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Pharmacology in MS Advanced Practice Management

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1 Pharmacology in MS Advanced Practice Management
Heidi Maloni APRN, BC

2 Objectives Discuss basic principles of pharmacology, pharmacokinetics and pharmacodynamics. Describe the pharmacotherapeutics of drugs used in MS Identify 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 excretion Pharmacodynamics: the study of the biochemical physiological effects of drugs or mechanism of action and interaction Pharmacotherapeutics 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 system Each drug is identified by 3 names: chemical, generic, trade or marketing name N-4-(hydroxyphenyl) acetamide; acetaminophen; Tylenol sodium hypochlorite; bleach; Clorox 4-(diethylamino)-2-butynl ester hydrochloride; oxybutynin chloride; Ditropan Drugs are derived from: plants, humans, animals, minerals, and chemical substances Drugs are classified by clinical indication or body system A 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 structure Generic: 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 books Trade name: proprietary (patented) name of med Plant= 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 Role Safe drug administration Nurses are professionally, legally, morally, and personally responsible for every dose of medication they prescribe or administer Know the usual dose Know usual route of administration Know significant side effects Know major drug interactions Know major contraindication Use the nursing process References for knowing: American Hospital Formulary Service Drug Information; USPDI; PDR; F&C;

5 Pregnancy Safety Teratogenicity: 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, erythromycin Blactams= penecillins cephalopsorins Anticonvulsants are folic acid antagonists

7 History: A summary of major drug discoveries
Opium tincture, coca, and ipecac Digitalis Smallpox vaccine Morphine Quinine, atropine, codeine Ether and chloroform Insulin Phenytoin Cortisone Polio vaccines Carbamazepine Oral contraceptives Antivirals immunomodulators 17th century 1785 1796 1815 19th century 1840’s 1922 1940’s Mid-1940’s 1955 and 1961 1960 Late 1950’s Mid-1970’s 1990’s

8 Phases Affecting Drug Activity Mechanisms of Drug Action
Dose Disintegration of dose absorption drug receptor From dissolution of drug distribution interaction metabolism elimination Effect 1.Pharmaceutical Pharmacokinetic Pharmacodynamic Phase Phase Phase Pharmacokinetic: the alteration of a drug concentration at target site by a second drug Pharmacodynamics: reduction or enhancement of the effect of a drug by another withour altering its concentration at the site of action

9 Pharmacokinetics 1. Absorption : route, dose, dosage form, and bioavailability cell membrane, blood flow, nature of the drug 2. Distribution via circulation plasma protein binding: expressed as a degree, very high to very low with. Binding site competition: consequences for toxicity and drug interaction tissue binding: fat (cumulative effect), bone barriers (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 soluble Ionized (polar) is water soluble and does not easily diffuse through cell membrane Nature of drug: liquids, elixers, syrubs more readily absorbed than enteric coated Passive transport: diffusion from area of higher concentration to area of lower concentration until equilibrium Active transport: go against the concentration gradient Bioavailability-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 standards Absorption influenced by route Drugs only modify existing body fx Rate of absorption influenced by : cell membrane (single cell layer is faster-intestine) than several layers (skin) and surface area Blood flow influences absoption-sublingual is fast-sub cue is slow; IV vs IM Nature=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 stomach Route: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, elimination Absorption: cell membrane of proteins and lipids; ionized or water soluble drugs have difficulty crossing cell membrane Cell membrane can have lg surface area, active or passive transport Rich blood flow to absorption site enhances absorption Nature= 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 tissues Biotransformation: chemical inactivation by conversion to a more water soluble compound for excretion Distribution influenced by ionization, by cardiac output, regional blood flow—most drugs go to organs c rich blood supply-heart liver kidney brain Drugs 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 concentration BBB- distributes lipid soluble drugs. Drugs easily transported across placenta: steroids, antibiotics, narcotics, anesthetics

10 Pharmacokinetics Metabolism or biotransformation, primarily liver to increase water solubility Delayed metabolism (excessive or prolonged response) Stimulated metabolism (tolerance) Hepatic first-pass-give > dose or parenterally Biological half-life Elimination: kidneys, lungs, intestines, sweat, salivary and mammary glands Lipid soluble drugs are not excreted Altering urine pH can encourage elimination Biotransformation or metabolism chemically inactivates the drug- or makes it water soluble Chemical alterations are produced by microsomal enzyme system—to incr. polarity drugs become oxidized, hydrolyzed, reduced Microsomal enzyme systems can be depressed by hepatic fx-starvation, obstructive jaundice—liver, kidney heart dz prolong or decrease metabolism Tolerance: stimulated metabolism results in tolerance- substances that incr activity : CNS depressants, pecticides, food preservatives, dyes, xanthines---repeated administration stimulated 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 parenterally Excretion: lipid soluble not excreted; alkalize urine to excrete acid drug with sodium bicarb—acidify c vit C to excrete base drugs Alcohol partially excreted by lungs Breast 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 receptor Pharmacodynamics=mechanism of drug action on living tissue Antagonism: one drug blocks or reverses the therapeutic effect of another drug Antagonism can be harmful when therapeutic benefit is reduced by presence of another drug eg beta blockers reduce benefit of beta agonist used in asthma Synergism is the effect of 2 drugs is additive Study 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 action Lock and key= model –drug molecule fits into the receptor Affinity= propensity of a drug to bind or attach itself to a given receptor Agonist= drug that has affinity for or stimulates physiological activity at cell receptors normally stimulated by naturally occurring substances Antagonist= drug designed to inhibit or counteract the effects by other drugs or undesired physiological effects caused by illness may be competitive and noncompetitive Drug enzyme interaction= interaction between drug and cellular enzyme to alter the physiological response Nonspecific= 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., methotrexate drug antagonist

12 Drug Response An enhanced or diminished effect of one drug when used with another Summation: 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 index Biologic ½ life Drug 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 agent Summation=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 SE Synergism= combined effect greater than sum of individual agent alone Potentiation+ one drug increases the effect of the other Combined effect is greater than the sum of each individual agent independently One drug increase the effect of another drug- one drug inhibits the clearance of another Onset: rapid- effect within 24 hrs; delayed will not be evident until the interacting drug is administered for days or weeks Plasma level is r/t of drug in serum and drug in tissue—onset of action, peak action, duration of action termionation ½ 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 on In hepatic dysfunction or renal disorders drug elimination may be prolonged—lower doses may be advised Prednisone: peak effect is 1-2 hrs- duration of action30-36 hrs Fluoxetine average range of elimination ½ life is 168hrs (7days)- Peak Therapeutic Range Absorption Elimination

13 Adverse Effects Any response to a drug which is unfavorable, and unintended, occurring at doses used for prophylaxis, diagnosis or therapy, or for the modification of physiological function Mechanism: iatrogenic response, immune (allergic) response or local irritation Causality Severity: mild, moderate, severe APN role: promote health, prevent illness, restore health, alleviate suffering with respect for individual’s rights and dignity APN role: educate re: side effects, management strategies, and when to report persistent or adverse effects; understand risk/benefit An 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 dependent Drug action: means by which a drug produces an alteration in function Unfavorable: noxious, hurtful, damaging to tissue-may occur immediately or take weeks or months (example: opioid , immediate drowsiness; but constipation is often delayed Mechanism: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 effect Allergic reaction: a reaction unexplained by the known RX effect of the drug, manifested by typical signs and symptoms of an immunological response Irritant effect: local- characterized by inflammation Causality: temporal (chronological r/t between event and drug administration; Dechallenge- resolution following decreasing the dose or DC; rechallenge: recurrence following readministration Known 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, schedule 2. OTC and CAM use 3. Age, gender, race, height, weight 4. Medical condition for which drug is prescribed 5. Manual dexterity, mobility, literacy, sight and hearing 6. Adherence ??? 7. Hx of allergies (food & drug), adverse drug effects 8. Psychosocial Hx.: tobacco, caffeine, alcohol, recreational drugs, sexual orientation and no. of partners, childbearing potential, & financial/educational status 9. Exposure to environmental & occupational substances

15 Drugs Causing LFT Abnormalities
Almost any drug but digitalis and prednisone Most common offenders: antibiotics (quinolones, nitrofurantoin, penicillins, azoles) Anti-epileptics NSAIDS Acetaminophen Drugs 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 history Assume medication-induced causes Normal AST <40 AST/ALT that is > 10x-15x nml in necrosis AST/ALT usually <300 in alcoholic damage

17 Liver Function Tests: Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phophatase, Lactic Dehydrogenase, Albumin, Ammonia, Bilirubin, Prothrombin, Gamma-glutamyl Transferase Alanine Aminotransferase (AST, SGPT) Normal range: men 10-40U/L; women 7-35U/L Significance: Marker of hepatic injury; found primarily in liver; more specific indicator of liver damage than AST Factors that increase: acute MI, pancreatitis, acute renal infarct, CHF, mono, liver dz., heparin, skeletal muscle dz. Factors that decrease: not clinically significant Aspartate Aminotransferase (AST, SGOT) Normal range: men U/L; women 10-36U/L Significance: 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 contraceptives Factors that decrease: chronic dialysis, B6 deficiency Alkaline Phosphatase Normal range: U/L Significance: Reflects bile formation and flow, non-specific measure of liver or bone disease Factors 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 colitis Factors that decrease: anemia, celliac dz, hypothyroidism, malnutrition, sarcoma, vit D intoxication, zinc depletion Lactic Dehydrogenase (LDH) Normal range: IU/L men; IU/L female Significance: 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, lorazepam Factors 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 oxidize Occurs mostly in liver or gut wall during absorption Inducers can decrease the therapeutic levels of substrates e.g., modafinil and CYP3A inducer carbamazepine Inhibitors can increase or potentiate a drug effect e.g, modafinil and CYP3A inhibitors, ketoconazole CYP 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 enzyme The rate of drug metabolism effects the plasma drug levels Inhibitors: drugs that prevent the enzyme from metabolizing the substrates Activators: drugs that increase the enzyme's ability to metabolize the substrates

19 Common CP3A Use in MS Substrates Inhibitors Inducers
alprazolam cimetidine carbamazepine amitriptyline ciprofloxacin dexamethasone clarithromycin buspirone cyclosporine garlic supplements cannabinoids danazol glucocorticosteroids caffeine ethynyl estradiol modafinil carbamazepine fluconazole oxcarbazepine cyclophosphamide grapefruit phenobarbitol dexamethasone phenytoin diazepam St. John’s Wort progesterone 17 ß estrodiol Increase the potential oxybutinin for toxicity from substrate tolterodine trazadone sildenafil, tadalafil, verdenafil decrease therapeutic methylprednisilone level of substrate clarithromycin Statins CYP3A involved in metabolism of over 50% of currently prescribed drugs-important to understand drug reactions due to drug metabolism by inhibition or induction of CP3A Tobacco and alcohol use can alter plasma concentrations-tobacco decreases serum levels of antipsychotics Inhibitors 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 inhibitor Adverse 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 Pharmacogenomics Personalized drug therapy based on genes- AmpliChip- ID slow and fast metabolizers so dosages can be adjusted May explain some “idiosyncratic” reactions Can learn a lot by a good family drug history 7-15% 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 drugs Race 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, olanzapine Example –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, dextromethorphan Asians need lower doses of crestor and warfarin Amplichip FDA approved test for variations in genes that affect metabolism of CYP2D6 and CYP2C19 AmpliChip identifies slow or fast metabolizers so dosages can be adjusted

21 APN Role Learn 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 patient Ask specific questions about adverse effects and side effects associated with drug history Monitor, document, identify slow and fast metabolizers and adjust dosages per individual patient Keep cultural context in mind when planning education for families and patients Check your cultural competence and measure attitudes at Lower doses of Lithium in blacks, asians (Japanese and Taiwanese); antipsychotics in Hispanics Two 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 Glucocorticoids Indication: acute exacerbation (no evidence for long term benefit); speeds recovery; use in functional deficits of visual, motor, cerebellar system Mechanism of action: decrease CNS inflammation; close BBB Side 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
Glucocorticoids naturally occurring hormones IM adrenocorticotropic hormone (ACTH®) U/d for 2-3wks administered as synthetic prep IV methylprednisolone (Solu-medrol®) 1G QD 3-5 days IV dexamethasone (Decadron®) mg/d 3-5d (contains sulfites) PO prednisone, taper: 60mg QD, 7 d; 60mg qod, 8d; 40mg qod, 8d; 20mg qod, 8d Increase 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 vaccination ACTH 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/d cyclophosphamide (Cytoxan®) IV, adjust dose to leukocyte count, 1g/m2 methotrexate (Folex®) PO 7.5mg/wk mitoxantrone (Novantrone®) IV 12mg/m2 q 3mos for up to 2yrs; lifetime dose 140mg/m2 Indication: progressing MS Mechanism of action: interfere with cell reproduction; suppress T & B cell production Pregnancy Category D & X Azathioprine: half life 5 hrs- onset 4-8 wks hepatotoxicity if dose > 2.5mg/kg/d Methotrexate- 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; photosensitivity Mitoxzantrone: 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, leukopenia Interactions: 1) steroid conserving effect, allopurinol, live vaccines cyclophosphamide (Cytoxan®) IV, adjust dose to leukocyte count, 1g/m2 Side effects: bone marrow suppression; hemorrhagic cystitis Interactions: cocaine toxicity, probenecid methotrexate (Folex®) PO 7.5mg/wk Side effects: bone marrow suppression, diarrhea, stomatitis Interactions: alcohol or hepatotoxic drugs, acyclovir injection, NSAIDS, probenecid or salicylates, live vaccine mitoxantrone (Novantrone®) IV 12mg/m2 q 3mos for up to 2yrs Side effects: cardiotoxicity, severe myelosuppression Interactions: 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/d pemoline (Cylert®) PO 37.75mg/d titrated by to 112.5mg/d methylphenidate (Ritalin®) PO 5-20mg/bid or tid dextroamphetamine (Dexadrine®) PO 5-60mg/tid Caffeine 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 MS Mechanism of Action: stimulate cerebral cortex; antagonizes adenosine receptors; block reuptake of dopamine Pregnancy 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 threshold Interactions: other CNS stimulants, MAO’s, pimozide (Tourette’s), antidepressants, guanethidine, cold & sinus & allergy meds, caffeine, appetite suppressant, bupropion, clonidine, asthma meds, cocaine dextroamphetamine Side effects: irritability, restlessness, trouble sleeping, dry mouth, fast, pounding or irregular heartbeat Interactions: tricyclic antidepresants, beta blockers, CNS stimulants, amantadine, digitalis, MAO inhibiters, thyroid hormones, meperidine, cold, sinus & allergy meds, caffeine, asthma meds, cocaine caffeine Side effects: heart arrhythmias, incr. nervousness, GI irritation, withdrawal = irritability, headache, incr wkness Interactions: CNS stimulants, MAO inhibitors Avoid amphetamines in persons c hypertension, cardiovascular drugs, undue restlessness, anxiety or agitation Look for sleep disturbance, weight loss, dry mouth, altered thought process—last dose of day 6hrs before bedtime. Withdrawl-taper off habit-forming potential Ritalin 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)
modafinil Side effects: dizziness, unclear thinking, blurred vision, anxiety, insomnia, nausea, headache, nervousness Interactions: Same as for other CNS stimulants PLUS cyclosporine, diazepam, phenytoin, propranolol, theophylline, warfarin, tricyclic antidepressants, steroid contraceptives pemoline (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: jaundice Interactions: no significant drug interactions but r/o liver dz.; caffeine Chewable form of pemoline MUST be chewed before swallowing Associated with life threatening hepatic failure Two FDA black box warnings (1996/1999) LFT’s at baseline and q 2wks throughout therapy. Written informed consent required Cylert half-life of 12 hrs peak effect 3-4 wks Pemoline, 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 UK Most liver failures were in children % incr risk of liver failure with pemoline 21 cases of liver failure BC ineffective during modafinil use and for one month after use.

29 Drugs Affecting Fatigue
amantadine (antiviral;dopamine agonist) 100mg tid PO Action: releases dopamine Side effects: livedo reticularis, edema, anxiety, sleepiness, hallucinations 4-aminopyridine and 2,3-aminopyridine 30-40mg/d PO Action: K+ channel blocker-not FDA approved Side Effects: seizures, confusion, nausea, hepatitis, dizziness, paresthesias, insomnia SSRI antidepressants (negligible effect in clinical trials) Action: increase serotonin Side effects: agitation, insomnia, sexual dysfunction (anorgasmia), weight gain, dizziness, headache, nausea, loose stools, sleepiness, initial anorexia, tremor, weight loss then weight gain, nervousness Safest in overdose=SSRI –drugs of choice, more effective and less potential SE -high instance of anorgasmia

30 Drugs Affecting Depression
Selective serotonin reuptake Inhibitors fluoxetine (Prozac®, Sarafem®) PO 20-80mg/10-20mg paroxetine (Paxil® and CR) PO 20-50mg/ sertraline (Zoloft ®) PO mg citalopram (Celexa ®) PO 20-60mg escitalopam (Lexapro ®) PO 10-20mg fluvaxamine (Luvox ®) mg Indications: mild to moderate depression, OCD, panic disorder, PMS, PTSD, anxiety, bulimia, pain, enuresis, stress incontinence, fatigue Mechanism of action: Neurotransmitter effect, cell membrane stability Side Effects: nausea, insomnia, nervousness, headache Pregnancy Category: B (buproprion, fluoxetine, sertraline); C (all others); D lithium SSRI 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 effect Taper off over 5 wks Zoloft- high doses required for effect; Paxil= most anticholinergic; Luvox= wkest efficacy, use in OC; Celexa- fewer interactions SSRIincrease risk of GI bleed- 12 fold higher in combo with NSAIDS Therapeutic effect similar so selection made on SE Prozac-depression, OCD, bulemia, panic, PMS, Paxil PTSD PMS, Panic, anxiety Zoloft OCD, panic, PTSD, PMS

31 Norepinephrine and Serotonin Reuptake Inhibitors
venlafaxine (Effexor ®, XR) PO mg; mg duloxetine (Cymbalta ®) PO 40-60mg Side Effects: same as SSRI, wt. loss, raises diastolic, > somnolence Tricyclics amitriptyline (Elevil ®) PO mg desipramine (Norpramin ®) PO mg imipramine (Tofranil ®) PO nortriptyline (Pamelor ®) PO doxepin (Sinequan ®, Adapin ®) PO mg Side effects: Anticholinergic, sedation, insomnia, agitation, orthostatic hypotension, cardiac arrhythmia with TCA, GI distress, weight gain, sexual dysfunction All the above: caution in hepatic impairment Seizures at doses > 600mg There is a shower of dopamine for nicotine, heroine, cocaine, sex and chocolate. ½ life 9-12h Prozac is a potent inhibitor of CYP 2D6 and 3A4 SSRI safe, no anticholinergic effects; wellbutrin no weight gain, few anticholinergic SE rare hypotension or sexual dysfunction Anticholinergic: 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 XL Side effects: agitation, rarely seizures, low incidence of sexual dysfunction or orthostatic hypotension, little sedation, anticholinergic Contraindications: (antipsychotics and MAOI’s) thioridazine (Mellaril ®) and pimozide (orap ®) duloxetine contraindicated in uncontrolled narrow angle glaucoma buproprion contraindicated in seizure risk TCA’s and antithyroid drugs Potentially fatal interactions: antiarrhythmics (c TCA) and MAOI’s CTP2D6 inhibition: Potent: fluoxetine, paroxetine; Moderate: buproprion, citalopram, escitalopram, sertraline; Little or none: venlafaxine, duloxetine, TCA’s except desipramine may inhibit fluvoxamine potent inhibitor CYP 1A3, CYP 2C19, CYP3A4 Caution in liver failure, elderly, adolescents, pts c cardiac dz. ETOH and CNS depressants can have additive effect on drowsy Inhibit 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 drugs Action: corrects overactive catecholamine state by inhibit of synapse release Side effects: hand tremor, thirst, incr urination, diarrhea, nausea, weight gain Toxic: blurred vision, confusion, dizziness divalproex 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; pain Action: quinidine inhibits the metabolism of dextromethorphan allowing more to roam in CNS and acting on NMDA receptors to decrease glutaminergic signaling Side effects: headache, dizziness, spasticity May increase serotonin Emotional lability, emotional incontinence, pathological laughing and crying Effects 10% c MS though

35 Drugs Affecting the Urinary Tract
Urinary antimicrobials Sulfonamide: sulfamethoxazole and trimethoprin, DS (Septra ®, Bactrim ®) Side effects: anorexia, diarrhea, nausea, vomiting, rash, pruritus, headaches, dizziness Cephaloporins: cefixime (Suprex®), cefpodoxime (Vantin®) 3rd generation safest in pregnancy for UTI Quinolones: 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, candidiasis Used for UTI or prophylactic use Most common use of antibiotics in MS; usually from gr neg bacilli (ecoli) Bacteriocidal or antimoicrobial possible allergic rx; may potentiate anticoagulant, phenytoin, methotrexate, hypoglycemics (sulfa drugs) Antibiotics may reduce the effect of OTC Advice to take full course Look for pseudomembranous colitis (diarrhea) Possible fungal overgrowth May have allergy to Sulfa drugs Avoid antacids Possible GI side effects and rash Anitiseptics exert antibacterial activity on urine with no or little systemic effect Amoxacillin- broad spectrum may have GI upset Acidic urine: avoid fruit juices, milk, dairy, antacids, eat > protein, cranberries, prunes, plums, blueberries, Vit C Phenazopyridine (Pyridium) –urinary tract analgesic-is used to relieve pain of UTI—causes redish urine-may stain soft contact lenses 2 day therapy with antibiotic Macrodantin-urine may be rust-yellow or brownish Bacteriostatic: TMP-SMX block dihydrofolic acid Methenamine acts by releasing formaldahyde in an acid environment- good for long term suppression b/c of wide bacterial spectrum, low toxicity and loe resistance Cephalosporins 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 antiseptics methenamine (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 food Side effects: drowsiness, nausea, vomiting, rash, headache, pruritus, “brownish” urine Urinary analgesics Phenazopyridine (Pyridium®) Analgesic and anesthetic effect on urinary mucosa Used for pain and burning on urination Side effects: GI distress, red urine may stain clothing pH- decrease antacids, milk products, citrus, -mor protein, cranberries, added vit C, prunes , plums, blueberries Sulfonomides precipitate with formaldehydes and form crystals in urine , avoid concommitant use; give 2h after azoles—potentiated by antimuscurinics Effects 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 hyperreflexia Action: anti-muscarinic/anticholinergic (block muscarinic effects of acetylcholine) receptor specific; antispasmodic Side effects: dry skin, eyes & mucous membranes; constipation or diarrhea; nausea; tachycardia; blurred vision; somnolence; headache Caution: narrow angle glaucoma oxybutynin (Ditropan, XL®) PO 5mg qid/5-30mg QD oxybutynin 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 QD solifenacin (Vesicare®) PO 5-10mg QD trospium (Sanctura®) PO 20mg bid-not metabolized; take on empty stomach; best SE profile Preganancy Category B (oxybutynin®); C all others Muscarinic receptors are located in smooth muscle and effector organs of cholinergic receptor fibers There are 5muscarinic receptors M3 is located in smooth muscle, salivary glands & eye SLUD salivation, lacrimation, urination, defecation Anticholinergic 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 bid propantheline bromide (Pro-Banthine®) PO 15mg tid baclofen (Lioresol®) PO 5-80mg Antidepressant TCA: (for anticholinergic effects) imipramine (Tofranil®) PO mg HS Pregnancy Category: C Indication: Nocturia desmopressin (DDAVP®/vasopressin®) PO mg; nasal spray 10micrograms/0.1ml/rhinal tube spray to 40ug Pregnancy Category B Side effects: rhinitis, nasal congestion, abdominal cramps, hyponatremia Anticholinergics Mad as a hatter CNS (stimulant) delerium, restlessness, agitation-stupor; blind as a bat-Eyes, dilated pupils, decr. Accomodation Dry as a bone- mucus membranes; skin hot as a hare

39 Urinary Hesitancy and Retention
bethanecol (Urecholine®) PO 10-50mg qid Action: cholinergic, stimulates parasympathetic, muscurinic with selective action on detrusor and bowel smooth muscle. “SLUD” Side effects: bradycardia, hypotension, sweating, salivation, vomiting, diarrhea, intestinal cramps tamsulosin (Flomax®) PO mg 1/2h after meal terazosin (Hytrin®) PO 1-5mg HS Action: alpha adenergic blockers: decr peripheral vascular resistance; bladder wall receptors Side effects: hypotension, syncope, dizziness, somnolence, shortness of breath, stuffy nose, peripheral edema; caution with other alpha blocks, cimetidine, warfarin, other antihypertensives Pregnancy Category C all but tamsulosin: B Cholinergic drugs act as mediatorsparasympathetic NS Cholinergic blocking: anticholinergic-block action of parasympatheic Cholinergic drugs: stimulate paristalsis, and incr urination; terminate curare effects; promote salivation and sweating; Tx myesthenia Give 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 constipation Diet & lifestyle: fluids, fruit & vegetables, exercise Emollients: 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 diabetes Saline 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/C Constipation: hard stools, sensation of incomplete evacuation, obstruction, straining and manual evacuation or less than 3 defacations/wk SE: nausea, abdominal bloating, cramping, flatulence—diarrhea and frequency—possible urticaria r/t allergic rx Contraindicated in bowel obstruction Electrolyte imbalance Tegaserod: liver, renal , gallbladder precautions Lactulose- acids that produce an incr in fluid accumulation, distention, peristalsis, and BM SE: flatulance, cramping, belching, gas—excessive doses= diarrhea and nausea Decreased effect c antibiotics Fiber and bulk laxatives decrease effect of tetracycline, anticoagulants, digitalis, and salicylates Saline and osmotics interact c magnesium antacids and tetracycline Do not dose stimulants with dairy or antacids Lubricants interfere c absorption of OC, digitalis, antibiotics, anticoagulants, fat soluble vitamins Mineral oil decreases vit K-bleeding problems Saline laxatives: retain and increase water content of feces cramping, watery stool-occurs in ½ to 3hours- laxative of choice for specimen; fecal impaction; food poisoning Stimulants increase peristalysis by irritating intramural nerve plexi by contact irritation- Tx effect 1-12 hrs Bulk- increase water and volume—if fluid intake is not substantial they may increase impaction Lubricants; mechanical Emollients act as dispesing or wetting agents, facilitate mix of fat and water—no side effects or interactions- safest irritates-15min to 1h Medications 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) 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 Bowel Side effects: flatulence, cramping, belching, gas; excessive doses may cause diarrhea and nausea Decrease the effect of: antibiotics especially tetracycline, anticoagulants, digitalis, fat soluble vitamins, oral contraceptives and salicylates Do not dose stimulant laxatives with antacids or dairy

42 Drugs Affecting Sexuality
Indication: erectile dysfunction Action: PDE-5 inhibitors increase concentration of NO allowing cGMP which mediates erectile response and enhanced blood flow to penis and clitoris-onset: 30min sildenafil citrate (Viagra®) PO mg (18h ½ life) tadalafil (Cialis®) PO 5-20mg vardenafil (Levitra®) PO mg Side 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, ETOH Caution: cardiovascular dz; recent MI, bleeding disorder, hepatic impairment Potent CYP3A inhibitors: azoles, grapefruit juice, erythromycin, protease inhibitors Pregnancy Category B Phosphodiesterase inhibitors-block enzyme. Allow cyclic guanasine monophosphate Maximum effect-1h Titrate doses A-blockers except Tamsulosin Cialis 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 viagra Cialis and levitra more PDE5 specific and may not cause blue vision Cialis 24-36h duration

43 Intracavernosal injection and intraurethral insertion
Action: vasodilator; relaxation of smooth muscle to allow for engorgement and trapping alprostadil,prostaglandin E, (Prostin VR®, Caverject®) IC 5-40/80ug reconstitute alprostadil (Muse®) pellet, IU ug papaverine (Pavabid®) IC 30-60/80mg phentolamine/regitine 0.5-1mg-used in combination with the above Side effects: priapism, injection site bleeding, dizziness, fibrosis, burning, difficulty ejaculating, tingling of glans, aching during injection Contraindications: sickle cell, Peyronie’s dz. Caution: anticoagulants Autoinjector available; apply pressure 3-5min to injection site Pregnancy 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 dosing Refrigerate 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, tachycardia Contraindication: psychiatric pts, renal & hepatic dz., ulcer Interaction: TCA, SSRI, tyramines, CNS stimulants, caffeine apomorphine (Uprima®):dopamine agonist, central mediation, incr NO; morphine derivative 2-4mg sublingual, allow to dissolve, do not repeat for 8hs Side effects: nausea, hypotension, syncope, flushing, dizziness, yawning, sweating, somnolence L-Arginine (VasoRect®, AginMax®): amino acid dietary supplement, incr. NO; PO 5G/d (given tid) Side effects: mild hypotention; no systemic effects Avoid alcohol; caution in cardiac disease

45 Drugs Affecting Spasticity
Muscle Relaxants baclofen (Lioresal®): 20-80mg/d up to 240mg/d PO baclofen pump ug/d intrathecally Action: GABA analog, down regulates Ca+ influx; decreases muscle response to tonic stretch & decreases clonus & spasms Side effects: drowsiness, nausea, ataxia, dizziness, confusion; possible hepatic dysfunction; avoid alcohol and CNS depressants tizanidine (Zanaflex®): 4-32mg divided doses PO; slow titration Action: alpha 2-adrenergic agonist with decr. excitatory transmitter release Side effects: somnolence, dry mouth, bradycardia, hypotension, hepatotoxicity; avoid alcohol, CNS depressants, diazepam, alpha 2 agonists, potentiated by OC & anti-HTN dantrolene sodium (Dantrium®): mg bid PO Action: decreases Ca+ flux, uncoupling depolarization Side effects: significant weakness and drowsiness; hepatotoxicity (monitor LFT); estrogen incr. risk of hepatotoxicity; avoid verapamil, CNS depressants Frequent 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 activity Side effects: drowsiness, weakness, CNS depression, ataxia, memory impairment; avoid ETOH, CNS depressants, incr. cimetidine, potentiates sertraline clonazepam (Klonapin®) 0.5mg tid PO Action: Same as above Side effects: same as above with hypersalivation, GI upset, liver disorders Antagonize CYP450 inducers e.g. phenytoin, carbamazepine, phenobarbitol; caution c azoles & antifungals Valium SE limits use- works in high doses only do not use innarrow-angle glaucoma Avoid abrupt cessation

47 Agents of Spasticity clonidine (Catapres®) 0.1mg tid PO & transdermal
Action: central alpha 2 adrenergic block Side effects: dry mouth, drowsiness, dizziness, weakness, constipation, rash, impotence, orthostatic hypotension; antagonized by TCA, potentiates CNS depressants gabapentin (Neurontin®) mg tid botulinum toxin A (Botox®)(BTX®) 400U IM Action: inhibit release of acetylcholine at neuromuscular junction-reduces spasticity and preserves function via targeted muscle grps. >effect at 3-4wks; lasts 3months Side effects: pain on injection, fever

48 Drugs for Nociceptive Pain
salicylate (Aspirin®) PO 1600mg bid max acetaminophen (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 antagonism Action: 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 imbalance Side effects: GI bleed, peptic ulcer, nephritis, peripheral edema, headache, dizziness, constipation, rash, fluid retention Contraindicated: renal dz, bleeding disorders, hypersensitivity (allergy to ASA, nasal polyps, asthma) Action: arachidonic acid –formation of prostaglandin Prostaglandin 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 CNS NSAIDS enter cell and attach to cyclooxygenase enzymes (COX) these then cannot act c fatty acids to produce prostaglandins. COX1 and COX2 NSAIDS weak acids allowing them to crossinto tissue and inflammatory sites Highly 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 retention Prostaglandins enhance mucus and bicarb production >30% experience GI sx Monitor periodically for GI bleed- stool guiac; Hb, HCT; LFT; kidney fx tests; weight changes Take with food; do not recline after taking; report fluid retention Tylenol is central prostaglandin inhibition Extensive hepatic metabolism

49 Selective NSAIDS misoprostol (Cytotec®) is a synthetic prostaglandin to protect GI (SE: diarrhea) PO bid diclofenac + misoprostol (Arthrotec®) H2 blockers and proton pump inhibitors COX 2 inhibitor selective agents: celecoxib (Celebrex®), rofecoxib (Vioxx®)*, valdecoxib (Bextra®)* Side effects: CVD, edema, GI, incr LFT Caution: CYP2C9/2D6;HTN, DM, PVD, smoking, hyperlipidemia, CVD Contraindicated: stroke, ischemic heart dz., CABG Pregnancy Category: B (acetaminophen, ketoprofen, naproxen, flurbiprofen, diclofenac, diflunisal; C (the rest); D (salicylates); X misoprostol FDA removed from market Cyclo-oxiginase enzymes=selective

50 Drugs For Neuropathic Pain
Topical agents Oral agents Membrane stabilizing: Antiepileptics Antiarrhythmic Corticosteroids Dorsal horn inhibition: Antidepressants Gaba agonists-Baclofen NMDA antagonists: Ketamine Dextromethorphan Methadone Opioids Intrathecal agents Chemicals 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, coughing Transdermals: fentanyl (Duragesic®), buprenorphine lidocaine/prilocaine (EMLA®) lidocaine patch 5% aspirin cream clonidine 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 norepinephrine imipramine (Tofranil®)PO 200mg QD max, amitriptyline (Elevil®), PO 150mg QD max nortriptyline (Pamelor®) PO 150mg QD max desiprimine (Norpramin®) PO to 200mg QD max SE: sedation, hypotension, seizures, dry mouth, weight gain duloxetine (Cymbalta®) PO 120mg max venlafaxine (Effexor®) PO 375mg QD max dose SE: nausea, dizziness, sedation, constipation, dry mouth Often 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 1853 phenytoin used to tx. pain in early 40’s carbamazepine used for pain in 1960 Action: block sodium channels and nerve membrane stabilizing agents Side 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 Drugs carbamazepine (Tegretol®, XR)-assoc c neural tube defects Preg Cat: D phenytoin (Dilantin®)-hirsutism, gingival hyperplasia, constipation valproic Acid (Depakene®) Preg Cat.: D tremor; wt. gain clonazepam (Klonopin®) Preg Cat: D anticholinergic Newer antiepileptic drugs are better tolerated, have fewer drug interactions and less affect on cognitive function gabapentin (Neurontin®) 900 titrated to 3600mg tid 1/1000 suicide tiagabine (Gabitril®) up to 56mg/d in 2-4 divided doses lamotrigine (Lamictal®)-rash in 10%-hypersensitivity rx topiramate (Topamax®) wt. loss; incr. fluids oxcarbazepine (Carbatrol,Trileptal®), XR) Preg Cat: D pregabalin (Lyrica®)100mg tid(2-10X more potent than neurontin) felbamate (Felbatol®), aplastic anemia, acute hepatic failure, cardiotoxic levetiracetam (Keppra®) zonisamide and vigabatrin less cognitive impact, hypersensitivity vigabatrin, 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 daily Gabapentin- not metabolized, does not induce or inhibit enzymes-Se are mild and transient --eliminated by kidney Raise seizure threshold, have an inhibitory effect on GABA binding and inhibit glutamate transmitter release Vigabatrin: synthetic derivative of GABA and inhibits GABA-aminotransferase-prevenyts GABA brkdown and incr. functional pool of GABA Lyrica- 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…

55 Antiarrhythmics for Nociceptive Pain
Mexilitine (Mexitil®) sodium channel modulator SE: palpitations, chest pain, tremor, GI, dizziness double vision, nervousness Lidocaine

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,weakness tramadol (Ultram®) Tramadol/acetaminophen (Ultracet®) weak agonist at opioid receptors; inhibits NE & 5HT reuptake with 30% of activity of morphine-no withdrawl effects SE: lowers seizure threshold; tiredness, dizziness, constipation, sedation, headache- habit forming Opioid 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 agonist Intrathecal pump (baclofen with morphine) Opiats are derived from opium both natural and synthetic 4 receptors (MU, Kappa, Sigma, Delta-analgesia associated c Mu and Kappa- repiratory depression mediated through MU Those c codeine allergy will have allergy to ultram Opioid agonist: affinity for receptors- act centrally in CNS and peripheral in gut as antidiarrheal and supresses cough reflex Morphine 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 CP Pumps- risk of electrical or medhanical failure; infection, fibrosis, extrusion; neurotoxicity; sedation, constipation; hypotention Patients 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.

58 Combination Opioids propoxyphene/acetaminophen (Balacet®, Darvocet®) propoxyphene/ASA/caffeine (Darvon Compound®) oxycodone/ibuprofen (Combunox®) oxycodone/acetaminophen (Percoset®, Tylox®) oxycodone/ASA (Percodan®) codeine/acetaminophen (Tylenol#3,#4®) dihydrocodeine/ASA/caffeine (Synalgos-DC®) dihydrocodeine/acetaminophen/caffeine (Panlor-DC, SS®) hydrocodone/ibuprofen (Vicoprofen®) hydrocodone/acetaminophen (Lortab®, Vicodon®, Maxidone®, Norco®, Zydone®) Side Effects: vertigo, faintness, constipation, nausea, vomiting, flatulence, sedation, urinary retention, dizziness, diaphoresis

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 gut Vit D produced by exposure to sunlight Fat-soluble: A, D, E, K Water-soluble: B complex group and C Antioxidant vitamins A, C, E may have effect in MS Pregnancy 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. E Steroid use Decrease levels of free radicals which may be a factor in myelin and nerve damage—antioxidants stimulate immune system- and this could be harmful Top 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) toxic Interactions: minocycline, HMG-CoA reductase inhibitors and OC Vitamin D: hormone and vitamin-important in bone loss; mildly immunosuppressive; >1000mmg/d=liver injury Contraindications: hypercalcemia, sarcoidosis, hypoparathyroisism, renal dz Interactions: cardiac glycosides Vitamin E anti-oxidant, suggested as MS tx.-no adverse effect from one small study-suggest dietary sources; With PUFA diets use E to replace losses Contraindications: angioplasty, retinitis pigmentosa, K deficiency Interactions: anticoagulants and antiplatelets Vitamin K no known relevance to MS Interactions: coumadin Vit D proinflammatory cytokines 15min of sunlight for dose Vit 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 MS B3/Niacin: used as antilipidemic; no application in MS B6/Pyridoxine: deficiencies and excess may cause polyneuropathy; no application in MS and may decrease effectiveness of DMA- nerve injury at >50mg/d B9/Folic Acid: may be decreased in serum of MS pts. May decr. toxicity of methotrexate Contraindications: may mask Vit B12 deficiency; possible worsening of seizure disorder and schizophrenia Interactions: decreases serum levels of phenytoin, mysoline, and phenobarbital Supplements have twice the bioavailability of diet Antioxidants stimulate t cells and macrophages but also reduce free-radical induced oxidative injury but could antagonize effect of immunomodulating and immunosuppressive agents 400mcg/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 neuropathy Interaction: folic acid may mask deficiency C/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 stones Contraindications: angioplasty; Hx. kidney stones Interaction: anticoagulants

63 Minerals Calcium: nerve conduction, muscle contraction, blood clotting, treat osteoporosis; mild immunosuppressive -further clinical trials needed; Dose mg divided doses As citrate(Citracal, Solgar): on empty stomach As carbonate (TUMS, Caltrate): need acid to absorb, take c food; lactate gluconate Contraindications: hypothyroidism, hyperphosphatemia, renal insufficiency, sarcoidosis; risk kidney stones Interactions: thiazide diuretics absorption: biphosphonates, fluoroquinolones, levothyroxine, tetracycline, iron, zinc, magnesium, tannins, laxatives, fiber, phytates and oxaltic acid bind calcium in foods e.g., spinach, cocoa, kale, soybeans HIV decr survival study of calcium= attack rate decreased Take 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 =acid Steroids and anticonvulsants damaging to bone Citrate- 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 study Zinc: 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, hemochromatosis Interactions: diuretics, tetracycline, fluoroquinolones Selenium: 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 effect LA found in sunflower oil, soybean oil, corn oil, walnut oil, wheat germ oil, grape seed oil, & safflower oil PO17-23g Contraindications: allergy to daisy plant family GLA found in primrose oil, blackcurrent seed oil, barage seed oil, & spirulina PO mg/d Contraindications: incr risk of seizures, prolongs bleeding time Interactions: phenothiazines and other epileptogenic medications, anticonvulsants, anticoagulants and antiplatlets Take vitamin E to prevent Vit. E deficiency 5 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/d Contraindications: diabetes, bleeding disorders Interactions: oral hypoglycemics, insulin, anticoagulants EPA & DHA found in fish oils, (salmon, Atlantic herring and mackerel, bluefin tuna, sardines & cod liver) Dose < 3g combined EPA & DHA/d Vitamin E supplementation necessary Diet concerns with mercury contaminants Contraindications: bleeding disorders, diabetes, aspirin sensitivity, bipolar, depression Interactions:anticoagulants, oral hypoglycemic and insulin, antihypertensives Pregnancy category: not enough information Flaxseed- 15-ml oil for constipation

67 Dietary Supplements Herbal used in MS
cranberry tablets: UTI prophylaxsis psyllium: constipation Valerian: insomnia St. John’s Wort: mild depression; two large clinical trial showed no effect for moderate and severe depression Interactions: 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-stimulating Fatigue is worsened by: chamomile, Asian & Siberian ginseng, barberry Steroid side effects worsened by: aloe, bayberry, Asian ginseng, licorice Hormones melatonin and DHEA activate the immune system Herbs recommended with serious side effects (no proven worth) yohimbe, chaparral, comfrey, lobelia Chaparral-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 600mg modafinil 400mg amitriptyline HS 75mg baclofen 60mg tolterodine 4mg sertraline 150mg depo-provera 150mg q 3mos ciprofloxacin 500mg for 3 d St. 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 albicans Maggie 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 face Evaluate risk What is your assessment? How would you manage?

71 How would you treat? The disease The symptoms Advice on supplements
Bladder Fatigue Depression Spasticity Pain Advice on supplements Advice on birth control Baclofen change to tizanidine??

72 References Abruzzo, 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 from Bowling, A. The National Multiple Sclerosis Society. Clinical bulletin. Information for health professionals retrieved on July 20, 2005 from Bowling, 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, 2005 from Kalb, 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 from Munoz, C. & Hilgenberg, C. (2005). Ethnopharmacology. American Journal of Nursing, 105(8), The Worldwide Physiologist: Cytochrome P450 retrieved on July 18, 2005 from

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