* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Psychoactive medications (Antipsychotics)
Discovery and development of direct Xa inhibitors wikipedia , lookup
Orphan drug wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Compounding wikipedia , lookup
Atypical antipsychotic wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
Drug design wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Theralizumab wikipedia , lookup
Plateau principle wikipedia , lookup
Prescription costs wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of direct thrombin inhibitors wikipedia , lookup
A Drug Therapy Smorgasbord Practical Issues for Dietitians Presented by David B. Goldwater R.Ph Clinical Consultant Pharmacist Objectives 1. Review Practical Pharmacokinetic principals to create a deeper understanding of absorption, distribution and excretion of drugs. 2. Review several commonly used drugs often reviewed for consideration by Dietitians which involve considerations of pharmacokinetics and specific drug/ food interactions. 2 Objectives continued…. 3. Discuss important considerations for Warfarin interactions with enteral feedings 4. Review the Pharmacodynamic effects of antipsychotics with specific focus on weight gain and blood sugar control 3 Closer Collaboration between Pharmacists and Dietitians Changes to revised Dietary F Tag: F325. June 2008 AND Definition of MRR in revised Pharmacy F Tag F425 (Dec 2006) BOTH REVISIONS have strengthened the need for communications between our two disciplines. 4 Changes to F428 –Med Regimen Review (Dec 2006) Thorough evaluation of the medication regimen of a resident by a pharmacist with the goal of promoting positive outcomes and minimizing adverse consequences associated with medications; The review includes: preventing, identifying, reporting, and resolving medication-related problems, medication errors, or other irregularities AND collaborating with others members of the interdisciplinary team.” 5 Personal impact of working closer with dietitians Appreciation of the positive influence on outcome for residents due to collaborations with Dietitians in LTC. 2. A strong interest in speaking to you as a group today. 3. The topics chosen for review today, have come directly from collaborations and discussions with individual Dietitians in my personal practice. 4. On a lighter note…………. 1. 6 Personal Impact of Working closer with Dietitians British dietiCIAN Canadian dietiTIAN American dietiTIAN Basic Concepts of Pharmacokinetics Practical Issues For Dietitians Pharmacokinetics Study of what the body does to a drug. How the body → moves drug in and out. (Absorption Distribution Excretion) 9 Pharmacodynamics Study of the influence (dynamics) of the DRUG on the BODY 10 FIRST ORDER KINETICS 1. The majority of drugs are eliminated in this way. 2. A constant fraction of the drug in the body is eliminated per unit time. 3. The rate of elimination is proportional to the amount of drug in the body. 11 FIRST ORDER ELIMINATION Concentration in plasma Time 12 Volume of Distribution (For drugs which follow first order kinetics) The Volume of Distribution (Vd) is the amount of drug in the body divided by the concentration in the blood. Highly LIPID SOLUBLE DRUGS, such as digoxin, have a very High Vd.(500liters). LIPID INSOLUBLE DRUGS, such as neuromuscular blockers, remain in the blood, and have a Low Vd. 13 Clearance (Cl) (For drugs which follow first order kinetics) The Clearance (Cl) of a drug is the VOLUME of plasma from which the drug is COMPLETELY removed per unit time. The amount of drug eliminated is PROPORTIONAL to the concentration of the drug in the blood. 14 Elimination (For drugs which follow first order kinetics) RATE of elimination EQUAL TO Clearance x Concentration in the blood. _______________________________________________________________________________________ Elimination HALF LIFE (t1/2) EQUAL TO Time taken for plasma conc. to reduce by 50%. 15 RULE OF THUMB 100% Elimination After 5 HALFLIVES (Symbol for Half-life is t ½ ) 16 Half-life: Implications We can determine how long it takes to reach steady state E.g. DIGOXIN ……t ½ = 40hrs 1. 2. It takes approximately 200 hrs ~8 days for DIGOXIN to reach STEADY STATE LEVELS. It takes approximately ~8 days for DIGOXIN to be COMPLETELY ELIMINATED from the system. 17 Simple, isn't it? What we discussed above is a SINGLE COMPARTMENT model, This is what would occur if the bloodstream was the only compartment in the body (or if the Vd = the blood volume). But the human body is more complex than this! There are many compartments: muscle, fat, brain tissue etc. In order to describe this, we use MULTICOMPARTMENT models. 18 MULTICOMPARTMENT MODELS Q. Why does a patient wake up after 5 minutes after an injection of Thiopentone, when we know that it takes several hours to eliminate this drug from the body? A. Initially the drug is ALL in the blood and this blood goes to "vessel rich" organs; principally the brain. The drug then redistributes into other tissue compartments. (fat, muscle etc) In response to the decrease in brain concentration the net effect is that the patient wakes up 5 minutes later! 19 Elimination: MULTI COMPARTMENT MODEL Rapid distribution phase α Equilibrium phase (Plateau) Concentration Elimination phaseβ Time 20 A SIMPLE TWO COMPARTMENT MODEL The first part is the rapid redistribution phase: (alpha phase.) The plateau (equilibrium phase) (where blood concentration = tissue concentration) The slower phase, the beta phase, is the elimination phase where blood and tissue concentrations fall in tandem 21 BIOAVAILABIILITY This is the fraction of the administered dose that reaches the systemic circulation. Bioavailability is 100% for intravenous injection. It varies for other routes depending on incomplete absorption, first pass hepatic metabolism etc. When we plots plasma concentration Vs. time, the bioavailability is the area under the curve. 22 BIOAVAILABILITY (for a drug given orally) Concentration BIOAVAILABILITY is the AREA UNDER THE CURVE in plasma Time 23 DOSAGE REGIMEN The strategy for ADMINISTRATION DOSING is to administer ONLY, sufficient amounts of drug to attain therapeutic effect, but not enough to produces toxicity! THEREFORE WE APPLY THESE PRINCIPLES…… STEADY STATE CONCENTRATION is achieved AFTER FIVE half lives, therefore…. At STEADY STATE Maintenance Dose = Rate of Elimination WE THEREFORE CONCLUDE THAT…… Rate of Administration = Rate of Elimination 24 DOSAGE REGIMEN Drugs will accumulate within the body if the drug has not been fully eliminated before the next dose. This is OK only IF, we are willing to wait 5 half lives for the drug to be fully effective ………but what if we cannot wait that long? Then we need to "load" the volume of distribution WITH the drug to achieve target plasma concentrations RAPIDLY. 25 Hepatic Drug Clearance Many drugs are extensively metabolized by the liver. The rate of elimination depends on: The liver's inherent ability to metabolize the drug The amount of drug presented to the liver for metabolism. 26 Hepatic Drug Clearance (First Pass effect) This is important because orally administered drugs go from Ingestion →gut → portal vein → liver. The liver DIVERTS a varying chunk of the administered drug by (pre-systemic elimination) and therefore less is available to the body for therapeutic effect. EXAMPLE: This is why we give a higher dose of ORAL morphine, for the equipotent INTRAVENOUS dose 30 MG ORAL Morphine is EQIPOTENT TO 1 MG IV Morphine. ORAL: PARENTERAL RATIO = 3 : 1 27 Drug distribution FACTORS THAT EFFECT WHERE THE DRUG ENDS UP: 1. BLOOD FLOW tissues with the highest blood flow receive the drug first. 2. PROTEIN BINDING drugs stuck to plasma proteins are crippled, because they can only go where the proteins go 3. LIPID SOLUBILITY & DEGREE OF IONIZATION this describes the ability of drugs to enter tissues (highly lipid soluble / un-ionized drugs can basically go anywhere). 28 Protein Binding Most drugs bind to proteins: Albumin OR Alpha-1 Acid Glycoprotein (AAG), FREE drug is usually the preferred state, because FREE drug can travel throughout the body, in and out of tissues and exert a biological effect. Free drug on the other hand is subject to metabolizing enzymes. 29 Protein Binding HIGHLY BOUND drug has a longer duration of action and a lower volume of distribution. Why is this important? 1. For HIGHLY protein bound drugs, we need to give more of it to get a therapeutic effect; as so much is stuck to protein. 2. If another drug comes along and starts to compete with the drug for the binding site on the protein → the amount of FREE drug is ↑ ↑ INCREASED 30 Clinical Implications for HIGHLY Protein Bound Drugs DRUG-A ------ 97% BOUND TO ALBUMIN……3% free drug. Addition of DRUG-B displaces DRUG-A from its binding sites Causing 3% reduction in Protein binding for DRUG-A RESULTS in a 50% increase in FREE DRUG-A concentration from 3% to 6% DRUG-X ------ 70% BOUND TO ALBUMIN……30% free drug. Addition of DRUG-Y displaces DRUG-X from its binding sites Causing 3% reduction in Protein binding for DRUG-X RESULTS in a NEGLIGIBLE increase of FREE DRUG-X concentration from 30% to 33% 31 Clinical Implications for HIGHLY Protein Bound Drugs The HIGHLY BOUND drugs that we really need to focus on are: warfarin, diazepam, propranolol, phenytoin. For example, a patient on warfarin is admitted with seizures, you treat the patient with phenytoin, next thing you know - his INR is 10. The amount of albumin does not appear to be hugely relevant. In disease states such as sepsis, the serum albumin drops drastically, but the free drug concentration does not appear to increase HOWEVER: For residents with LOW serum Albumin there is a formula that we apply to DILANTIN levels results to adjust the DILANTIN level 32 Warfarin Resistance & Enteral feeding: New understanding of An Old Problem Practical Issues For Dietitians History of Enteral feedings & Warfarin Warfarin resistance first reported in the early 1980’s was POSITIVELY associated with CONTINUOUS enteral tube feedings. Attributed to large amounts of vitamin K contained within the feedings. Patients commonly received several hundred micrograms per day of vitamin K! 34 CORRECTIVE ACTIONS TAKEN The pharmaceutical industry subsequently responded to this problem…… Resulting in significantly reduced vitamin K content of liquid enteral nutrition formulations. Most current liquid enteral formulations NOW CONTAIN LESS THAN 80 MCG/LITER OF VITAMIN K. 35 Why does this issue still occur? Still some anecdotal reports of difficulty in achieving therapeutic anticoagulation when warfarin was given concomitantly with CONTINUOUS LIQUID ENTERAL FEEDINGS Still some anecdotal reports of significant increases in the (INR) when the enteral feeding was discontinued. Schurgers and associates (2004) performed a study to ascertain the CLINICAL IMPACT OF VITAMIN K SUPPLEMENTATION on the anticoagulation effect of the ORAL ANTICOAGULANT ACENOCOUMAROL.[6] 36 Is VIT K CONTENT In Enteral Feeding STILL THE ISSUE? NOT LIKELY ! They concluded that other factors outside of enteral vitamin K intake were playing a greater role in these ANECDOTAL observations BECAUSE…. ……..THE TOTAL VIT K INGESTED IN ENTERAL FEEDING WAS SIGNIFICANTLY LOWER THAN THE SUPPLEMENTAL DOSES USED IN THE STUDY 37 Guidelines for Daily Vit K Intake Guidelines from the Food and Nutrition Board of the Institute of Medicine for adequate intake of Vit K are as follows: in healthy adult men : Vit-K 120 mcg/day In healthy adult women: Vit-K 90 mcg/day 38 Findings by Schurgers and colleagues [5] A statistically significant decrease in INR by 0.4 was found when…. The subjects’ supplemental vitamin K intake was increased to 150 mcg/day. This was in addition to their baseline 55 mcg/day ______________________________________ The GRAND TOTAL of dietary vitamin K intake was 205 mcg /day 39 Findings by Schurgers and colleagues [5] They confirmed that supplemental intake of up to 100 mcg/day of vitamin K did NOT significantly interfere with oral anticoagulant therapy in healthy individuals already receiving about 55 mcg of dietary vitamin K. THEY CONCLUDED: vitamin K intake of about 150 mcg daily is NOT likely to affect That a total warfarin requirements.[5] 40 Dickerson and Colleagues Review Dickerson and colleagues studied (INR) values in 6 patients requiring continuous enteral feeding during the first 10 days of warfarin therapy.[6] For 3 consecutive days, feedings were interrupted for 1 hour before and after warfarin administration. On 3 other consecutive days, feedings were NOT interrupted for warfarin administration. The INR increased by a mean of 0.74 during the 3day interval when the enteral feedings were interrupted for warfarin. In contrast, the INR decreased by a mean of 0.13 during the 3-day interval when enteral feedings were NOT interrupted . 41 Dickerson and Colleagues CONCLUSION Holding enteral feeding 1 hour BEFORE and 1 hour AFTER warfarin administration …….lessens warfarin resistance This strategy is recommended for warfarin administration DURING CONTINUOUS ENTERAL FEEDINGS. 42 KEY POINTS: Warfarin Management in Enteral Nutrition 1,6,7 1. Consider an alternative method of anticoagulation. 2. Monitor INR frequently. 3. Administer warfarin BETWEEN feedings for patients receiving INTERMITTENT tube feedings. 4. Stop feedings ONE hour before and ONE hour after warfarin administration for patients receiving CONTINUOUS tube feedings,. 43 KEY POINTS: 5. Consider increasing the rate of feedings to avoid loss of calories.*** 6. Administer warfarin consistently (ie, hold feedings for all doses) 7. Do not add warfarin directly to the enteral nutrition. 8. Warfarin dose requirements may change if the enteral regimen is altered or if the oral diet is resumed. 44 KEY POINTS: 9. Warfarin dose requirements may change if the enteral regimen is altered or if the oral diet is resumed. 10. If Enteral feedings are Initiated in a patient stable on warfarin, the warfarin may require a dose increase 11. If WARFARIN is initiated in a patient currently receiving enteral nutrition, the warfarin may require a dose decrease upon resumption of oral diet. 45 Selected References 1. Lourenco R. Enteral feeding: drug/nutrient interaction. Clin Nutr. 2001;20:187- 193. 2. Penrod LE, Allen JB, Cabacungan LR. Warfarin resistance and enteral feedings: 2 case reports and a supporting in vitro study. Arch Phys Med Rehabil. 2001; 82:1270-1273. 3. Coumadin (package insert). Princeton, NJ: Bristol-Myers Squibb; 2007. 4. Food and Nutrition Board, Institute of Medicine. In: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001:162-196. 3. Schurgers LJ, Shearer MJ, Hamulyak K, Stocklin E, Vermeer C. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in health subjects. Blood. 2004;104:2682-2689. 4. Dickerson RN, Garmon WM, Kuhl DA, Minard G, Brown RO. Vitamin K- independent warfarin resistance after concurrent administration of warfarin and continuous enteral nutrition. Pharmacotherapy. 2008; 28:308-313. 5. Engle KK, Hannawa TE. Techniques for administering oral medications to critical care patients receiving continuous enteral nutrition. Am J Health Syst Pharm. 1999; 56:1441-1444. Other Drug-Enteral feeding interactions Practical Issues For Dietitians Study by Dickerson et. Al. Roland N. Dickerson, George O. Maish III, Gayle Minard and Rex O. Brown. Clinical Relevancy of the Levothyroxine − Continuous Enteral Nutrition Interaction Nutr Clin Pract 2010 25: 646 48 STUDY CONCLUSION: 1. More than half of our patients receiving concurrent Levothyroxine–continuous EN developed subclinical or overt hypothyroidism within the first 2-3 weeks of therapy. 2. Holding EN for ONE hour PRE- and POST Levothyroxine administration, may be ineffective for some patients. 3. If a Levothyroxine dosage escalation is attempted following development of hypothyroidism, only a 25-mcg dosage increment is suggested. 49 STUDY CONCLUSION: 4. Serial (e.g. weekly) monitoring of TFT’s for all patients receiving concurrent levothyroxine and EN therapy is recommended. 5. TFT monitoring should be continued until a pharmacokinetic-pharmacodynamic steady state is achieved. 6. If an incremental dosage increase is chosen for therapeutic management of hypothyrotic patients, the dosage should be reduced when the EN is discontinued. 7. Further study to ascertain the best method for managing patients with concurrent levothyroxine-EN is warranted. 50 Megace-ES Vs. PLAIN Megace? Practical Issues For Dietitians Indications FDA APPROVED: Megace® ES oral suspension is indicated for the treatment of anorexia, cachexia, or an unexplained significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS) NON-FDA-APPROVED INDICATION † † For the treatment of anorexia, cachexia, or unexplained weight loss in the elderly. 52 PLAIN Megace vs. Megace ES Plasma concentrations of Megestrol Acetate after administration of 625 mg (125 mg/mL) of Megace® ES oral suspension IS EQUIVALENT UNDER FED CONDITIONS TO 800 mg (40 mg/mL) of Megestrol Acetate oral suspension (see figure below). 53 EQUIVALENT under FED STATE 54 Megace-ES 625mg/5ml . (Empty Stomach) EFFECTIVE SERUM LEVEL in UNFED Condition = Megace 800mg/20ml (Original Formulation) Serum level NOT EFFECTIVE in UNFED Condition - ES = Empty Stomach Megace ES has improved bioavailability in the UNFED condition vs. original formula Megace and ORIGINAL has equivalent bioavailability in the FED condition The fed condition is achieved by subjects eating a high-calorie (800-1000 calories) and high-fat (approximately 50% of total calories) meal. 57 FDA Definition The fed condition is achieved by subjects eating a high-calorie & high-fat meal. HIGH-CALORIE (800-1000 calories) *** Plus *** HIGH-FAT (aprox 50% of total calories) 58 An FDA example meal 2 eggs fried in butter 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes, 8 ounces of whole milk. 59 Could a resident who is not eating actually ingest 100% of this meal prior to admin of Regular Megace suspension? 60 Assess Effectiveness The trial studies for the treatment weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS) only looked at effectiveness at 12 weeks duration. Use Megace-ES for 12 weeks. If NO or LITTLE response after 12 weeks, then taper and then D/C 61 Serious and Otherwise Important Adverse Reactions Hypersensitivity Pregnancy Fetal Effects Thromboembolic Disease Adrenal Insufficiency 62 WARNINGS AND PRECAUTIONS Use with caution in patients with a history of thromboembolic disease Clinical cases of overt Cushing’s Syndrome have been reported in association with the chronic use of Megestrol acetate. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic Megestrol acetate in the stressed and non-stressed state. New onset and exacerbation of pre-existing diabetes have been reported. 63 Megace: Adverse Consequences of DVT or PE Thromboembolism is of most significant concern Residents of long term care who are less mobile in general and more prone to mild dehydration, may be at greater risk for the these complications. For the clinician in the long term care setting, a careful evaluation of risk benefit ratio must be considered and based on the evidence to date. 64 Advantages of MEGACE-ES LESS VOLUME and reduced viscosity Megace ES has 75% less total volume per dose compared with Megace 800 mg/20 mL. Megace ES is also 94% less viscous than original formula Megace. This may be important for patients struggling with their ability and desire to eat. Megace ES is substantially less viscous than some common OTC products, including Mylanta®‡1 Lower viscosity may make Megace ES easier to take and may be important for patients who have trouble swallowing 65 Mirtazepine (Remeron)* Although commonly used for the purposes of promoting weight gain……. No studies exist to date that have specifically explored the use of Mirtazepine as an appetite stimulant in the long term care setting. * D. Rudolph : Appetite Stimulants in Long Term Care: A Literature Review. The Internet Journal of Advanced Nursing Practice. 2010 Volume 11 Number 1 66 Newest ORAL Anticoagulant Since The Approval of Warfarin (Over 50 Years Ago) Practical Issues For Dietitians Newest ORAL Anticoagulant Since The Approval of Warfarin (Over 50 Years Ago) PRADAXA® (Dabigatran) Pronounced….. D a – bee – g´a t t – t r a n Approved October 2010 68 PRADAXA® (Dabigatran) THE FIRST DIRECT ORALTHROMBIN INHIBITOR 69 PRADAXA® (Dabigatran) Pronounced…..D a – bee – g´a t t – t r a n USA INDICATIONS AT THIS TIME ! Indicated to reduce the risk of stroke and systemic embolism in patients with NON VALVULAR ATRIAL FIBRILLATION. ADDITIONAL INDICATION (Approved in Canada and Europe (Only!) For thromboprophylaxis in patients S/P hip and knee replacement surgeries 70 Warfarin… DISADVANTAGES Warfarin has a long history of SUCCESSFUL clinical use but also has many limitations to its use. Warfarin has an unpredictable and variable effect, It has a narrow therapeutic window requiring frequent INR monitoring It possesses numerous food and drug interactions, which all contribute to poor compliance in the ambulatory setting. 71 Particularly Dangerous Drug Interactions In Long Term Care Compiled by AMDA American Medical Directors Association & ASCP American Society of Consultant Pharmacists WARFARIN WARFARIN NSAIDS SULFA DRUGS Bactrim WARFARIN WARFARIN MACROLIDS E- mycin Azithromycin QUINALONES Levaquin Cipro WARFARIN PHENYTOIN 72 Major Advantage of Warfarin Warfarin has an antidote available for patients with major bleeding, 73 Dabigatran…. Pros and Cons MAJOR ADVANTAGE Dabigatran DOES NOT REQUIRE ROUTINE MONITORING Few drug interactions are seen with Dabigatran. DISADVANTAGE There is no specific antidote for Dabigatran in patients with major bleeding. 74 MECHANISM OF ACTION Dabigatran and its metabolites, Acyl-Gluc-u-ron-ides (Acyl-Gluc) are competitive, DIRECT THROMBIN INHIBITORS. THROMBIN (aka Serine Protease) enables the conversion of FIBRINOGEN into FIBRIN during the coagulation cascade….. Inhibition of THROMBIN prevents the development of a thrombus. Dabigatran and Acyl-Gluc INHIBIT: Clot-bound and Un-bound THROMBIN …..in addition to INHIBITING thrombin-induced platelet aggregation 75 Pharmacokinetics Dabigatran is metabolized to 4 different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg. 76 ABSORPTION The absolute bioavailability of dabigatran following oral administration is approximately 3 to 7%. (Area under the curve) After oral administration of dabigatran etexilate, Cmax occurs at 1 hour postadministration in the fasted state. 77 ABSORPTION Co-administration of PRADAXA with a HIGH-FAT meal …..ONLY DELAYS the TIME to Cmax by approximately 2 hours HOWEVER Has NO EFFECT ON THE ACTUAL BIOAVAILABILITY OF DABIGATRAN itself. Key Cmax = Maximum Concentration 78 DISTRIBUTION Dabigatran is approximately 35% bound to human plasma proteins. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily. 79 ELIMINATION Dabigatran is eliminated primarily in the urine After oral administration of radio labeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours. 80 METABOLISM After oral administration, dabigatran etexilate is converted to dabigatran by esterase catalyzed hydrolysis to the active principal dabigatran. DABIGATRAN IS NOT A SUBSTRATE INHIBITOR OR INDUCER OF CYP450 ENZYMES. 81 ADMINISTRATION CAUTION 1. The oral bioavailability of PRADAXA increases by 75% when the pellets are taken without the capsule shell ……………… compared to the intact capsule formulation. 2. PRADAXA capsules should therefore NOT BE BROKEN, CHEWED, OR OPENED before administration. 3. PRADAXA may be administered WITH or WITHOUT FOOD 82 CRITICAL IMPLICATIONS DABIGATRAN is NOT APPROPRIATE in the following situations: Administration via G-Tube In residents who have difficultly swallowing whole capsules 83 Drug Interactions Interacting Drug Dabigatran Comments Effect Rifampin Ketoconazole However, the manufacturer of dabigatran does not recommend a dosage adjustment Clopidogrel However capillary bleeding times were not further prolonged compared to clopidogrel monotherapy Amiodarone However, the manufacturer of dabigatran does not recommend a dosage adjustment Quinidine At present, the use of dabigatran is contraindicated with quinidine, a potent Pglycoprotein inducer Verapamil Increased If VERAPAMIL given 1 hr BEFORE Dabigatran Verapamil NO change If VERAPAMIL given 2 hr AFTER Dabigatran However, the manufacturer of dabigatran does not recommend a dosage adjustment Always give Dabigatran 2 hr BEFORE VERAPAMIL DOSAGE AND ADMINISTRATION PRADAXA 150 mg by mouth TWICE daily, with or without food. (For creatinine clearance (CrCl) >30 mL/min) PRADAXA 75 mg by mouth TWICE daily, with or without food. (For creatinine clearance (CrCl) 15-30 mL/min) 85 Metabolic Effects of Atypical Antipsychotics Practical Issues For Dietitians SCHIZOPHRENIC SYMPTOM CLUSTERS POSITIVE SYMPTOMS NEGATIVE SYMPTOMS COGNITIVE SYMPTOMS Suspicious Affective flattening Impaired alertness Unusual thought content Alogia Impaired working memory Delusions Anhedonia Inability to speak due to mental deficiency or a manifestation of dementia. Absence of pleasure from the performance of acts that would ordinarily be pleasurable Hallucinations Impaired executive function- Avolition Lack of motivation Conceptual disorganization 87 ATYPICAL Antipsychotics COMMON SIDE EFFECTS Movement disorders HypERprolactinemia Sleep disorders Weight gain/ obesity Diabetes Cardiovascular Dyslipidemia Extrapyramidal side effects Cognitive effects 88 Adapted from Diepiero J 6th Edition 2005. page 1221 RELATIVE SIDE EFFECTS OF ATYPICAL ANTIPSYCHOTICS Brand Generic ANTICHOLINERGIC ORTHO- EPS STASIS Abilify® Aripiprazole Risperdal® Risperidone + + + ++ + ++ Geodon® Ziprasidone Zyprexa® Olanzapine Seroquel® Quetiapine Clozaril® Clozapine + ++ + ++++ + ++ ++ ++++ ++ ++ + + + NEGLIGIBLE + LOW ++ +++ MODERATE MODERATE-HIGH ++++ HIGH 89 ADA CONSENSUS ON ANTIPSYCHOTIC DRUGS, OBESITY AND DIABETES Brand Generic Clozaril® Clozapine +++ + + Zyprexa® Olanzapine +++ + + Risperdal® Risperidone ++ D D Seroquel® Quetiapine ++ D D Abilify® ** Aripiprazole +/- -- -- Geodon® ** Ziprasidone +/- -- -- WEIGHT DIABETES GAIN RISK DYSLIPIDEMIA [+] increased effect [D] discrepant results [─] no effect [ ** ] Newer Drugs w/ limited long term data American Diabetes Assoc; American Psychiatric Assoc; American Assoc of Clinical Endocrinologists; North American Assoc for the Study of Obesity. Diabetes Care. 2004; 27:596 Diabetes Secondary to Atypical Antipsychotics Schizophrenia has been identified as a risk factor for diabetes Mellitus independent of medication.28 An increased prevalence of diabetes has been associated with bipolar disorder.29 End organ damage may begin 7 yrs before a diabetes Dx. 30 91 Diabetes Secondary to Atypical Antipsychotics Use of antipsychotics may be associated with a higher risk of diabetes & glucose dysregulation 6.17 Symptoms include fatigue, wt loss, polyuria & polydipsia. Risk factors may be difficult to interpret in patients. Diabetes is a risk factor for cardiovascular disease, kidney disease, retinopathy and neuropathy.17,28 92 Weight Gain &Obesity Individuals with Schizophrenia or bipolar D/O are more at risk than the general population for weight gain & obesity. 23, 24 Antipsychotics have been associated with various degrees of weight gain. 17,25 Weight gain can decrease medication compliance. 17 93 Weight Gain &Obesity Body Mass Index17,26 Abdominal obesity waist circumference17 = BMI (kg/m2) Overweight BMI =25-29 Obesity BMI> 30 MEN > 102 cm (40 in) Women >88 cm (35 in) Management Strategies • Monitor weight, BMI wait circumference at baseline & at regular intervals • Intervention recommended if BMI> 25&/or abdominal 1 BMI unit obesity, or if INCRESE of 1 BMI unit (except if underweight) Selected References 6. 17. 28. 23. 24. 25. Lahaman AF et al: Working Group on Schizophrenia. American Psychiatric Association. Practice Guidelines for the treatment of patients with schizophrenia, 2nd edition. Am J Psychiatry 2004;161 (suppl-2):1-56 Marder SR, et al. Physical health monitoring of patients with schizophrenia. Am J Psychol. 2004;161(8):1334-49 Canadian Database Association .Screening & prevention.2003 Clinical Practice Guideline. Avail on the web: www.databasecalcpg2003/downloads/screenprevent.pdf Alison DB et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry 1999; 60 (4):215-220 Keck PE et al. Bipolar disorder, obesity & pharmacotherapy-associated weight gain. J Clin Psychiatry 2003:64(121) 1426-1435 Schwartz TL et al. Psychiatric medical induced obesity: treatment options. Obs. Rev. 2004:5(4);233-238 28. Canadian Database Association: Screening and Prevention. 2003 Clinical Practice Guidelines. 29. Reginold WT et.al. Increased prevalence of type 2 DM among psychiatric inpatients with Bipolar-1 affective and schizoaffective D/O independent of psychotropic drug use. J Affect Disord. 2002 70(1): 19-26 30. Lelter LA et.al. Diabetes Screening in Canada. DAIASCAN Study:Prevelence of undiagnosed diabetes and glucose intolerance in family physician offices. DIABETES CARE 2001 24(6) 1038-43 Weight gain with Antipsychotics Greatest gain Olanzapine (Zyprexa) Clozapine (Clozaril) Significant gain Most ( Older original TYPICAL Antipsychotics) Moderate gain Risperidone (Risperdal) Quetiapine (SeroQUEL) Little or No gain Aripiprazole (Abilify) Ziprasidone (Geodon) American Diabetes Association: American Psychiatric Association: American society of Clinical Endocrinologists: North American Association for the Study of Obesity. Diabetes Care 2004: 27: 596. Gangul R. J Clin Psychiatry: 1999; 60 (Suppl 21): 20-24. 96 Metabolic Complications of Atypical Antipsychotics: Results from the CATIE Study * Reference value compared to baseline OLANZAPINE QUETIAPINE RESPERIDONE ZIPRASIDONE CLOZAPINE ARIPIPRAZOLE Zyprexa Seroquel Risperdal Geodon Clozaril Abilify Weight Change lbs/ Month 2 lbs 0.5 lbs 0.4 lbs -0.3 lbs 0.5 lbs --- HbA1c (%) 0.4 0.04 0.07 0.1 0.1 --- 13.7 7.5 6.6 2.9 13.2 0.9 9.4 6.6 -1.3 -8.2 7.3 -0.7 40.5 21.2 -2.4 -16.5 52.6 0.6 Blood Glucose (mg/dl) Total Cholesterol * * (mg/dl) Triglyceride (mg/dl) The CATIE TRIAL (Clinical Antipsychotic Trials of Intervention Effectiveness) Eng J Med 2005;353:1209-1223 * Data for Clozapine & Aripiprazole are from separate sources N Questions / Comments?