Presentation on theme: "Pharmacology in MS Advanced Practice Management"— Presentation transcript:
1 Pharmacology in MS Advanced Practice Management Heidi Maloni APRN, BC
2 ObjectivesDiscuss basic principles of pharmacology, pharmacokinetics and pharmacodynamics.Describe the pharmacotherapeutics of drugs used in MSIdentify the role of advanced practice nurse in MS pharmacological management.Pharmacokinetics: The action of the drug in the body over time, inclusing the process of absorption, distribution, localization in tissues, biotransformation and excretionPharmacodynamics: the study of the biochemical physiological effects of drugs or mechanism of action and interactionPharmacotherapeutics study of the uses of drugs in the tx. Of dz.
3 Advanced Practice Pharmacology Background Pharmacology: study of a drug’s effects within a living systemEach drug is identified by 3 names: chemical, generic, trade or marketing nameN-4-(hydroxyphenyl) acetamide; acetaminophen; Tylenolsodium hypochlorite; bleach; Clorox4-(diethylamino)-2-butynl ester hydrochloride; oxybutynin chloride; DitropanDrugs are derived from: plants, humans, animals, minerals, and chemical substancesDrugs are classified by clinical indication or body systemA drug is any substance used in the dx, cure, tx, or prevention of a dz or condition.Chemical name: description of drug’s chemical composition and molecular structureGeneric: nonproprietary name (official) is often assigned by the manufacturer with the approval of the US Adopted Name Council, and is the name listed in pharmacology reference booksTrade name: proprietary (patented) name of medPlant= digitalis from foxglove or taxol from yew tree; alkaloids from nature are combined with acids in the lab to form water soluble salts (morphine sulfate); glycosides= plant substances that on hydrolysis yield a sugar plus one or more active substances (digoxin); Gums= plant exudates that may swell and form gelatinous masses with water (psyllium seeds)-used as laxatives or to soothe irritated skin or mucus membranes; oils=highly viscous liquids (peppermint, fixed oils, olive castor oil)
4 Safe drug administration APN RoleSafe drug administrationNurses are professionally, legally, morally, and personally responsible for every dose of medication they prescribe or administerKnow the usual doseKnow usual route of administrationKnow significant side effectsKnow major drug interactionsKnow major contraindicationUse the nursing processReferences for knowing: American Hospital Formulary Service Drug Information; USPDI; PDR; F&C;
5 Pregnancy SafetyTeratogenicity: ability to produce an abnormality in the fetus (thalidomide)Mutogenicity: ability to produce a genetic mutation (diethylstilbestrol, methotrexate)
6 Pregnancy Safety Categories A: studies indicate no risk to the fetus(levothyroxan; low dose vitamins, insulin)B: studies indicate no risk to animal fetus; information in humans is not available(naproxen;acetaminophen; glatiramer acetate; macrolides; B lactams)C: adverse effects reported in animal fetus; information in humans not available(Inf-B; methylprednisolone; topiramate; fluoroquinolones)D: evidence of human fetal risk, but potential benefits may be acceptable despite risks(mitoxantrone; cladribine; cyclophosphamide; all ACE in 2nd and 3rd trimester; ARBs; lithium; streptomycin; tetracyclines; carbamazepine, valproic acid)X: fetal abnormalities reported and positive evidence of fetal risk in humans is available from animal and human studies(methotrexate; misoprostol; quinine)Macrolides=azithromycin, erythromycinBlactams= penecillins cephalopsorinsAnticonvulsants are folic acid antagonists
7 History: A summary of major drug discoveries Opium tincture, coca, and ipecacDigitalisSmallpox vaccineMorphineQuinine, atropine, codeineEther and chloroformInsulinPhenytoinCortisonePolio vaccinesCarbamazepineOral contraceptivesAntiviralsimmunomodulators17th century17851796181519th century1840’s19221940’sMid-1940’s1955 and 19611960Late 1950’sMid-1970’s1990’s
8 Phases Affecting Drug Activity Mechanisms of Drug Action DoseDisintegration of dose absorption drug receptorFrom dissolution of drug distribution interactionmetabolismeliminationEffect1.Pharmaceutical Pharmacokinetic PharmacodynamicPhase Phase PhasePharmacokinetic: the alteration of a drug concentration at target site by a second drugPharmacodynamics: reduction or enhancement of the effect of a drug by another withour altering its concentration at the site of action
9 Pharmacokinetics1. Absorption : route, dose, dosage form, and bioavailabilitycell membrane, blood flow, nature of the drug2. Distribution via circulationplasma protein binding: expressed as a degree, very high to very low with. Binding site competition: consequences for toxicity and drug interactiontissue binding: fat (cumulative effect), bonebarriers (skin, placenta, BBB)Pharmacokinetics is the study of the concentration of drugs during the process of absorption, distribution, biotransformation excretion.Cell membranes are lipid based. Absorption depends on acid or base, ionized and unionized, water soluble- lipid solubleIonized (polar) is water soluble and does not easily diffuse through cell membraneNature of drug: liquids, elixers, syrubs more readily absorbed than enteric coatedPassive transport: diffusion from area of higher concentration to area of lower concentration until equilibriumActive transport: go against the concentration gradientBioavailability-percentage of active drug available to target tissue. Biologically equivalent if equal concentrations are in blood and tissue and therapeutically equivalent if provide equal therapeutic effectiveness as in clinical trials. FDA regulating bioavailability by uniform manufacturing standardsAbsorption influenced by routeDrugs only modify existing body fxRate of absorption influenced by : cell membrane (single cell layer is faster-intestine) than several layers (skin) and surface areaBlood flow influences absoption-sublingual is fast-sub cue is slow; IV vs IMNature=Solubility (in solution. Lipid), Ph, an acid drug (ASA) is readily absorbed in an acid environment (stomach), concentration, > concentrations more readily absorbed, example loading dose and maintenance dose (steroids, antibiotics); dosage form: slow release, enteric coating-to prevent dissolution in stomachRoute:enteral: into GI tract, PO, sublingual, buccal, rectal; parenteral: subcue, IM, IV, intrathecal(subarachnoid), epidural and specific: intraarticular, intraosseous, intraperitoneal, intraplueral; pulmonary (bronchodilators); topical (only lipid soluble compounds are absorbed)The action of drugs in the body over a period of time. Concentration that a drug attains at its site of action is influenced by absorption, distribution, biotransformation, eliminationAbsorption: cell membrane of proteins and lipids; ionized or water soluble drugs have difficulty crossing cell membraneCell membrane can have lg surface area, active or passive transportRich blood flow to absorption site enhances absorptionNature= lipophilic, dissolution, concentration & pH; acidic drugs become nonionized in an acid environment and base drugs tend to ionize in acid environment (stomach) and not absorbed well.Bound molecules are pharmacologically inactive and becomes a circulating storage depot—this allows drug to be available for longer time—sulfonamide bind highly so antiinfective action is long lasting.Distribution- transport to tissuesBiotransformation: chemical inactivation by conversion to a more water soluble compound for excretionDistribution influenced by ionization, by cardiac output, regional blood flow—most drugs go to organs c rich blood supply-heart liver kidney brainDrugs may become attached to protein (albumin) which decreases the concentration of free drug and limiting amt to site of action. Happens in equilibrium- as free drug is eliminated- bound give up to allow free—extending “life” of drug. Coumadin and propanolol very highly bound >90%. Care with ASA secondary to binding site competition. Care c administration that may raise concentrationBBB- distributes lipid soluble drugs. Drugs easily transported across placenta: steroids, antibiotics, narcotics, anesthetics
10 PharmacokineticsMetabolism or biotransformation, primarily liver to increase water solubilityDelayed metabolism (excessive or prolonged response)Stimulated metabolism (tolerance)Hepatic first-pass-give > dose or parenterallyBiological half-lifeElimination: kidneys, lungs, intestines, sweat, salivary and mammary glandsLipid soluble drugs are not excretedAltering urine pH can encourage eliminationBiotransformation or metabolism chemically inactivates the drug- or makes it water solubleChemical alterations are produced by microsomal enzyme system—to incr. polarity drugs become oxidized, hydrolyzed, reducedMicrosomal enzyme systems can be depressed by hepatic fx-starvation, obstructive jaundice—liver, kidney heart dz prolong or decrease metabolismTolerance: stimulated metabolism results in tolerance- substances that incr activity : CNS depressants, pecticides, food preservatives, dyes, xanthines---repeated administration stimulated enzymes..so effect diminishes c prolonged administration (hypnotics)Hepatic 1st pass- PO drugs go to liver and metabolized leaving only a small dose available to site—may need to incr dose or administer parenterallyExcretion: lipid soluble not excreted; alkalize urine to excrete acid drug with sodium bicarb—acidify c vit C to excrete base drugsAlcohol partially excreted by lungsBreast milk is acidic-therefore base compounds have high concentration-narcotics. Cummulative effect of drugs occurs in infants.Delayed metabolism= cumulative drug effects manifested as excessive or prolonged response
11 Pharmacodynamics Drug action produce effect by: drug receptor interaction (example: opioids)Affinity: “lock and key”Agonist (morphine)Antagonist (naloxone)drug enzyme interaction (example: neostigmine)nonspecific drug interaction (example: general anesthetic; cathartics; ointments; detergents)drug agonist receptorPharmacodynamics=mechanism of drug action on living tissueAntagonism: one drug blocks or reverses the therapeutic effect of another drugAntagonism can be harmful when therapeutic benefit is reduced by presence of another drug eg beta blockers reduce benefit of beta agonist used in asthmaSynergism is the effect of 2 drugs is additiveStudy of biochemical and physiological effects of drugs and the mechanism of action-Action is the means by which a drug produces alteration in fx at sites of actionLock and key= model –drug molecule fits into the receptorAffinity= propensity of a drug to bind or attach itself to a given receptorAgonist= drug that has affinity for or stimulates physiological activity at cell receptors normally stimulated by naturally occurring substancesAntagonist= drug designed to inhibit or counteract the effects by other drugs or undesired physiological effects caused by illness may be competitive and noncompetitiveDrug enzyme interaction= interaction between drug and cellular enzyme to alter the physiological responseNonspecific= lack of identifiable drug structural specificity-destroys the integrity of the cells- detergent; H2O2;Enzymatic action- resemble enzymes on cells and inhibit the action of that enzyme, are antimetabolites i.e., methotrexatedrug antagonist
12 Drug ResponseAn enhanced or diminished effect of one drug when used with anotherSummation: 1+1=2 (codeine + ASA)Synergism: 1+1=3 (bupropion + fluoxetine)(propranolol + lisinopril)Potentiation: 0+1=2 (caffeine + ibuprofen)(diazepam + codeine)Plasma level and therapeutic indexBiologic ½ lifeDrug interactions occur when highly protein bound drugs displace other highly protein bound drugs from binding sites to increase the free drug concentrations in the plasma; medications enhance or inhibit hepatic metabolism of other drugs, or when drugs increase or decrease renal elimination.Combined effect of two drugs produces a result that equals the sum of the individual effects of each agentSummation=additive effect, the combined effect of two drugs produces a result that equals the sum of the individual effects of each agent. Two analgesics provide additive or > relief than one alone---could give lower doses with lower SESynergism= combined effect greater than sum of individual agent alonePotentiation+ one drug increases the effect of the otherCombined effect is greater than the sum of each individual agent independentlyOne drug increase the effect of another drug- one drug inhibits the clearance of anotherOnset: rapid- effect within 24 hrs; delayed will not be evident until the interacting drug is administered for days or weeksPlasma level is r/t of drug in serum and drug in tissue—onset of action, peak action, duration of action termionation½ life: if a drug 40 mg has a ½ life of 7days at that time 20mg is excreted; in 7 more days 10mg is excreted; in 7 more days 5mg is excreted; 7 more days 2.5mg…and so onIn hepatic dysfunction or renal disorders drug elimination may be prolonged—lower doses may be advisedPrednisone: peak effect is 1-2 hrs- duration of action30-36 hrsFluoxetine average range of elimination ½ life is 168hrs (7days)-PeakTherapeutic RangeAbsorptionElimination
13 Adverse EffectsAny response to a drug which is unfavorable, and unintended, occurring at doses used for prophylaxis, diagnosis or therapy, or for the modification of physiological functionMechanism: iatrogenic response, immune (allergic) response or local irritationCausalitySeverity: mild, moderate, severeAPN role: promote health, prevent illness, restore health, alleviate suffering with respect for individual’s rights and dignityAPN role: educate re: side effects, management strategies, and when to report persistent or adverse effects; understand risk/benefitAn unintended or undesirable response to a drug. Side effect is an additional effect, desired or undesired and predictable which is not the primary purpose of giving the drug—intensity is dose dependentDrug action: means by which a drug produces an alteration in functionUnfavorable: noxious, hurtful, damaging to tissue-may occur immediately or take weeks or months (example: opioid , immediate drowsiness; but constipation is often delayedMechanism:Iatrogenic (phenothiazines result in drug induced parkinsons) pharmacological effect- a known, inherent Rx effect of the drug either in excessive degree of the desired effect or unintended side effectAllergic reaction: a reaction unexplained by the known RX effect of the drug, manifested by typical signs and symptoms of an immunological responseIrritant effect: local- characterized by inflammationCausality: temporal (chronological r/t between event and drug administration; Dechallenge- resolution following decreasing the dose or DC; rechallenge: recurrence following readministrationKnown effect; objective measurable physiological effect (BP, labs, serum); effect from events unrelated to clinical status or other tx.
14 APN Role Take a Medication History 1. Name, dose, route, schedule2. OTC and CAM use3. Age, gender, race, height, weight4. Medical condition for which drug is prescribed5. Manual dexterity, mobility, literacy, sight and hearing6. Adherence ???7. Hx of allergies (food & drug), adverse drug effects8. Psychosocial Hx.: tobacco, caffeine, alcohol, recreational drugs, sexual orientation and no. of partners, childbearing potential, & financial/educational status9. Exposure to environmental & occupational substances
15 Drugs Causing LFT Abnormalities Almost any drug but digitalis and prednisoneMost common offenders: antibiotics (quinolones, nitrofurantoin, penicillins, azoles)Anti-epilepticsNSAIDSAcetaminophenDrugs are metabolized in the liver in two phases- oxidation phase 1 and conjugation phase 2-phase 1 metabolism involve CYP450 enzymes
16 Abnormal LFT Repeat to confirm Order CPK enzyme test Assess alcohol historyAssume medication-induced causesNormal AST <40AST/ALT that is > 10x-15x nml in necrosisAST/ALT usually <300 in alcoholic damage
17 Liver Function Tests: Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phophatase, Lactic Dehydrogenase, Albumin, Ammonia, Bilirubin, Prothrombin, Gamma-glutamyl TransferaseAlanine Aminotransferase (AST, SGPT)Normal range: men 10-40U/L; women 7-35U/LSignificance: Marker of hepatic injury; found primarily in liver; more specific indicator of liver damage than ASTFactors that increase: acute MI, pancreatitis, acute renal infarct, CHF, mono, liver dz., heparin, skeletal muscle dz.Factors that decrease: not clinically significantAspartate Aminotransferase (AST, SGOT)Normal range: men U/L; women 10-36U/LSignificance: non-specific marker of hepatic injury found in brain, cardiac, skeletal, kidney, liver.Factors that increase: Acute MI, acute renal infarct, acute pulmonary infarct, anemia, mono. Liver dz (hepatitis, alcoholism, drug toxicity), malignancies, skeletal muscle dz, tissue necrosis, 3rd degree burns, trauma, tylenol, ASA, heparin, INH, oral contraceptivesFactors that decrease: chronic dialysis, B6 deficiencyAlkaline PhosphataseNormal range: U/LSignificance: Reflects bile formation and flow, non-specific measure of liver or bone diseaseFactors that increase: Alcoholism, CHF, CMV, Fanconi’s syndrome, healing, Hodgkin’s, mono, liver dz, lung ca, Paget’s dz, rickets, pregnancy, pulmonary and MI, sarcoid, sepsis, sickle cell, ulcerative colitisFactors that decrease: anemia, celliac dz, hypothyroidism, malnutrition, sarcoma, vit D intoxication, zinc depletionLactic Dehydrogenase (LDH)Normal range: IU/L men; IU/L femaleSignificance: non-specific isoenzyme found in most tissue. Incr. indicated tissue damage.Factors that increase: alcoholism, anemia, burns, cancer, CVA, CHF, DT’s, hepatitis, mono, muscular dystrophy, myxedema, pain, pulmonary embolism, sickle cell, trauma, codeine, lithium, lorazepamFactors that decrease: irradiation tx., oxalates, favorable response to cancer tx.
18 Cytochrome P450 Recognizing Interactions Major enzyme system for metabolizing a drug by using iron to oxidizeOccurs mostly in liver or gut wall during absorptionInducers can decrease the therapeutic levels of substrates e.g., modafinil and CYP3A inducer carbamazepineInhibitors can increase or potentiate a drug effect e.g, modafinil and CYP3A inhibitors, ketoconazoleCYP classified in isoforms that are genetically derived: CYP3A (50%), CYP2D6 (30%), CYP1A2, 2C9/10, 2C19, 2E1 (10%)Substrates: drugs that are metabolized as substrates by the enzymeThe rate of drug metabolism effects the plasma drug levelsInhibitors: drugs that prevent the enzyme from metabolizing the substratesActivators: drugs that increase the enzyme's ability to metabolize the substrates
19 Common CP3A Use in MS Substrates Inhibitors Inducers alprazolam cimetidine carbamazepineamitriptyline ciprofloxacindexamethasone clarithromycinbuspirone cyclosporine garlic supplementscannabinoids danazol glucocorticosteroidscaffeine ethynyl estradiol modafinilcarbamazepine fluconazole oxcarbazepinecyclophosphamide grapefruit phenobarbitoldexamethasone phenytoindiazepam St. John’s Wortprogesterone17 ß estrodiol Increase the potentialoxybutinin for toxicity from substratetolterodinetrazadonesildenafil, tadalafil, verdenafil decrease therapeuticmethylprednisilone level of substrateclarithromycinStatinsCYP3A involved in metabolism of over 50% of currently prescribed drugs-important to understand drug reactions due to drug metabolism by inhibition or induction of CP3ATobacco and alcohol use can alter plasma concentrations-tobacco decreases serum levels of antipsychoticsInhibitors are potent or moderate. Potent= an inhibitor causes a 5 fold increase in plasma concentration of another drug primarily dependent on CP3A for metabolism. Grapefruit inhibits intestinal not hepatic in > quantities In quantities of 1 qt/d can be a potent inhibitorAdverse rx occur if inhibitor or inducer and substrate must be taken together Example: In MS pt on ditropan for bladder and modafinil for fatigue is drinking 1 qr of grapefruit or clarithromycin for URI can decrease tx level of oral contraceptives or ditropan—or incr ditropan anticholinergic SE
20 PharmacogenomicsPersonalized drug therapy based on genes- AmpliChip- ID slow and fast metabolizers so dosages can be adjustedMay explain some “idiosyncratic” reactionsCan learn a lot by a good family drug history7-15% caucasians (4-18% Middle Eastern Jews) poorly metabolize CYP2D6 –either rapid or slow (antidepressants, beta blockers, antiarrhythmics, antipsychotics, narcotics, dextromethorphan)25% of Asians slowly metabolize CYP2C19 (clomipramine, diazepam, imipramine, omeprazole, propranolol)Ethnopharmacology-the study of the effect of ethnicity on phamacokinetics (absorption, metabolism, distribution, excretion) The genetic ability to produce CYP450 enzymes varies with race and ethnic grp.Similarities and differences in ethnic group response to drugsRace is used to predict response to a drug-hispanics may require lower doses of antipsychotics and blacks were more at risk for tardive dyskinesia from antipsychotics than whites. New atypical antipsychotics better for blascks, asians and hispanics (risperidone, clozapine, olanzapineExample –new BiDil (isosorbide and hydralazine) for treating heart failure in AA; blacks more likely to have faster tx response and higher plasma concentrations and greater side effects to TCA’s—and greater SE with lithium (lethargy & dizziness)CYP2D6:unique in that the gene is often duplicated-leaving some with faster than normal enzyme activity- “ultrarapid metabolizers”.; and some have two nonfunctional copies of gene and are slow metabolizers Example: TCA; venlafaxine, fluoxetine, paroxetine; haldol, resperdol, lopressor, levatrol. Inderol, timolol, codeine, tramadol, atomoxetine, dextromethorphanAsians need lower doses of crestor and warfarinAmplichip FDA approved test for variations in genes that affect metabolism of CYP2D6 and CYP2C19AmpliChip identifies slow or fast metabolizers so dosages can be adjusted
21 APN RoleLearn about the specific drugs that are most likely to elicit a varied response in people from different ethnic groups, as well as potential for adverse effects.Conduct a cultural assessment on each patientAsk specific questions about adverse effects and side effects associated with drug historyMonitor, document, identify slow and fast metabolizers and adjust dosages per individual patientKeep cultural context in mind when planning education for families and patientsCheck your cultural competence and measure attitudes atLower doses of Lithium in blacks, asians (Japanese and Taiwanese); antipsychotics in HispanicsTwo useful, basic questions: what do you think caused your health problems and what treatment do you think will help?Cultural assessment: Leininger or Giger and Davidhizar
22 GlucocorticoidsIndication: acute exacerbation (no evidence for long term benefit); speeds recovery; use in functional deficits of visual, motor, cerebellar systemMechanism of action: decrease CNS inflammation; close BBBSide effects: hypertension; diabetes; cataracts; ulcers; mood changes high & low and mania; difficulty sleeping; fluid retention; restlessness; joint pain (hip); stomach ulcers, weight gain, acne, osteoporosis (thinning of the bones).Pregnancy Cat. C; secreted in breast milk
23 Pharmaceutical Management of MS Acute Exacerbations Glucocorticoidsnaturally occurring hormonesIM adrenocorticotropic hormone (ACTH®) U/d for 2-3wksadministered as synthetic prepIV methylprednisolone (Solu-medrol®)1G QD 3-5 daysIV dexamethasone (Decadron®) mg/d 3-5d (contains sulfites)PO prednisone, taper: 60mg QD, 7 d; 60mg qod, 8d; 40mg qod, 8d; 20mg qod, 8dIncrease appetite and water retention- low salt K rich diet; lower resistance to infection. Inc use in pregnancy may cause infant growth slowing; pass into breast milk and can stunt growth; do not associate with someone with recent live vaccinationACTH is an anterior pituitary hormone that stimulates production of corticosteroids by the adrenal glands. Not used as synthetics have longer action and fewer SE
24 Immunosuppressive Agents/ Antineoplastic Agents azathioprine (Immuran®) PO mg/kg/dcyclophosphamide (Cytoxan®) IV, adjust dose to leukocyte count, 1g/m2methotrexate (Folex®) PO 7.5mg/wkmitoxantrone (Novantrone®) IV 12mg/m2 q 3mos for up to 2yrs; lifetime dose 140mg/m2Indication: progressing MSMechanism of action: interfere with cell reproduction; suppress T & B cell productionPregnancy Category D & XAzathioprine: half life 5 hrs- onset 4-8 wks hepatotoxicity if dose > 2.5mg/kg/dMethotrexate- peak in 1-2 h NSAIDS+ methotrexate toxicity; alkalinization of urine will help prevent renal toxicity (per uric acid nephropathy); ck for mouth ulcers; encourage fluids- 3000/d; photosensitivityMitoxzantrone: cummulative life-time dose 140mg/m2—blue-green color to urine and sclera; MUGA prior to tx, at 100mg/m2 dose; before each course following 100mg/m2
25 azathioprine (Immuran®) PO 2.5-3.0mg/kg/d Side effects: anorexia, nausea, vomiting, leukopeniaInteractions: 1) steroid conserving effect, allopurinol, live vaccinescyclophosphamide (Cytoxan®) IV, adjust dose to leukocyte count, 1g/m2Side effects: bone marrow suppression; hemorrhagic cystitisInteractions: cocaine toxicity, probenecidmethotrexate (Folex®) PO 7.5mg/wkSide effects: bone marrow suppression, diarrhea, stomatitisInteractions: alcohol or hepatotoxic drugs, acyclovir injection, NSAIDS, probenecid or salicylates, live vaccinemitoxantrone (Novantrone®) IV 12mg/m2 q 3mos for up to 2yrsSide effects: cardiotoxicity, severe myelosuppressionInteractions: live vaccine, probenecid & sulfinpyrazone, antithyroid agents, ganciclovir, AZT, azathioprine,Probenecid-gout uricosuric allopurinol also hyperueicemia (gout)
26 Drugs Affecting Fatigue CNS Stimulants modafinil (Provigil®) PO 200mg/dpemoline (Cylert®) PO 37.75mg/d titrated by to 112.5mg/dmethylphenidate (Ritalin®) PO 5-20mg/bid or tiddextroamphetamine (Dexadrine®) PO 5-60mg/tidCaffeine PO mg q4h max 1000mg/d; metabolizes to theophylline(60-180mg in a 5oz cup; Starbuck’s tall drip 12oz=240mg; solo espresso=89mg)Indications: narcolepsy and fatigue in MSMechanism of Action: stimulate cerebral cortex; antagonizes adenosine receptors; block reuptake of dopaminePregnancy Category C & B (pemoline)May produce psychological and physical dependence/tolerance
27 methylphenidate dextroamphetamine caffeine Side effects: heart arrhythmia, HTN, loss of appetite, nervousness, trouble sleeping; decreases convulsive thresholdInteractions: other CNS stimulants, MAO’s, pimozide (Tourette’s), antidepressants, guanethidine, cold & sinus & allergy meds, caffeine, appetite suppressant, bupropion, clonidine, asthma meds, cocainedextroamphetamineSide effects: irritability, restlessness, trouble sleeping, dry mouth, fast, pounding or irregular heartbeatInteractions: tricyclic antidepresants, beta blockers, CNS stimulants, amantadine, digitalis, MAO inhibiters, thyroid hormones, meperidine, cold, sinus & allergy meds, caffeine, asthma meds, cocainecaffeineSide effects: heart arrhythmias, incr. nervousness, GI irritation, withdrawal = irritability, headache, incr wknessInteractions: CNS stimulants, MAO inhibitorsAvoid amphetamines in persons c hypertension, cardiovascular drugs, undue restlessness, anxiety or agitationLook for sleep disturbance, weight loss, dry mouth, altered thought process—last dose of day 6hrs before bedtime.Withdrawl-taper off habit-forming potentialRitalin counterindicated in glaucoma, depression, motor tics, HTN take on empty stomach, min ac.Caffeine- most commonly used stimulant /7mill KG consummed/yr caffeine is metabolized to theophyilline
28 pemoline (beneficial effect at 3-4 wks) modafinilSide effects: dizziness, unclear thinking, blurred vision, anxiety, insomnia, nausea, headache, nervousnessInteractions: Same as for other CNS stimulants PLUS cyclosporine, diazepam, phenytoin, propranolol, theophylline, warfarin, tricyclic antidepressants, steroid contraceptivespemoline (beneficial effect at 3-4 wks)Side effects: Most common: anorexia, insomnia, weight loss; Less common: dizziness, daytime sedation, irritability, depression, nausea, rash abdominal pain. Rare: jaundiceInteractions: no significant drug interactions but r/o liver dz.; caffeineChewable form of pemoline MUST be chewed before swallowingAssociated with life threatening hepatic failureTwo FDA black box warnings (1996/1999)LFT’s at baseline and q 2wks throughout therapy.Written informed consent requiredCylert half-life of 12 hrs peak effect 3-4 wksPemoline, an agent used in ADHD treatment, has been associated with hepatotoxicity with the majority of cases occurring in pediatric patients. To our knowledge, this is the second reported case of pemoline-induced liver failure resulting in liver transplantation. The mechanism of action remains unclear, with several hypotheses being postulated including hypersensitivity reactions, dose-related phenomena, and autoimmune-mediated reactions. CONCLUSIONS: With increasing evidence linking pemoline to liver failure, this agent should not be considered first-line therapy for ADHD. Prior to initiating therapy, baseline liver function tests should be obtained and closely monitored, and parents and patients should be educated on the signs and symptoms of liver toxicity. Not available in Canada and UKMost liver failures were in children % incr risk of liver failure with pemoline21 cases of liver failureBC ineffective during modafinil use and for one month after use.
29 Drugs Affecting Fatigue amantadine (antiviral;dopamine agonist) 100mg tid POAction: releases dopamineSide effects: livedo reticularis, edema, anxiety, sleepiness, hallucinations4-aminopyridine and 2,3-aminopyridine30-40mg/d POAction: K+ channel blocker-not FDA approvedSide Effects: seizures, confusion, nausea, hepatitis, dizziness, paresthesias, insomniaSSRI antidepressants (negligible effect in clinical trials)Action: increase serotoninSide effects: agitation, insomnia, sexual dysfunction (anorgasmia), weight gain, dizziness, headache, nausea, loose stools, sleepiness, initial anorexia, tremor, weight loss then weight gain, nervousnessSafest in overdose=SSRI –drugs of choice, more effective and less potential SE -high instance of anorgasmia
30 Drugs Affecting Depression Selective serotonin reuptake Inhibitorsfluoxetine (Prozac®, Sarafem®) PO 20-80mg/10-20mgparoxetine (Paxil® and CR) PO 20-50mg/sertraline (Zoloft ®) PO mgcitalopram (Celexa ®) PO 20-60mgescitalopam (Lexapro ®) PO 10-20mgfluvaxamine (Luvox ®) mgIndications: mild to moderate depression, OCD, panic disorder, PMS, PTSD, anxiety, bulimia, pain, enuresis, stress incontinence, fatigueMechanism of action: Neurotransmitter effect, cell membrane stabilitySide Effects: nausea, insomnia, nervousness, headachePregnancy Category: B (buproprion, fluoxetine, sertraline);C (all others); D lithiumSSRI first choice – less SE 24h ½ life but prozac is a 7d ½ life-no joy in sex, but most significant SE= nausea, nervousness, insomnia (change in sleep patterns), headache 4-6 wks to see effectTaper off over 5 wks Zoloft- high doses required for effect; Paxil= most anticholinergic; Luvox= wkest efficacy, use in OC; Celexa- fewer interactionsSSRIincrease risk of GI bleed- 12 fold higher in combo with NSAIDSTherapeutic effect similar so selection made on SEProzac-depression, OCD, bulemia, panic, PMS,Paxil PTSD PMS, Panic, anxietyZoloft OCD, panic, PTSD, PMS
31 Norepinephrine and Serotonin Reuptake Inhibitors venlafaxine (Effexor ®, XR) PO mg; mgduloxetine (Cymbalta ®) PO 40-60mgSide Effects: same as SSRI, wt. loss, raises diastolic, > somnolenceTricyclicsamitriptyline (Elevil ®) PO mgdesipramine (Norpramin ®) PO mgimipramine (Tofranil ®) POnortriptyline (Pamelor ®) POdoxepin (Sinequan ®, Adapin ®) PO mgSide effects: Anticholinergic, sedation, insomnia, agitation, orthostatic hypotension, cardiac arrhythmia with TCA, GI distress, weight gain, sexual dysfunctionAll the above: caution in hepatic impairmentSeizures at doses > 600mg There is a shower of dopamine for nicotine, heroine, cocaine, sex and chocolate.½ life 9-12hProzac is a potent inhibitor of CYP 2D6 and 3A4SSRI safe, no anticholinergic effects; wellbutrin no weight gain, few anticholinergic SE rare hypotension or sexual dysfunctionAnticholinergic: dry mouth, mydriasis, cycloplegia, urinary retention, decreased GI motility, taccycardia, memory impairment, delerium (more in elderly). Pilocarpin eye drops for dry eyes- 5mg PO
32 Dopaminergic reuptake blocking agents (also serotonon & 5HT) buproprion (Wellbutrin ® and XL) PO mg / mg XLSide effects: agitation, rarely seizures, low incidence of sexual dysfunction or orthostatic hypotension, little sedation, anticholinergicContraindications: (antipsychotics and MAOI’s)thioridazine (Mellaril ®) and pimozide (orap ®)duloxetine contraindicated in uncontrolled narrow angle glaucomabuproprion contraindicated in seizure riskTCA’s and antithyroid drugsPotentially fatal interactions: antiarrhythmics (c TCA) and MAOI’sCTP2D6 inhibition: Potent: fluoxetine, paroxetine;Moderate: buproprion, citalopram, escitalopram, sertraline;Little or none: venlafaxine, duloxetine, TCA’s except desipramine may inhibitfluvoxamine potent inhibitor CYP 1A3, CYP 2C19, CYP3A4Caution in liver failure, elderly, adolescents, pts c cardiac dz.ETOH and CNS depressants can have additive effect on drowsyInhibit metabolism of TCA and lead to toxicity: cimetidine, OC
33 Mood stabilizing drugs lithium carbonate (Eskalith®, Lithobid JDS®)Interactions: diuretics, NSAIDS, ACE, ARBS, haloperidol, carbamazepine, calcium channel blocks, azoles, fluoxetine, antithyroid drugsAction: corrects overactive catecholamine state by inhibit of synapse releaseSide effects: hand tremor, thirst, incr urination, diarrhea, nausea, weight gainToxic: blurred vision, confusion, dizzinessdivalproex sodium (Depakote®)carbamazepine (Tegretol®)Lithium: catecholamines: seratonin, nor epinephrine and dopamine. Mania incr NA in cell by 200%- ½ life of 24h; peak 1-3 hrs; clinical response is reported in 1-3 wks. Exacerbated cardiovascular dz. Excreted unchanged by kidney Give after meals, increase fluid (3L) and sodium intake Lithium decreases sodium reabsorption from renal tubules with NA depletion---avoid coffee, tea, cola-excessive exercise, saunas, hot weather
34 Psuedobulbar Affect TCA’s SSRI’s dextromethorphan and quinidine (AVP-923)Indications: uninhibited brain stem response to emotional stumuli secondary to disruption of cortico-ponto-cerebellar pathways; painAction: quinidine inhibits the metabolism of dextromethorphan allowing more to roam in CNS and acting on NMDA receptors to decrease glutaminergic signalingSide effects: headache, dizziness, spasticityMay increase serotoninEmotional lability, emotional incontinence, pathological laughing and cryingEffects 10% c MS though
35 Drugs Affecting the Urinary Tract Urinary antimicrobialsSulfonamide: sulfamethoxazole and trimethoprin, DS (Septra ®, Bactrim ®) Side effects: anorexia, diarrhea, nausea, vomiting, rash, pruritus, headaches, dizzinessCephaloporins: cefixime (Suprex®), cefpodoxime (Vantin®) 3rd generation safest in pregnancy for UTIQuinolones: ciprofloxacin, XR (Cipro ®), levofloxacin (Leviquin®), oxfloxacin (Floxin®), trovafloxacin (Trovan®), norfloxacin (Noroxin®), Gatifloxacin (Tequin®), gemifloxacin (Factive®), moxifloxacin (Avelox®)Side effects: dizzy, drowsy, photosensitivity, rash, GI upset, headache, diarrhea, pruritis, candidiasisUsed for UTI or prophylactic use Most common use of antibiotics in MS; usually from gr neg bacilli (ecoli)Bacteriocidal or antimoicrobialpossible allergic rx; may potentiate anticoagulant, phenytoin, methotrexate, hypoglycemics (sulfa drugs)Antibiotics may reduce the effect of OTCAdvice to take full courseLook for pseudomembranous colitis (diarrhea)Possible fungal overgrowthMay have allergy to Sulfa drugsAvoid antacidsPossible GI side effects and rashAnitiseptics exert antibacterial activity on urine with no or little systemic effectAmoxacillin- broad spectrum may have GI upsetAcidic urine: avoid fruit juices, milk, dairy, antacids, eat > protein, cranberries, prunes, plums, blueberries, Vit CPhenazopyridine (Pyridium) –urinary tract analgesic-is used to relieve pain of UTI—causes redish urine-may stain soft contact lenses 2 day therapy with antibioticMacrodantin-urine may be rust-yellow or brownishBacteriostatic: TMP-SMX block dihydrofolic acidMethenamine acts by releasing formaldahyde in an acid environment- good for long term suppression b/c of wide bacterial spectrum, low toxicity and loe resistanceCephalosporins are r/t pnc-bacteriocidal. Prescribed for those allergic to PCN drug interactions c alcohol, anticoagulants, NSAIDS Give c food
36 Drugs Affecting Urinary Tract Urinary antisepticsmethenamine (Hiprex ®, Mandelamine®)-must have an acidic urine (pH<5.5)Do not use c drugs that alkalize urine e.g., antacids- serious interaction with certain sulfonamides (sulfamethizole, Thiosulfil Forte®)nitrofurantoin (Macrobid ® or Macrodantin ®)-take c foodSide effects: drowsiness, nausea, vomiting, rash, headache, pruritus, “brownish” urineUrinary analgesicsPhenazopyridine (Pyridium®)Analgesic and anesthetic effect on urinary mucosaUsed for pain and burning on urinationSide effects: GI distress, red urine may stain clothingpH- decrease antacids, milk products, citrus, -mor protein, cranberries, added vit C, prunes , plums, blueberriesSulfonomides precipitate with formaldehydes and form crystals in urine , avoid concommitant use; give 2h after azoles—potentiated by antimuscurinicsEffects depends on release of formaldahyde which requires an acid medium and formaldehyde is bacterocidl or bacterostatic—drug of choice in long term suppression of infection with low toxicity and low resistance
37 Drugs Affecting Bladder Indications: neurogenic bladder; urgency, frequency, incontinence; detruser muscle hyperreflexiaAction: anti-muscarinic/anticholinergic (block muscarinic effects of acetylcholine) receptor specific; antispasmodicSide effects: dry skin, eyes & mucous membranes; constipation or diarrhea; nausea; tachycardia; blurred vision; somnolence; headache Caution: narrow angle glaucomaoxybutynin (Ditropan, XL®) PO 5mg qid/5-30mg QDoxybutynin patch (Oxytrol®) 3.9mg/d twice wkly (low incidence SE)tolterodine (Detrol®, LA) PO 1-2mg bid; 2-4mg QD (LA best SE profile)darifenacin (Enablex®) PO mg QDsolifenacin (Vesicare®) PO 5-10mg QDtrospium (Sanctura®) PO 20mg bid-not metabolized; take on empty stomach; best SE profilePreganancy Category B (oxybutynin®); C all othersMuscarinic receptors are located in smooth muscle and effector organs of cholinergic receptor fibersThere are 5muscarinic receptors M3 is located in smooth muscle, salivary glands & eyeSLUD salivation, lacrimation, urination, defecationAnticholinergic hot as a hair; mad as a hatter, blind as a bat, dry as a bone (incr temp, mydiasis, decr sweat, dry mouth
38 Indication: Nocturia Anticholinergic/antispasmodics continued: hycoscyamine Sulfate (Levsin®, Levsinex/timed release®) PO mg qid ac/ mg bidpropantheline bromide (Pro-Banthine®) PO 15mg tidbaclofen (Lioresol®) PO 5-80mgAntidepressant TCA: (for anticholinergic effects)imipramine (Tofranil®) PO mg HSPregnancy Category: CIndication: Nocturiadesmopressin (DDAVP®/vasopressin®) PO mg; nasal spray 10micrograms/0.1ml/rhinal tube spray to 40ug Pregnancy Category BSide effects: rhinitis, nasal congestion, abdominal cramps, hyponatremiaAnticholinergics Mad as a hatter CNS (stimulant) delerium, restlessness, agitation-stupor; blind as a bat-Eyes, dilated pupils, decr. AccomodationDry as a bone- mucus membranes; skin hot as a hare
39 Urinary Hesitancy and Retention bethanecol (Urecholine®) PO 10-50mg qidAction: cholinergic, stimulates parasympathetic, muscurinic with selective action on detrusor and bowel smooth muscle. “SLUD”Side effects: bradycardia, hypotension, sweating, salivation, vomiting, diarrhea, intestinal crampstamsulosin (Flomax®) PO mg 1/2h after mealterazosin (Hytrin®) PO 1-5mg HSAction: alpha adenergic blockers: decr peripheral vascular resistance; bladder wall receptorsSide effects: hypotension, syncope, dizziness, somnolence, shortness of breath, stuffy nose, peripheral edema; caution with other alpha blocks, cimetidine, warfarin, other antihypertensivesPregnancy Category C all but tamsulosin: BCholinergic drugs act as mediatorsparasympathetic NSCholinergic blocking: anticholinergic-block action of parasympatheicCholinergic drugs: stimulate paristalsis, and incr urination; terminate curare effects; promote salivation and sweating; Tx myestheniaGive on empty stomach SLUD cholinergic: salivation, urination, lacrimation, diarrhea cholinergics incr peristalysis and urination, promote salivation and sweating, lower interoccular pressure- tx. Myesthenia and terminate curarization
40 Drugs Affecting Bowel Fecal urgency or incontinence imipramine (Tofranil®)propantheline (Pro-Banthine®)antidiarrheals (bulk forming; opioids, anticholinergics; antimicrobials)Agents for constipationDiet & lifestyle: fluids, fruit & vegetables, exerciseEmollients: docusate (colace®)Fiber and bulk producing agents: psyllium hydrophillic mucilloid (Metamucil®, Konsyl®); methylcellulose (Citrucel®)Intestinal lubricants: mineral oil (decr vit K to fetus)Hyperosmotic agents: MOM; Glycerin suppository; lactulose (Miralax®, Kristalose®); polyethylene glycol (Glycolax®, GoLytely®, Colyte®, NuLytley®)-caution in diabetesSaline laxatives: sodium biphosphate (Fleet enema®)Stimulants: peri-colace Bisacodyl®; senokot; castor oil; cascara (Sagrada®); tegaserod (Zelnorm®)5HT receptor antagonist- PO 2-6mg bid (diarrhea, abd. cramps)Pregnancy: unlabeled or B/CConstipation: hard stools, sensation of incomplete evacuation, obstruction, straining and manual evacuation or less than 3 defacations/wkSE: nausea, abdominal bloating, cramping, flatulence—diarrhea and frequency—possible urticaria r/t allergic rxContraindicated in bowel obstructionElectrolyte imbalanceTegaserod: liver, renal , gallbladder precautionsLactulose- acids that produce an incr in fluid accumulation, distention, peristalsis, and BM SE: flatulance, cramping, belching, gas—excessive doses= diarrhea and nauseaDecreased effect c antibioticsFiber and bulk laxatives decrease effect of tetracycline, anticoagulants, digitalis, and salicylatesSaline and osmotics interact c magnesium antacids and tetracyclineDo not dose stimulants with dairy or antacidsLubricants interfere c absorption of OC, digitalis, antibiotics, anticoagulants, fat soluble vitaminsMineral oil decreases vit K-bleeding problemsSaline laxatives: retain and increase water content of feces cramping, watery stool-occurs in ½ to 3hours- laxative of choice for specimen; fecal impaction; food poisoningStimulants increase peristalysis by irritating intramural nerve plexi by contact irritation- Tx effect 1-12 hrsBulk- increase water and volume—if fluid intake is not substantial they may increase impactionLubricants; mechanicalEmollients act as dispesing or wetting agents, facilitate mix of fat and water—no side effects or interactions- safest irritates-15min to 1hMedications with anticholinergic activity, aluminum containing antacids, iron supplements, calcium channel blockers, opioids, and others frequently cause constipation.You'll see a new prescription laxative called Miralax. It's just powdered polyethylene glycol (PEG)...an osmotic agent that causes water to be retained in the colon. It's the same as the PEG in GoLytely and Colyte. Some physicians already prescribe small doses of Colyte or GoLytely "off-label" for chronic constipation...but these products also contain electrolytes that make them taste salty and bitter. Miralax has no taste...because it doesn't have electrolytes. The usual dose is 17 g/day...about one heaping tablespoonful in 8 ounces of water. Tell patients it takes 2 to 4 days to work. Be careful...Miralax sounds and looks a lot like the Parkinson's drug, Mirapex (pramipexole).
41 Drugs Affecting BowelSide effects: flatulence, cramping, belching, gas; excessive doses may cause diarrhea and nauseaDecrease the effect of: antibiotics especially tetracycline, anticoagulants, digitalis, fat soluble vitamins, oral contraceptives and salicylatesDo not dose stimulant laxatives with antacids or dairy
42 Drugs Affecting Sexuality Indication: erectile dysfunctionAction: PDE-5 inhibitors increase concentration of NO allowing cGMP which mediates erectile response and enhanced blood flow to penis and clitoris-onset: 30minsildenafil citrate (Viagra®) PO mg (18h ½ life)tadalafil (Cialis®) PO 5-20mgvardenafil (Levitra®) PO mgSide effects: sudden vision loss; hypotension, headache, facial flushing, GI, dyspepsia, nasal congestion, blue-green visual aura (sildenafil), tachycardia, priapism (erections > 4h risk damage)Contraindication: nitrates, concomitant alpha blocker, ETOHCaution: cardiovascular dz; recent MI, bleeding disorder, hepatic impairmentPotent CYP3A inhibitors: azoles, grapefruit juice, erythromycin, protease inhibitorsPregnancy Category BPhosphodiesterase inhibitors-block enzyme. Allow cyclic guanasine monophosphate Maximum effect-1hTitrate dosesA-blockers except TamsulosinCialis will be promoted for its long duration of action. One dose lasts up to 36 hours...compared to 4 hours with Viagra. This is both an advantage and disadvantage. The advantage is convenience. Patients take Cialis at least a half hour before sex and don't have to take it again for 36 hours. A disadvantage is that side effects might last longer... headache, dyspepsia, muscle aches, and facial flushing. Drug interactions might also be more of a problem due to the long half-life. Cialis is metabolized by CYP3A4 enzymes. Caution patients against using the full 20 mg dose if they are taking any of the potent 3A4 inhibitors...erythromycin, ritonavir, ketoconazole, or itraconazole. If a man on Cialis needs an alpha-blocker, select Flomax (tamsulosin) 0.4 mg/day. Don't combine Cialis with the others...Uroxatral...doxazosin...terazosin...prazosin. These increase the risk of postural hypotension and dizziness. Cialis is like Viagra when it comes to the interaction with nitrates. Make sure people don't take Cialis with a nitrate. No legitimate generics for viagraCialis and levitra more PDE5 specific and may not cause blue visionCialis 24-36h duration
43 Intracavernosal injection and intraurethral insertion Action: vasodilator; relaxation of smooth muscle to allow for engorgement and trappingalprostadil,prostaglandin E, (Prostin VR®, Caverject®)IC 5-40/80ug reconstitutealprostadil (Muse®) pellet, IU ugpapaverine (Pavabid®) IC 30-60/80mgphentolamine/regitine 0.5-1mg-used in combination with the aboveSide effects: priapism, injection site bleeding, dizziness, fibrosis, burning, difficulty ejaculating, tingling of glans, aching during injectionContraindications: sickle cell, Peyronie’s dz.Caution: anticoagulantsAutoinjector available; apply pressure 3-5min to injection sitePregnancy Category C: MUSE®Papaverine active in body longer-self exam for possible scarring- possible penile deformity and loss of erection potential pain free, > risk of priapism, scarring)Wait 24h between dosingRefrigerate Alprostadil Injection USP. Keep the medicine from freezing.Alprostadil for Injection while in the powder form can be stored at room temperature (between 15 and 25 °C or 59 and 77 °F) for 3 months. After it is mixed, the solution must be used immediately.Refrigerate alprostadil suppositories. Keep from freezing. They may be stored at room temperature for 14 days. Use a condom with MUSE when having intercourse with pregnant woman
44 Indication: Nonconventional ED and libido enhancement yohimbine PO 5.4mg tid: vasodilator/aphrodisiac;Side effects: anxiety, nervousness, hypertension, headache, tremor, flushing, dizziness, GI, tachycardiaContraindication: psychiatric pts, renal & hepatic dz., ulcerInteraction: TCA, SSRI, tyramines, CNS stimulants, caffeineapomorphine (Uprima®):dopamine agonist, central mediation, incr NO; morphine derivative2-4mg sublingual, allow to dissolve, do not repeat for 8hsSide effects: nausea, hypotension, syncope, flushing, dizziness, yawning, sweating, somnolenceL-Arginine (VasoRect®, AginMax®): amino acid dietary supplement, incr. NO; PO 5G/d (given tid)Side effects: mild hypotention; no systemic effectsAvoid alcohol; caution in cardiac disease
45 Drugs Affecting Spasticity Muscle Relaxantsbaclofen (Lioresal®): 20-80mg/d up to 240mg/d PObaclofen pump ug/d intrathecallyAction: GABA analog, down regulates Ca+ influx; decreases muscle response to tonic stretch & decreases clonus & spasmsSide effects: drowsiness, nausea, ataxia, dizziness, confusion; possible hepatic dysfunction; avoid alcohol and CNS depressantstizanidine (Zanaflex®): 4-32mg divided doses PO; slow titrationAction: alpha 2-adrenergic agonist with decr. excitatory transmitter releaseSide effects: somnolence, dry mouth, bradycardia, hypotension, hepatotoxicity; avoid alcohol, CNS depressants, diazepam, alpha 2 agonists, potentiated by OC & anti-HTNdantrolene sodium (Dantrium®): mg bid POAction: decreases Ca+ flux, uncoupling depolarizationSide effects: significant weakness and drowsiness; hepatotoxicity (monitor LFT); estrogen incr. risk of hepatotoxicity; avoid verapamil, CNS depressantsFrequent dosing of tizanadine b/c short half life No weakness with tizanadine
46 Agents of Spasticity diazepam (Valium®): 2-10mg qid PO Action: inhibits glutamate and aspartate, therefore inhibits spinal motoneuron activitySide effects: drowsiness, weakness, CNS depression, ataxia, memory impairment; avoid ETOH, CNS depressants, incr. cimetidine, potentiates sertralineclonazepam (Klonapin®) 0.5mg tid POAction: Same as aboveSide effects: same as above with hypersalivation, GI upset, liver disordersAntagonize CYP450 inducers e.g. phenytoin, carbamazepine, phenobarbitol; caution c azoles & antifungalsValium SE limits use- works in high doses only do not use innarrow-angle glaucomaAvoid abrupt cessation
47 Agents of Spasticity clonidine (Catapres®) 0.1mg tid PO & transdermal Action: central alpha 2 adrenergic blockSide effects: dry mouth, drowsiness, dizziness, weakness, constipation, rash, impotence, orthostatic hypotension; antagonized by TCA, potentiates CNS depressantsgabapentin (Neurontin®) mg tidbotulinum toxin A (Botox®)(BTX®) 400U IMAction: inhibit release of acetylcholine at neuromuscular junction-reduces spasticity and preserves function via targeted muscle grps. >effect at 3-4wks; lasts 3monthsSide effects: pain on injection, fever
48 Drugs for Nociceptive Pain salicylate (Aspirin®) PO 1600mg bid maxacetaminophen (Tylenol®) PO up to 2- 4g/d (toxic at 5-8g/d)NSAIDs: indomethacin (Indocin®), ibuprofen (Motrin®, Nuprin, Advil®), naproxen (Aleve®, Naprosyn®), diclofenac (Voltaren®), sulindac (Clinoril®), oiroxicam (Feldene®), ketoprofen (Oruvail®), nabumetone (Relafen®) peripheral prostaglandin antagonismAction: inhibit production of prostaglandin which protect the lining of the stomach, ensure adequate renal function, maintain balance in CNS so NSAIDs can cause GI irritation and bleeding, renal insufficiency, edema, hypertension, and CNS imbalanceSide effects: GI bleed, peptic ulcer, nephritis, peripheral edema, headache, dizziness, constipation, rash, fluid retentionContraindicated: renal dz, bleeding disorders, hypersensitivity (allergy to ASA, nasal polyps, asthma)Action: arachidonic acid –formation of prostaglandinProstaglandin is a hormone-like unsaturated fatty acid that acts on target organs affecting vasomotor ton, capillary permeability, platlett aggragation, endocrine fx and autonomic NS and CNSNSAIDS enter cell and attach to cyclooxygenase enzymes (COX) these then cannot act c fatty acids to produce prostaglandins. COX1 and COX2NSAIDS weak acids allowing them to crossinto tissue and inflammatory sitesHighly protein bound so interact c other protein bound drugs such as warfarin care in decreased kidney fx.Severe reactions: CHF due to salt and water retentionProstaglandins enhance mucus and bicarb production >30% experience GI sxMonitor periodically for GI bleed- stool guiac; Hb, HCT; LFT; kidney fx tests; weight changesTake with food; do not recline after taking; report fluid retentionTylenol is central prostaglandin inhibitionExtensive hepatic metabolism
49 Selective NSAIDSmisoprostol (Cytotec®) is a synthetic prostaglandin to protect GI (SE: diarrhea) PO biddiclofenac + misoprostol (Arthrotec®)H2 blockers and proton pump inhibitorsCOX 2 inhibitor selective agents: celecoxib (Celebrex®), rofecoxib (Vioxx®)*, valdecoxib (Bextra®)*Side effects: CVD, edema, GI, incr LFTCaution: CYP2C9/2D6;HTN, DM, PVD, smoking, hyperlipidemia, CVDContraindicated: stroke, ischemic heart dz., CABGPregnancy Category: B (acetaminophen, ketoprofen, naproxen, flurbiprofen, diclofenac, diflunisal; C (the rest);D (salicylates); X misoprostolFDA removed from marketCyclo-oxiginase enzymes=selective
50 Drugs For Neuropathic Pain Topical agentsOral agentsMembrane stabilizing:AntiepilepticsAntiarrhythmicCorticosteroidsDorsal horn inhibition:AntidepressantsGaba agonists-BaclofenNMDA antagonists:KetamineDextromethorphanMethadoneOpioidsIntrathecal agentsChemicals act to change the receptor threshold histamine, serotonin, bradykinin are released whrn tissues are injured. Prostaglandins, leukotrienes, & leukotrienes and thriomboxanes stimulated.
51 Topical Agents capsaicin (Zostrix®): 0.075% 4X/d SE: burning, sneezing, coughingTransdermals:fentanyl (Duragesic®), buprenorphinelidocaine/prilocaine (EMLA®)lidocaine patch 5%aspirin creamclonidine gel (0.05% qid)Mild to moderate pain- messy- takes patience and desire—use gloves. Lidocaine may cause skin irritation. No systemic effects- safe-may use up to 3 patches at one time max dose 3 patches/d for 2 wks at 12hrs
52 TCA’s and SNRI Mainstay treatment of painful neuropathies Act to inhibit reuptake of serotonin and norepinephrineimipramine (Tofranil®)PO 200mg QD max,amitriptyline (Elevil®), PO 150mg QD maxnortriptyline (Pamelor®) PO 150mg QD maxdesiprimine (Norpramin®) PO to 200mg QD maxSE: sedation, hypotension, seizures,dry mouth, weight gainduloxetine (Cymbalta®) PO 120mg maxvenlafaxine (Effexor®) PO 375mg QD max doseSE: nausea, dizziness, sedation, constipation, dry mouthOften used for burning pain. Duloxetine: 60mg QD; Effexor: 37.5mg QD incr 37.5 wkly to 375QD; Desipramine: 25mg HS incr by 25mg wkly to 200mgQD; Elevil and Pamelor: 10mg HS, incr by 10mg QD to 150mgQD
53 Antiepileptics (AED’s) Trousseau coined “neuralgic epilepsy” in 1853phenytoin used to tx. pain in early 40’scarbamazepine used for pain in 1960Action: block sodium channels and nerve membrane stabilizing agentsSide effects: sedation,nausea,vertigo, dizziness, rash, fatigue, diplopia, liver toxicity, interfere c cognitive fx (side effects minimized with long acting formulas)Trousseau thought that the episodic spasms of pain he saw in pts with trigeminal neuralgia were thought to be changes on the trigeminal nerve and they looked like epilepsy block NA channels and block the repetitive firing of the nerve
54 Antiepileptic Drugscarbamazepine (Tegretol®, XR)-assoc c neural tube defects Preg Cat: Dphenytoin (Dilantin®)-hirsutism, gingival hyperplasia, constipationvalproic Acid (Depakene®) Preg Cat.: D tremor; wt. gainclonazepam (Klonopin®) Preg Cat: D anticholinergicNewer antiepileptic drugs are better tolerated, have fewer drug interactionsand less affect on cognitive functiongabapentin (Neurontin®) 900 titrated to 3600mg tid 1/1000 suicidetiagabine (Gabitril®) up to 56mg/d in 2-4 divided doseslamotrigine (Lamictal®)-rash in 10%-hypersensitivity rxtopiramate (Topamax®) wt. loss; incr. fluidsoxcarbazepine (Carbatrol,Trileptal®), XR) Preg Cat: Dpregabalin (Lyrica®)100mg tid(2-10X more potent than neurontin)felbamate (Felbatol®), aplastic anemia, acute hepatic failure, cardiotoxiclevetiracetam (Keppra®)zonisamide and vigabatrin less cognitive impact, hypersensitivityvigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin)Tegretrol depresses circulating thyroid hormones also taper dose and try discontinue at 3 mo intervals- up to 800mg dailyGabapentin- not metabolized, does not induce or inhibit enzymes-Se are mild and transient --eliminated by kidneyRaise seizure threshold, have an inhibitory effect on GABA binding and inhibit glutamate transmitter releaseVigabatrin: synthetic derivative of GABA and inhibits GABA-aminotransferase-prevenyts GABA brkdown and incr. functional pool of GABALyrica- son of gabapentin-lower doses=fewer SE schedule V b/c makes people feel high, like high dose valium—reports of withdrawl so don’t stop abruptly- headache, nausea…
56 The sodium channel modulators work on peripheral sensitization In neuropathic pain it is best to use polypharmacy---a lower dose of the drug from two or three different categories--with better efficacy and fewer AR
57 Non-Narcotic and Narcotic Opioids Cannabis: dronabinol (Marinol®) PO 10mg; Sativex® (mouth spray)Dizziness, tiredness,weaknesstramadol (Ultram®) Tramadol/acetaminophen (Ultracet®)weak agonist at opioid receptors; inhibits NE & 5HT reuptake with 30% of activity of morphine-no withdrawl effectsSE: lowers seizure threshold; tiredness, dizziness, constipation, sedation, headache- habit formingOpioid Agonists:Pregnancy Category C: morphine (Avinza®, Kadian®, MS Contin®, MSIR®), codeine, fentanyl (Duragesic®) hydrocodone, hydromorphone (Dilaudid®, Palladone®)Pregnancy Category B: meperidine (Demerol®), methadone (Dolophine®) , levorphanol, oxycodone, oxymorphone, propoxyphene (Darvon®)methadone is a NMDA receptor agonistIntrathecal pump (baclofen with morphine)Opiats are derived from opium both natural and synthetic4 receptors (MU, Kappa, Sigma, Delta-analgesia associated c Mu and Kappa- repiratory depression mediated through MUThose c codeine allergy will have allergy to ultramOpioid agonist: affinity for receptors- act centrally in CNS and peripheral in gut as antidiarrheal and supresses cough reflexMorphine elicits > histamine release. The present results are in accord with experimental studies indicating that neuropathic pain is poorly responsive but not totally unresponsive to opioids. The results do not support the routine use of strong opioids in MS patients with CPPumps- risk of electrical or medhanical failure; infection, fibrosis, extrusion; neurotoxicity; sedation, constipation; hypotentionPatients are asking about Sativex, a new cannabis extract for neuropathic pain caused by multiple sclerosis. It's just been approved in Canada...but not in the U.S. Sativex contains delta-9-tetrahydrocannabinol (THC)... similar to Marinol (dronabinol) and marijuana. It's also being studied for rheumatoid arthritis...pain...and spinal cord injury. Sativex is a mouth spray. It has a fast onset like inhaled marijuana...but without the tars and other contaminants. Marinol's unpredictable absorption makes it harder to use. Warn patients that the DEA considers Sativex a Schedule I drug, so even personal importation into the U.S. is illegal.
59 Dietary Supplements Vitamins Vitamins: organic compounds that help maintain normal metabolic function, growth and tissue repair.A balanced diet is best but supplemental therapy is essential during periods of nutritional challenge (rapid growth, pregnancy, lactation, illness)Vit K formed by bacteria in gutVit D produced by exposure to sunlightFat-soluble: A, D, E, KWater-soluble: B complex group and CAntioxidant vitamins A, C, E may have effect in MSPregnancy Category: A (thiamine B1, folic acid B9, pyridoxine B6); C (vit. D, cyanocobalamin B12, ascorbic acid C); X (vit. A)Unclassified: niacin B3, riboflavin B2, vit. K, vit. ESteroid useDecrease levels of free radicals which may be a factor in myelin and nerve damage—antioxidants stimulate immune system- and this could be harmfulTop botanical sales: echinacea, garlic, ginko, Coenzyme Q10; saw palmetto, ginseng, black cohash, soy, glucosamine, st johns wort, calcium, valerian
60 Vitamin K no known relevance to MS Vitamin A/ Beta-Carotene: antioxidant, immunological effects (more studies needed in MS)Contraindications: liver dz, osteoporosis, angioplasty, male smokers, asbestos workers; lg doses (10,000IU) toxicInteractions: minocycline, HMG-CoA reductase inhibitors and OCVitamin D: hormone and vitamin-important in bone loss; mildly immunosuppressive; >1000mmg/d=liver injuryContraindications: hypercalcemia, sarcoidosis, hypoparathyroisism, renal dzInteractions: cardiac glycosidesVitamin E anti-oxidant, suggested as MS tx.-no adverse effect from one small study-suggest dietary sources; With PUFA diets use E to replace lossesContraindications: angioplasty, retinitis pigmentosa, K deficiencyInteractions: anticoagulants and antiplateletsVitamin K no known relevance to MSInteractions: coumadinVit D proinflammatory cytokines 15min of sunlight for doseVit E free radical-induced oxidative injury destroys myelin-on the other hand may antagonize DMA
61 B1/Thiamine: possible to tx. fatigue in MS- B2/Riboflavin: may be effective for migraine; no application for MSB3/Niacin: used as antilipidemic; no application in MSB6/Pyridoxine: deficiencies and excess may cause polyneuropathy; no application in MS and may decrease effectiveness of DMA-nerve injury at >50mg/dB9/Folic Acid: may be decreased in serum of MS pts. May decr. toxicity of methotrexateContraindications: may mask Vit B12 deficiency; possible worsening of seizure disorder and schizophreniaInteractions: decreases serum levels of phenytoin, mysoline, and phenobarbitalSupplements have twice the bioavailability of dietAntioxidants stimulate t cells and macrophages but also reduce free-radical induced oxidative injury but could antagonize effect of immunomodulating and immunosuppressive agents400mcg/d in young woment to protect neural tube development
62 B12/Cyanocobalamin: no evidence for use in MS unless deficient Contraindications: Leper’s hereditary optic neuropathyInteraction: folic acid may mask deficiencyC/Ascorbic Acid: possible UTI prophylaxis and decrease duration of common cold (viral infections precipitate exacerbation); acidify urine; antioxidant good and bad-best to obtain antioxidant compounds through diet>1000mg/d may produce diarrhea and kidney stonesContraindications: angioplasty; Hx. kidney stonesInteraction: anticoagulants
63 MineralsCalcium: nerve conduction, muscle contraction, blood clotting, treat osteoporosis; mild immunosuppressive -further clinical trials needed; Dose mg divided dosesAs citrate(Citracal, Solgar): on empty stomachAs carbonate (TUMS, Caltrate): need acid to absorb, take c food;lactategluconateContraindications: hypothyroidism, hyperphosphatemia, renal insufficiency, sarcoidosis; risk kidney stonesInteractions: thiazide diureticsabsorption: biphosphonates, fluoroquinolones, levothyroxine, tetracycline, iron, zinc, magnesium, tannins, laxatives, fiber, phytates and oxaltic acid bind calcium in foods e.g., spinach, cocoa, kale, soybeansHIV decr survival study of calcium= attack rate decreasedTake calcium several times a day adequate D promotes calcium absorption—bedridden develop a negative calcium balance-ca lost from bones and excreted—take with meals =acidSteroids and anticonvulsants damaging to boneCitrate- best absorbed least SE; carbonate- most common take c meals-carbonate highest elemental ca
64 Iron: needed for tissue respiration; most common nutritional deficiency; absorption increased if taken c Vitamin C; coffee, tea, milk, eggs, whole grain breads and cereals, calcium decrease absorption; ferrous forms absorbed better than ferric forms.Magnesium: (constipation, migraine, tetanus associated spasms) decreases MS spasticity in one case studyZinc: stimulates immune function and may increase severity of dz.; Zinc gluconate lozenges decrease the severity of the common cold; involved in metabolism of PUFAs; avoid or limit in MS to low doses (10-15mg)Contraindications: HIV, hemochromatosisInteractions: diuretics, tetracycline, fluoroquinolonesSelenium: antioxidant effect; may prevent certain forms of cancer-suggest small doses 50mcg or <
65 Dietary Supplements Polyunsaturated Fatty Acids (PUFA) PUFA: omega-3 (alpha linoleic acid, ALA & eicosapentaenoic acid, EPA) and omega-6 (linoleic acid, LA & gamma-linoleic acid, GLA):Immunmodulatory effect; mortality effectLA found in sunflower oil, soybean oil, corn oil, walnut oil, wheat germ oil, grape seed oil, & safflower oilPO17-23gContraindications: allergy to daisy plant familyGLA found in primrose oil, blackcurrent seed oil, barage seed oil, & spirulinaPO mg/dContraindications: incr risk of seizures, prolongs bleeding timeInteractions: phenothiazines and other epileptogenic medications, anticonvulsants, anticoagulants and antiplatletsTake vitamin E to prevent Vit. E deficiency5 trials c post hoc results of significant effect on decreasing relapse severity and dz progression
66 ALA found in flaxseed oil, canola oil, walnut oil PO mg/d; IV mg/dContraindications: diabetes, bleeding disordersInteractions: oral hypoglycemics, insulin, anticoagulantsEPA & DHA found in fish oils, (salmon, Atlantic herring and mackerel, bluefin tuna, sardines & cod liver)Dose < 3g combined EPA & DHA/dVitamin E supplementation necessaryDiet concerns with mercury contaminantsContraindications: bleeding disorders, diabetes, aspirin sensitivity, bipolar, depressionInteractions:anticoagulants, oral hypoglycemic and insulin, antihypertensivesPregnancy category: not enough informationFlaxseed- 15-ml oil for constipation
67 Dietary Supplements Herbal used in MS cranberry tablets: UTI prophylaxsispsyllium: constipationValerian: insomniaSt. John’s Wort: mild depression; two large clinical trial showed no effect for moderate and severe depressionInteractions: indinavir, cyclosporine; may interfere with the effectiveness of OC, medications for heart dz, seizures and cancer
68 Herbals that may worsen MS Alfalfa, astragalus, echinacea, garlic, Asian ginseng: immune-stimulatingFatigue is worsened by: chamomile, Asian & Siberian ginseng, barberrySteroid side effects worsened by: aloe, bayberry, Asian ginseng, licoriceHormones melatonin and DHEA activate the immune systemHerbs recommended with serious side effects (no proven worth)yohimbe, chaparral, comfrey, lobeliaChaparral-creosote bush; irreversible hepatotoxicity; comfrey: hepatocarcinogen, hepatotoxic; lobelia: tachycardia, seizure, death, coma, hypotension; yohimbe-aphrodisiac, ED hypotention, cardiac conduction disorder, death
69 Case study: Maggie, 36yo c 5y HX of RRMS treated for UTI and exacerbation Current Medications:INFß1a (132ug/wk)carbamazepine 600mgmodafinil 400mgamitriptyline HS 75mgbaclofen 60mgtolterodine 4mgsertraline 150mgdepo-provera 150mg q 3mosciprofloxacin 500mg for 3 dSt. John’s Wort 900mg,Vit A 5000IU, Vit C 1500mg, Vit D 800mg, Omega-3 3G,Senokot 17.2mg,methyprednisilone 1G over 5d
70 Recent labs: AST 180U/L; ALT 175 U/L; LDH 900 U/L; leukocytes 7 Recent labs: AST 180U/L; ALT 175 U/L; LDH 900 U/L; leukocytes 7.4, Hgb 12.0, Hct 40; leukocyte count 9.9; U/A: leukocytes: 10 10; SG: 1.028; bacteria: escherichia coli, and candida albicansMaggie continues to c/o of lower extremity pain described as continuous “pins and needles”, VAS=4; urinary urgency, frequency, incontinence controlled; Ashworth scale=3; reports mild depression; constipation, MFIS=20,dizziness, rash on upper chest and faceEvaluate riskWhat is your assessment?How would you manage?
71 How would you treat? The disease The symptoms Advice on supplements BladderFatigueDepressionSpasticityPainAdvice on supplementsAdvice on birth controlBaclofen change to tizanidine??
72 ReferencesAbruzzo, J., Goildzieher, J., Masi, A., et al., (eds.) (Summer 2005). Nurse Practitioners’ Prescribing Reference. New York: Prescribing Reference, Inc.Bashir, K., & Whitaker, J., (2002). Handbook of Multiple Sclerosis. New York: Lippincott, Williams & Wilkins.Beydoun, A. (2001). Symptomatic treatment of neuropathic pain: a focus on the role of anticonvulsants. Medscape CME Circle Lecture. Retrieved on October 9, 2005 fromBowling, A. The National Multiple Sclerosis Society. Clinical bulletin. Information for health professionals retrieved on July 20, 2005 fromBowling, A., & Stewart, T. (2004).Dietary supplements and multiple sclerosis. A health professional guide. New York: Demos.Halper, J. (ed). (2001). Advanced concepts in multiple sclerosis nursing care. New York: Demos.Jellin, J., Prescriber’s Letter retrieved on July 25, 2005fromKalb, R. editor(2004). Multiple Sclerosis. The questions you have. The answers you need (3rd ed.). New York: Demos.Maloni, H. (2000). Pain in multiple sclerosis, an overview of its nature and management. Journal of Neuroscience Nursing, 32(3),Mckenry, L., & Salerno, E. (1998). Pharmacology in Nursing (20th ed.). St. Louis: Mosby.MedlinePlus, Drug information retrieved on July 20, 2005 fromMunoz, C. & Hilgenberg, C. (2005). Ethnopharmacology. American Journal of Nursing, 105(8),The Worldwide Physiologist: Cytochrome P450 retrieved on July 18, 2005 from