonin (SHT1 subtype specific) agonists. Effect is likely due to vasoconstriction of specific cerebral vessels. Ergotamine: stimulate smooth muscle and sympatholytic. May work in same mechanism as triptans. Folate: Major cofactor in one carbon metabolism. Molecular structure is combination of pteroate, p- aminobenzoate, and poly glutamate groups. Involved in synthesis of purines, TMP, and methionine. = Antibiotics: humans do not synthesize folates, but microbes do. Two key enzymes are dihydropteroate synthase and dihydrofolate reductase (same enzyme as methotrexate). These two enzymes are inhibited by sulfamethoxazole and trimethoprim (combination is called Bactrim). ll docsity.com = Methotrexateinhibits DHFR. Inhibiting DHFR traps all folate in oxidized form. To prevent deleterious effects on normal cells, give reduced form of folate called Lewcovorin (=Leucovorin rescue). Placental Transfer: Thalidomide caused phocomelia. Alcohol: Ethanol = Disulfiram is used as a treatment in alcoholics: it inhibits the enzyme aldehyde dehydrogenase so that when ethanol is ingested and converted to acetylaldehyde, the acetylaldehyde builds up and produces a terribly uncomfortable effects (metronidazole has a disulfiram like effect) = Ethylene glycol: toxic chemical found in antifreeze whose toxicity results from its metabolism to oxalic acid, glycolic acid, and glyoxilic acid; antidote is ethanol which competes for degradation by aldehyde dehydrogenase o Fomepizole (4-methy! pyrazole): alcohol dehydrogenase antagonist used as antidote to ethylene glycol or methanol (or other alcohol/glycol) poisoning. Cancer Analgesia: various pain meds include NSAIDs, tricyclics, opioids 12 docsity.com