Presentation on theme: "Back to Basics Practical Pharmacology"— Presentation transcript:
1 Back to Basics Practical Pharmacology Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDAssistant Professor, Dept of Family Medicine, University of OttawaClinical Pharmacist, Bruyere Academic Family Health TeamMarch 2013(Partially adapted from slides by Marc Riachi, R.Ph.)
2 ObjectivesReview all pharmacology in an abnormally short amount of time in preparation for LMCCList the four steps of rational prescribingUnderstand the pharmacological classes, generic examples and mechanisms of action of important tools in the practice of medicine.Understand how the kinetics and dynamics of these agents can affect their useHighlight clinical pearls in the proper use of these agents in practice.
3 Topics to be covered Antiplatelets and anticoagulants Antibacterials AntimycobacterialsAntifungalsNarcotic analgesicsAutonomic nervous systemAnti seizure drugsMigrainesAntidepressantsAntianxiety agentsAgents for insomniaAntidiabeticsAntilipemicsAntihypertensivesDiureticsNitratesAntiplatelets and anticoagulantsAntiasthmaticsBPHErectile dysfunctionDementiaParkinson’s disease and schizophreniaDyspepsia, GERD and PUDAntiemeticsIBDIBSOsteoporosisGoutOTC drugsAppendix I & IIRef: Marc Riachi, RPh
4 Topics to be covered in this lecture AntibacterialsAntimycobacterialsAntifungalsNarcotic analgesicsAutonomic nervous systemAnti seizure drugsMigrainesAntidepressantsAntianxiety agentsAgents for insomniaAntidiabeticsAntilipemicsAntihypertensivesDiureticsNitratesAntiplatelets and anticoagulantsAntiasthmaticsBPHErectile dysfunctionDementiaParkinson’s disease and schizophreniaDyspepsia, GERD and PUDAntiemeticsIBDIBSOsteoporosisGoutOTC drugsAppendix I & II
5 A Process for Rational Prescribing (your new best friend) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of OttawaMarch 2013
6 ObjectivesTo promote an efficient process for selecting optimal drug therapy for patientsTo promote a process for applying population level evidence based medicine to individual patients.
7 A Structure Requires Process To prescribe or not to prescribe?That is the question…Rational prescribing requires a process for selecting therapy: (in order)EfficacyToxicityCostConvenience
8 1. Efficacy – Ask About… Which HARD Outcomes Which SURROGATE Outcomes Mortality benefit?Morbidity benefit?Which SURROGATE OutcomesClinically relevant?THEN “What is the quality of the evidence to prove this?”Meta-analysis?Randomized Controlled Trial?Case series?Anecdotal evidence?
9 EfficacyIf there is no efficacy, why waste your time on the potential toxicity, cost and inconvenience of a drug?If there is proven efficacy at the population level, then balance this against the potential toxicity to the individual.
10 2. Toxicity – Ask About… Age? Newer agents = Less Safety Data BothersomeSevereCommonNot legalRareWho caresAge?Newer agents = Less Safety DataOlder agents = More Safety Data
11 3. Cost – Ask About… Patient cost vs Societal cost Covered under provincial formulary?Covered under private plans?
12 4. Convenience – Ask About… What is the likelihood of compliance?Frequency of administration?Daily vs QID?Special restrictions? (eg. bisphosphonates)PO vs IV?Home vs Office vs Hospital therapy?Many interactions?Special monitoring requirements?
13 A simple example: Metformin Januvia® VS Why is Metformin first line therapy?Januvia®
15 Toxicity Metformin Januvia® ?Unknown - too new Very rare risk of lactic acidosis?0.03 cases / 1000 pt-yrs (~ 50% fatal)Never clearly implicatedGI upset / diarrheaStart low, go slow!B12 / folate deficiency / anemia (6 - 8/100)Reduced absorption – easy to supplementAnorexiausually transientJanuvia®?Unknown - too new?PancreatitisToo few patients examinedGI upsetedema?elevated risk of infection?
16 Cost & Convenience Metformin Januvia® Ontario Drug Benefit: $ / tabCovered by ODBRxfiles 2012:~ $33 / 100 daysQD to TID poJanuvia®Ontario Drug Benefit:$ / tabCovered by ODBRxfiles 2012:~ $315 / 100 daysOnce daily po
18 Antibiotic Review (80% of the knowledge, 80% of the time) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of OttawaMarch 2013
19 ObjectivesReview clinically relevant pathogens in human disease in an ambulatory care settingReview antibiotic classes and spectra of activityFocus on bread and butter examples of eachReview treatment recommendations for common infections in primary care
20 Process Map the Bugs Map the Drugs Map the Battlefield “Know your enemy”Map the Drugs“Save your ammo”Map the Battlefield
21 Part 1 - Map the (Clinically Important) Bugs “Know your enemy” Gram NegativeAerobicβ-Lactamase NegativeCocci (spheres)Gram PositiveBacilli (rods)Anaerobicβ-Lactamase Positive
30 β-Lactamase EnzymesFirst penicillinase described in 1940’s even before penicillin was clinically available.Most bugs produce some type of β-lactamase enzyme that destroys β-lactam antibiotics (pen’s, ceph’s, carbapenems)Gm[+] cocci & β-lactamase [-]: only Group A strepgive Penicillin
32 Gram Positive Gram Negative Map the BugsAerobesGram Positive Gram NegativeCocci Bacilliβ-L[+] both β-L[+]&[-]AnaerobesBelowdiaphragmB.FragC.Diff3.
33 Map the Clinically Important Bugs AerobesGram [+] Gram [-]Cocci BacilliAtypicalsLegionella pneumoniaChlamydia pneumoniaMycoplasma pneumonia3.Anaerobes(esp. Gut organisms)Eg. C-Diff& B-frag4.
34 1 - Gram [+] Cocci Staphylococcus S. aureus S. epidermidis Methicillin resistant (MRSA)Methicillin sensitive (MSSA)S. epidermidisMethicillin resistant (MRSE)Methicillin sensitive (MSSE)Skin commensalRarely pathogenicStreptococcusGroup A (pyogenes) (β-Lact[-])Group B (agalactiae)Neonates, v. elderly, obstetricsS. pneumoniaetc. etc.Enterococcus(Formerly thought to be ‘Strep D’)E. faecalisE. faecium
35 2 - Gram [-] Bacilli Easy to Kill Proteus mirabilis Escherichia coli Klebsiella pneumoniaSalmonellaShigellaHaemophilus influenza(Moraxella catarrhalis) (actually a Gm[-] coccus)PEcKSS-HiMHard to KillSerratiaPseudomonasAcinetobacterCitrobacterEnterobacterSPACE bugs
36 Gram Negative vs Gram Positive Gm[-]: red on stain. (ie. Don’t retain stain) Gm[+]: blue-purple on stain;Gm[-]: must pass through pores Gm[+]: molecules < 100kDa pass easily.Gm[-]: b-lactamases concentrated in periplasmic space Gm[+]: b-lactamases diffuse outside cell;
37 Map the Bugs Summary Atypicals: Anaerobes: Gram positive aerobes: Mycoplasma pneumoChlamydia pneumoLegionella pneumoMap the Bugs SummaryAnaerobes:OralGut – Bfrag & CdiffGram positive aerobes:CocciStaphAureusMRSA (~8-10%)MSSAEpiderimidisMRSE (~65%)MSSEStrepGroup A strep (pyogenes)Group B strep (agalactiae)Strep ViridansStrep pneumo etc.EnterococcusFaecalisFaeciumBacilliListeriaGram negative aerobes:BacilliEasy to KillPEcKSS (Proteus, Ecoli, Klebsiella, Salmonella, Shigella)HiM (H.flu and Moraxella (actually a Gm[-]coccus))Hard to KillSPACE bugs (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter)CocciNeisseriagonorrhaeameningitidisMoraxella catarhallis
39 Map the Drugs Arms race! Older drugs tend to be simpler drugs Remember: “Bigger guns breed higher walls”Older drugs tend to be simpler drugsMore narrow spectrumBroad spectrum drugs breed resistanceSuperbugs developMRSA, VRE, ESBL, etcOlder drugs have more safety dataTend to be less toxicLearn their historyLearn their pharmacology
40 Part 2 - Map the Drugs “Save your Ammo” FluoroquinolonesPenicillinsTetracyclinesAminoglycosidesMacrolidesVancomycinCarbapenemsCephalosporinsClindamycinMetronidazole
41 Antibiotics – Mechanisms of Action From: Accessed Dec 28/12
43 Beta-Lactams - Cephalosporins 1st GenerationCephalexin (Keflex™)(or Cefadroxil) (po)Cefazolin (Ancef™) (iv)2nd GenerationCefuroxime (po & iv)3rd GenerationCeftriaxone, Cefotaxime, Ceftazidime (iv)Cefixime (Suprax™) (po)4th GenerationCefepime (iv)Increasing Gram[-] coverageCefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID- Same spectrum of activity, only BID, cheap and covered by ODB too.
44 Beta-Lactams – Other (FYI) (IV only, inpatient use only) Piperacillin (plus tazobactam)big gun, tazo = suicide substrate, like clavulanic acidCarbapenemsMeropenemImipenemErtapenemMonobactamsAztreonamBroad spectrum, big gun antibiotics that cover Gm[+], both easy and hard to kill Gm[-] bugs, even some anaerobes.
45 Antibiotics – Mechanisms of Action From: Accessed Dec 28/12
46 Fluoroquinolones 2nd generation 3rd generation 4th generation OfloxacinCiprofloxacinNorfloxacin3rd generationLevofloxacin4th generationMoxifloxacinCovers: strep & Gm[-]’sPEcKSS-HiM & SPACE bugsOfloxacinCiprofloxacinAnti-pseudomonal – the only PO option!NorfloxacinSame spectrum as Cipro (even anti-Pseudomonal) – but only for cystitis UTI.Concentrates in the G.U. system onlyN.B. Not good enough for pyelonephritis or systemic infection
47 Fluoroquinolones The “Respiratory FQs” Levofloxacin Moxifloxacin Concentrate in alveolar macrophagesGreater than serum concnLevofloxacinthe more active L-enantiomer of OfloxacinRenal clearanceMoxifloxacinHepatic clearanceEnhanced coverage of:Strep pneumoOral AnaerobesAtypicalsN.B. only Moxi cover B.fragNeither covers C.diff(Both will cover Clostrium non-difficile strains)Both have 100% oral bioavailabilityTherefore PO = IV dose
48 Antibiotics – Mechanisms of Action From: Accessed Dec 28/12
49 Macrolides Coverage of: Clarithromycin Azithromycin Erythromycin Atypicals, Strep pneumo, & Hi.M. (Hflu & Mcat)So, good for respiratory infections!N.B. But doesn’t cover PEcKSS or SPACE bugsErythromycinEfficacy: Poorer coverage of H.flu, MSSAToxicity:Prokinetic – diarrhea!Worse for QTc prolongationConvenience: QID dosingClarithromycinBetter Hflu &MSSA coverageLess QTc prolongation vs EShorter half-life vs AzithroBID dosing x 7-10daysNew daily ‘XL’ formulationAzithromycinAn azalide, (not a macrolide)Same spectrum of activityLess QTc prolongation vs E & C!Long t1/2 – QD dosing x 5dBUT can breed resistant S.pneumo (since below [MIC] for long periods of time)
50 Antibiotics – Mechanisms of Action From: Accessed Dec 28/12
51 Aminoglycosides Gentamicin Tobramycin Amikacin Reserved for Pseudomonas aeruginosaAmikacinAll excellent Gram[-] coverage:PEcKSS-HiM and SPACE bugsEfficacy: excellent Gm[-]Toxicity:NephrotoxicityOtotoxicityLess now with daily dosingCost:Cheap, old medsConvenienceNow Once daily IV/IM
52 Pharmacodynamics Relationship between Abx Concentration & Effect Concentration Dependent KillingHigher the peak, better the killi.e. Ratio of peak drug concentration and M.I.C. determines rate of kill.Eg. FQs, AGsTime Dependent KillingTime over MIC mattersi.e. Independent of peak concentration. Determined by length of time over MICEg. B-lactams (Pen, Ceph etc)Log [Conc]PeakLog [Conc]MICMICTime (h)Time (h)
53 Pharmacodynamics Relationship between Abx Concentration & Effect Concentration Dependent KillingHigher the peak, better the killi.e. Ratio of peak drug concentration and M.I.C. determines rate of kill.Eg. FQs, AGsWith renal impairment:Maintain the peak, lengthen the intervalThis ensures good rate of killing while allowing enough time to eliminate the drug and avoid toxicitiesFor eg:If CrCL = 90mL/min - Levofloxacin 750mg q24h poIf CrCL = 30mL/min – Levofloxacin 750mg q48h poPeakPeakLog [Conc]Log [Conc]MICMICTime (h)Time (h)
54 Pharmacodymamics Bactericidal vs Bacteriostatic Bactericidal AbxB-lactams (Pen, Ceph)Aminoglycosides (AGs)Fluoroquinolones (FQs)RifampinMetronidazoleVancomycinBacteriostatic AbxTetracyclinesMacrolidesClindamycinChloramphenicolRarely a clinically important characteristic, unless the patient is immunocompromised or the risk of death with delayed/incorrect therapy is high.
55 Combination Therapy Why? Broaden spectrum (eg. Mixed infection)Synergistic activity for hard to kill bugs(eg. Enterococcus or pseudomonas)Prevent resistance(eg. TB)Reduce dose and side effects
56 Map the Drugs Pharmacology Summary Many antibiotic classesBeta-lactams generally safest agents.Even at high dosesSome have overlapping mechanisms of actionAvoid combining similar mechanisms of actionCompeting effects may reduce effectiveness of one agentEg. Penicillins + vancomycin – cell wall synthesis inhibitorsEg. Tetracyclines + aminoglycosides –protein synthesis inhibitors via 30-S subunit of the ribosome
59 Map the Battlefield Rational Prescribing IndividualEfficacyCould be reduced, BUT:Empiric tx still effective if it is well chosen(Lower risk infections, properly dosed, clinically stable, true indication etc.)ToxicityReduced with narrow spectrum txCostReduced with older txConvenienceUsually less convenientPopulationEfficacyMaintained long term with lower resistance ratesToxicityReduced since lifespan of older drugs is maintainedCostReduced insurance costs, economic losses, hospital costs dealing with superbugsConvenienceVS.
61 Map the BattlefieldOtitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)Conjunctivitis: viral – no txSinusitis: viral – no txAECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)Oral anaerobes: abscess drainage – no tx(Amox 2g – pre dental sx?)C.A.P: S.pneumo, atypicals – (Amox, Macrolides (Clarithro/Azithro))CAP+comorb./risk factors, or NHAP: also HiM bugs (Combine AmoxClav or Cef2 + Macrolide (or use FQ))Pharyngitis: viral – no tx(Group A Strep – Pen VK)Bronchitis: viral – no txSkin abscess: drainage – no txCellulitis: MSSA, S.pneumo – (Clox, Cef1, Clinda)H.pylori: triple po tx PPI + (Clarithro +/- Amox +/- Metro)Pyelonephritis: PEcK – (Septra, Amox/Clav, FQ (not Norflox)UTI (Cystitis): PEcK – (Septra, Macrobid, Amox, Norflox)Cdiff / Bfrag: Metro / po VancoTraveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter) - Septra, FQ, (Azithro)
62 (Group A Strep, oral anaerobes, Neisseria) Map the BattlefieldPenicillin(Group A Strep, oral anaerobes, Neisseria)Amoxicillin / Ampicillin Cloxacillin(Strep & Enterococcus plus (Staph aureus, Staph epi)Easy-to-Kill Gm[-](ie. PEcKSS))Amox/Clav (Vancomycin)(for Strep & Entero & PEcKSS-HiM) (for MRSA / MRSE)(H.flu & Moraxella can be ~35% amox resistant) (~8-10% / ~ 65% resistant)
63 Beta-Lactams - Cephalosporins MSSA and Strep & PEcKSS(same as Amox)N.B. never Enterococcus!1st GenerationCephalexin (Keflex™) or Cefadroxil (po)Cefazolin (Ancef™) (iv)2nd GenerationCefuroxime (po & iv)3rd GenerationCeftriaxone, Cefotaxime, Ceftazidime (iv)Cefixime (Suprax™) (po)4th GenerationCefipime (iv)To boost: for PEcKSS-HiM(same as Amox/Clav)Increasing Gram[-] coverageSPACE bugs: The Big GunsCefadroxil (po) 500mg BID or 1g BID – good alternative to KEFLEX 250mg QID or 500mg QID- Same spectrum of activity, only BID, cheap and covered by ODB too.
64 SPACE bugs The Big Guns: 3rd and 4th generation Cephalosporins Carbapenems (Meropenem)Piperacillin/TazobactamAminoglycosides (Gentamicin, Tobramicin)Fluoroquinolones (Levofloxacin, Moxi, Cipro)
65 Reserved for Pseudomonas Ciprofloxacin (FQ)The only PO agent!(Use Norfloxacin for UTI if a FQ is needed)Ceftazidime (Cef3)Cefipime (Cef4)Tobramycin (AG)Piperacillin/TazobactamMeropenem
66 Need for Bigger gunsThere is a higher risk of Gram negative SPACE bugs with:More risk factors / comorbiditiesCOPD, HIV, Diabetes, CKD etcMore institutionalized settingsCommunity Retirement Home Nursing Home Hospital ward ICU ventilated pt in ICU.
67 Map the Battlefield PEN – for Group A Strep, oral anaerobes, Neisseria ?What to do for Strep/Entero?Amox po / Amp iv (also good for PEcKSS)How to boost? Amox/clav (for HiM-PEcKSS)?What to do for Staph?Clox (MSSA, MSSE); Else Vanco (MRSA, MRSE)What about Cef1? (cephalexin / cefadroxil po or cefazolin iv)Maps to Amox/Amp for PEcKSS and strepN.B. NOT Enterococcus (Cef’s never cover enterococcus!)How to boost? Cef2 (cefuroxime) for HiM-PEcKSSWhat about SPACE bugs?FQs, AGs, Cef3, Cef4, Pip/Tazo, Meropenem)Reserved for Ps aureginosa:(cipro, tobra, ceftazidime, cefipime, pip/tazo, meropenem)What about gut anaerobes? (Metro/PO Vanco)What about atypicals? (Macrolides, Tetracyclines (doxy))Where does Septra fit? (with Amox/Clav and Cef2)
68 Antibiotics contraindicated in pregnancy (category X) Tetracyclines (also in children < 9 y.o.): are incorporated into fetal skeleton/unerupted teethFluoroquinolonesErythromycin estolate (may cause toxic liver reaction), clarithromycinTMP: in 1st trimester because it is a folate antagonistSulfonamides: last trimester or if delivery is imminent because they interfere with the bile conjugating mechanism of the neonate and may displace bilirubin bound to albumin which may lead to jaundice and kernicterusNitrofurantoin (during labor and delivery only): can affect glutathione reductase activity and hence can cause hemolytic anemia (analogous to the problems it causes in patients with glucose-6-phosphate dehydrogenase deficiency) and hemolytic crises have been documented in newborns and fetusesAminoglycosides: nephrotoxic and ototoxic to the fetusHigh (>2 grams) single dose metronidazoleChloramphenicol (at term or during labour): limited glucuronidating capacity of the newborn’s liverRef: Marc Riachi, RPh
69 Antibiotics Preferred in Pregnancy PenicillinsIncluding those in combination with ß-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam)CephalosporinsErythromycin baseAzithromycinClindamycinMetronidazole(regular dose mg BID)Ref: Marc Riachi, RPh
70 Summary This is far from an exhaustive review Some parts have been highly simplified for use in clinical practiceSome memorization is needed with regular review of the material to retain this knowledgeDoing so will allow you to choose empiric antibiotics with greater comfort in difficult situations and unfamiliar settings.
73 Adapted from: Marc Riachi, RPh TB drugsAdapted from: Marc Riachi, RPh
74 Mycobaterium tuberculosis The Consumption Mostly latent, asymptomatic infection (90-95%)Activation risk ~ 10%Usually pulmonary; can occur anywhereSpreads via air dropletOne third of world population infected!Europe:, TB rates rose from 1600s to peak in the 1800s (caused ~25% of all deaths)Organism has "waxy" hard to penetrate cell wallAcid-fast bacilliCombinations of drugs needed to treatSlow growingTherefore requires extended treatment periodTreatment:Multiple side effects = reduced compliance by patient = further emergence of resistant strainsMDR, XDR strainsAdapted from: Marc Riachi, RPh
75 Available antimycobacterials First-line:Isoniazid (INH)Rifampin (RIF) or Rifampicin (RMP)Pyrazinamide (PZA)Ethambutol (ETB)Second-line:AmikacinFQs (Ciprofloxacin / Levofloxacin / Moxifloxacin)Clarithromycin / AzithromycinRef: Marc Riachi, RPh
76 Treatment - Active Pulmonary TB “4 drugs x 2 months, then 2 drugs x 4 mo”(N.B. 2x/weekly dosing must be D.O.T.)Ref: PHAC. Canadian Tuberuclosis Standards, 6th Ed p Access March 14, 2013.
77 Treatment – Latent TB RIF – GI toxicities, major drug interactions! INH – monitor LFTsHepatitis (rare < 20y.o.; >2% in >50y.o.)Drug interactions!RIF – GI toxicities, major drug interactions!Huge inducer of cytochrome P450Ref: PHAC. Canadian Tuberuclosis Standards, 6th Ed p Access March 14, 2013.
78 Which agents to use in active disease? Pulmonary or extrapulmonary disease:INH+RIF+PZA+ETBIf resistant to INH:RIF+PZA+ETB (+FQ if severe)If resistant to RIF:INH+PZA+ETB+FQif resistant to INH and RIF:PZA+ETB+FQ+amikacinIf resistant to INH, RIF and PZA or ETBETB (or PZA)+FQ+amikacin+two 2nd line agentsRef: Marc Riachi, RPh
80 Adapted from: Marc Riachi, RPh Anti-fungalsAdapted from: Marc Riachi, RPh
81 Drug info PZA (may inhibit mycobacterial metabolism): INH (inhibits formation of fatty acids found in the cell wall):Bactericidal; penetrates cavitationsHepatotoxicity (↑ with alcohol & rifampin) monitor LFTsperipheral neuropathy (give vit B6)GI symptoms, skin rash↑ phenytoin, carbamazepine & benzodiazepine blood levelsRIF (inhibits mRNA synthesis):Hepatotoxicity (↑ with alcohol) monitor LFTsPancytopeniaColours urine, feces, saliva, tears orange may permanently stain contact lensesInduces CYP450PZA (may inhibit mycobacterial metabolism):Bactericidal in acid environment (in macrophages)Hepatotoxicity (↑ with alcohol & rifampin) monitor LFTsHyperuricemia monitor uric acidGI symptoms and arthralgiasETB (may inhibit cell wall synthesis):BacteriostaticGI symptoms, hyperuricemiaOcular toxicity and change in color perception monitor at high dosesRef: Marc Riachi, RPh
82 Antifungals Oral Topical Injectables Azole anti-fungals Itra- (Sporanox),flu- (Diflucan),vori-,posa-ketoconazole (Nizoral)active vs. yeast and dermatophytesTerbinafine (Lamisil)Nystatinactive vs. yeast onlyTopicalCiclopirox(cream, lacquer, shampoo),nystatin(cream, pv, oral suspension),clotrimazole(cream, pv),miconazoleketoconazole(cream shampoo),terbinafine(cream, spray),tolnaftate(powder suitable for skin folds)Injectablesusually require I.D. consultRef: Marc Riachi, RPh
83 Which agents to use? Onychomycosis: Fungal skin: oral terbinafine, oral itraconazole, ciclopirox lacquer (use lacquer only for mild distal form; expensive)Fungal skin:topical clotrimazole, topical miconazole, topical terbinafine, topical ketoconazole. Nystatin is ineffective vs. dermatophytes. Candidal skin infections respond to nystatin. Use topical azoles for tinea versicolor (not terbinafine).Seborrheic dermatitis:topical ciclopirox, ketoconazoleOral candidiasis:Oral nystatin swish and swallow (not absorbed from GI tract). Oral fluconazole.Vulvovaginal candidiasis:topical azoles, po fluconazole one dose (now available without a prescription), boric acid pv suppositories (very irritative)Diaper rash:Topical nystatin, clotrimazole, miconazole, or ketoconazole.Ref: Marc Riachi, RPh
84 Drug info Terbinafine po: Very active vs dermatophytes headache, GI diarrhea, dyspepsia, abdominal paintaste disturbance (may persist post treatment)CYP2D6 inhibitor:Decreases formation of active metabolites of tamoxifenMay ↓ breakdown of TCA’s, fluoxetine, paroxetine, fluvoxamine, sertraline, tamsulosin, mirtazapine, haloperidol, some beta blockersAzole antifungals po:Itraconazole and ketoconazole particularly are strong inhibitors of CYP3A4 and so many drug interactions. Also hepatotoxic. Ketoconazole > itraconazole > terbinafine wrt hepatic toxicity. Itra may worsen heart failure symptoms. Ketoconazole is rarely used and is poorly tolerated; anorexia, nausea, vomiting high doses, and effects sexual function/sex hormones and steroidogenesis.Fluconazole is considered a moderate inhibitor of CYP3A4 and so less clinically important drug interactions. Strong CYP2C9, 2C19 inhibitor. QT prolongation with amiodarone, clarithromycin, TCA’s. Bioavailability of PO similar to IV; use PO if possible.Ref: Marc Riachi, RPh
86 Hypertension and BP Meds (The ABCD’s of HTN) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of OttawaMarch 2013
87 ObjectivesList first line classes of medication for the treatment of essential hypertensionExplain how co-morbid indications may change your choice in therapyApply a rational approach in selecting therapyUnderstand the dosing, monitoring and titration of key examples from each class of medication
88 Rational PrescribingRational prescribing requires a process for selecting therapy: (in order)EfficacyToxicityCostConvenience
89 Reduced sympathetic outflow, and heart rate BCDARBACEinhB-blockersCCB(DHP-type)Diuretics(Thiazide type)Angiotension Receptor BlockerAngiotensin Converting Enzyme InhibitorBeta-BlockerCalcium Channel Blocker (dihydropyridine type)-sartan-pril-olol-dipineLosartanValsartanCandesartanEtcRamiprilEnalaprilPerindoprilBisoprololMetoprololAtenololAmlodipineNifedipineFelodipineChlorthalidoneHydrochlorothiazideIndapamideBlocks conversion of AT1 to ATII (ACEinh) or blocks ATII receptors (ARB) =Inhibition of vasoconstriction, aldosterone, catecholamine, and arginine vasopressin release, water intake, and hypertrophic responsesReduced sympathetic outflow, and heart rate(b1 receptor – in heart)(cardioselective ~ A-M)(b2 receptor – in lungs)(Non-selective ~ N-Z)(“one heart; two lungs”)Relaxation of coronary & peripheral arterial smooth muscle(not AV node!)Inhibits Na+ & Cl- reabsorption in the cortical-diluting segment of the ascending loop of Henle= diuresis.Reduction in systemic vascular resistanceEfficacy: 1st line1st line1st line (< 65y.o.)
90 Toxicity: A B C D Hypotension HyperK+ Acute renal failure (ARF) AngioedemaMonitor: SCr, K+, BPBradycardiaBronchoconstriction (in brittle asthmatics with non-cardioselective bbl’s)Monitor: BP, HR, RREdemaOrthostatic hypotensionHypoNa+HypoK+ARFMonitor: SCr, lytes, BPCost:Generic - $$$ODB coveredGeneric - $$Generic: $$$Convenience:QDLosartan25mg to 100mgRamipril2.5mg to 10mgBisoprolol 2.5mg to 10mgAmlodipine 2.5mg to 10mgQAMChlorthalidone 25mg
91 Choosing TherapyIf efficacy (#1), cost (#3) and convenience (#4) are all more or less equivalent:Choose based on potential Toxicities (#2)Tailor the meds to the individual patient!Evidence of efficacy is population basedToxicities are individual.Some combos are additive others synergistic BP loweringRarely clinically relevantCan choose between groups A or B plus C or D (synergistic)N.B. Choice will also be guided by various comorbidites
92 Comorbidities ARB ACEinh B C D Indication HTN (ALLHAT) MI (HOPE trial) (ALLHAT)MI(HOPE trial)(VALIANT)(CAPRICORN, BHAT)CHF(CONSENSUS, SOLVD, ATLAS)(MERIT-HF, CIBIS II, COPERNICUS)DM2(HOPE)(IDNT, IRMA-2, RENAAL)CVA(HOPE, PROGRESS)(LIFE, SCOPE, MOSES)(ALLHAT, PROGRESS)PVDAfib(Diltiazem)
93 Second Line TherapyWhat if you have used all available 1st line options?2nd line options:Alpha blockersSpironolactoneHydralazineNitratesClonidineBeta-blockers (> 65 y.o.)etc.~ Equivalent efficacy – choose based on potential toxicity, cost or convenience factors.Ensure that you balance these factors in their order of importance.
94 Second Line Therapy Alpha blockers Spironolactone Hydralazine Nitrates Eg. Terazosin, Prazosin, DoxazosinToxicity: Risk of orthostatic hypotensionCost: cheap, genericConvenience: only QDGood 1st choice of 2nd line txDual treatment of BPH & BP if also needed in male patientsSpironolactoneEfficacy: mortality benefit in late stage CHF (NYHA class III or IV)Toxicity: risk of hyperK+esp with ARBs or ACEinh’sCost: cheap genericHydralazineMOA: direct vasodilation of arteriesToxicity: orthostatic hypotensionCost: cheap, genericConvenience: QID dosingNitrateseg. ISDN, ISMN, NTGMOA: smooth muscle vasodilation of vasculature (veins > arteries);Toxicity: headache, orthostatic hypotension, dizzinessCost: cheap/ genericConvenience: BID- QID dosing;
95 Process Start first drug Increase to moderate dose Monitor for efficacy (BP) and toxicityIf close to target:increase doseIf far from target:start new drugDose response curvesFlatten at top halfLess bang for your buckBPmg
97 Oral Anti-hyperglycemics Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of OttawaMarch 2013
98 ObjectivesList the classes of oral antihyperglycemic agents and understand their place in therapy.Determine the relative efficacy, toxicity, cost and convenience of these agents before choosing therapyRationalize prescribing of oral hypoglycemicsDescribe the current approach to pharmacologic management of type 2 diabetes.
99 Diagnosis of IFG, IGT Category FPG 2-hour after OGTT And/or IFG N/AIFG (isolated)AND< 7.8IGT (Isolated)< 6.1IFG and IGTIf FPG + risk factor for diabetes/IGT order a 2hPG in a 75-OGTT.If and no risk factor then IFG.Can J Diabetes 2003;27(2);S11
101 Kumamoto Study – HgbA1c & Complications Intensive vs. conventional insulin therapy (n=110)Median A1c % vs. 9.4%Retinopathy16Nephropathy1614141212Rate per patient-yearsRate per patient-years101088667%7%4422567891011567891011HbA1c (%)HbA1c (%)
102 Prevention of Diabetes in IGT Lifestyle modification(see Finnish Diabetes Trial)Moderate weight loss (5%) (esp. abd fat)Regular physical activity> 150 minutes per week58% RRR for type 2 Diabetes at four yearsPharmacotherapyMultiple effective trialsEg. LIFE trial - Losartan onset of new DM2***Based on the Finnish Diabetes Prevention Study and the Diabetes Prevention Program.Can J Diabetes 2003;27(2);S12
103 Pharmacological Prevention Studies StudyDrugDuration(years)RRR (%)DPPMetformin850mg BID2.831STOP-NIDDMAcarbose 100mg TID3.330DREAMRosiglitazone8mg daily3.055XENDOSOrlistat 120mg TID4.037DPPDiabetes Prevention ProgramMetformin was more effective in younger more obese subjects and less effective among older, thinner people.STOP-NIDDM- Study to Prevent Non-Insulin Dependent Diabetes MellitusTRIPODTroglitazone in Prevention of DiabetesThis glitazone was withdrawn from the market and was never availabe in CanadaXENDOSXenical in the prevention of diabetes in obese swedish subjectsProuded an average weight loss of 5.8 kgDREAMPublished Sept 2006.Included patients with IFG or IGT or both.
104 Non-Pharmacologic Tx Mainstay of therapy! Nutrition therapy ↓ A1c 1-2% CDA recommends counseling by a dietician for all type 2 diabeticsdiet for Type 2 diabetesCan J Diabetes 2003;27(2);S27
105 Comparison of antihyperglycemics PharmacotherapyComparison of antihyperglycemics
110 Drug ClassesOtherAlpha glucosidase inhibitors (Acarbose)Competitive inhibitor of pancreatic α-amylase and intestinal brush border α-glucosidases, resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose;Dose-dependent reduction in postprandial serum insulin and glucose peaks; inhibits the metabolism of sucrose to glucose and fructoseDPP4 inhibitors (Gliptins) – (Sitagliptin (Januvia), Saxagliptin (Onglyza))Prolongs the action of endogenous incretin hormones by blocking their breakdown by the enzyme, dipeptidyl peptidase-4 (DPP-4).This leads to more insulin release after eating.Incretin Analogues – (Liraglutide (Victoza), Exenatide (Byetta)) (sc inj)mimic endogenous incretin hormones
111 Rational Prescribing FOUR steps to Rational Prescribing: EFFICACY TOXICITYCOSTCONVENIENCE
112 EFFICACY – Ask… HARD Outcomes SURROGATE Outcomes Any mortality benefit?Any morbidity benefit?Then,SURROGATE OutcomesClinically relevant?
113 EFFICACY HARD Outcomes SURROGATE Outcomes Mortality benefit Morbidity Metformin – UKPDS-34 trialMorbiditySURROGATE OutcomesHgb-A1cBlood glucose levelsFasting or PrandialInsulin Sparing Effects
114 Effect of Metformin on Event Rates in the UKPDS Diabetes-related endpoint 32% p=0.002All-cause mortality 36% p=0.011 MI / CVADiabetes-related death 42% p=0.017But.. When added early to sulfonylurea risk of DM-related death (?statistical anomaly?)
115 EFFICACY A) Surrogate Outcome - Hgb-A1c ~ 1% to 2% ~ 0.5% to 0.8% METFORMIN (1% - 2%)SULFONYLUREA’s (1% - 2%)REPAGLINIDE (1% - 1.5%)GLITAZONE’s (0.4% - 1.5%)~ 0.5% to 0.8%ACARBOSEDPP4 inhibitors (‘GLIPTINS)NATEGLINIDENathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.
116 EFFICACY B) Surrogate Outcome - Insulin Sparing Effect METFORMINACARBOSEGLITAZONE’s (Pioglitazone)Gliptins (Sitagliptin, Saxagliptin)Incretin Analogies (Liraglutide, Exenatide)= Weight neutral or weight negative= Reduction of hyperinsulinemia
117 TOXICITY – Ask… Serious / Fatal Side Effects Bothersome / Common s.e. Age?Newer agents = Less Safety DataOlder agents = More Safety Data
131 Did I say, never? I meant NEVER! 1st line – METFORMIN2nd line - SULFONYLUREA or INSULINMeglitinide – if poor CrCL or irregular eating3rd line - GLIPTINs or ACARBOSE if patients absolutely REFUSE insulinNEVER USE GLITAZONEs!Did I say, never? I meant NEVER!
132 Individualization of Drug Therapy Patient FactorConsider→ Possibly preferred drugsRenal FailureRepaglinide (Gluconorm)Also: gliclazide, insulinHepatic DiseaseInsulin, repaglinide, acarboseCaution: glyburide, metformin, glitazonesHyoglycemiaMetformin, AcarboseAlso, repaglinide, nateglinide, gliclazide, glimepiride;ObeseIrregular MealtimesRepaglinide (may be preferred over SU)PPBG >10mmol/L and FBG minimally ↑’dRepaglinide or AcarboseInsulin lispro (Humalog) if PPBG very high
134 Insulins Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD Pharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of OttawaMarch 2013
135 **Animal-source insulin- demand has decreased now that human insulin is available. There are some patients who cannot control their diabetes on human insulin.**Beef insulin also available through Health Canada’s Special Access Programme.Humalog388 For the treatment of patients with Type 1 diabetes mellitus. LU Authorization Period: Indefinite. 389 For the treatment of patients with Type 2 diabetes mellitus using insulin in an intensive regimen with 3 or more injections per day or an insulin pump. LU Authorization Period: Indefinite. 390 For the treatment of patients with Type 2 diabetes mellitus who are either experiencing recurrent hypoglycemia OR are unable to achieve adequate post-prandial glucose control while on a less intensive regimen of regular insulin (1-2 injections per day).NovoRapidHumulin R, NPH vial $15, 3X5 cartridges 32$Humalog, Novorapid vial 23$, 3X5 cartidges $46New Drugs/Drug News vol 24 (3): May/June 2006
136 Insulins - Simplified Long = Basal Short = Prandial Premixed NPH, (N)Glargine (Lantus)Detemir (Levemir)Short = PrandialShortRegular (R)TorontoRapidLispro (Humalog)Aspart (NovoRapid)Glulisine (Apidra)Premixed30/70 (and 10/90, 20/80, 40/60, 50/50)Humalog Mix-25, NovoMix-30Which to choose?
137 Basic Concepts Hyperglycemia = Chronic Hypoglycemia = Acute So, go after Hypo’s first!Fed: 6h/24h = 25%Fasting: 18h/24h = 75%So, go after Fastings first!AM affects PM & HSSo, go after AM first!?Any hypo’s?- fix ‘em!then,FBS AMFBS NoonFBS PMFBS HS2h PPG AM2h PPG Noon2h PPG PM
139 Rational Prescribing FOUR steps to Rational Prescribing: EFFICACY TOXICITYCOSTCONVENIENCE
140 Long – Basal Insulins Efficacy: NPH = Lantus = Levemir = NPH EquivalentMorbidity benefits, A1c lowering effectDespite the marketing:Kinetics don’t affect overall efficacy:Slowest absorption: Thigh (best for basal insulins)Fastest absorption: Abdomen (best for prandial insulins)Lots of Lantus is injected BIDNPH can be used QHS for some
141 Long – Basal Insulins Toxicity: All: NPH: Lantus / Levemir: HypoglycemiaNPH:Peak effect at ~ 8hrs (4-10hrs)Risk of hypoglycemia (~ 5%? vs “peakless” insulins)Lantus / Levemir:Insulin analoguesIncreased breast cancer risk?more research needed
142 Long – Basal Insulins Cost: Convenience: All: covered under ODB N.B. No Rx required for any insulins – all OTCNPH: ~ $40Lantus: ~ $90Levemir: ~ $100Convenience:All sc injections, via penfillsAll QD – BID
143 Bottom Line – Basal Insulins All equivalentChoose therapy based on cost (NPH)For the very small proportion suffering from hypoglycemia due to the peak effect of NPH or lamenting BID dosing, consider Lantus or Levemir.
144 Starting Basal Insulin Fancy Way:calculate unit/kg dose = u/kg/day scRisk hypoglycemia on first dose – lose your patient’s buy-in forever.Primary Care Method:Initiate 5u or 10u qhs scTitrate by 1-2u q3-4d until AM FBS = mmol/L10% titrationsIf dose = 30’s – increase by 3 unitsIf dose = 40’s – increase by 4 unitsetc. etc.
147 Short – Prandial Insulins EfficacyEquivalent reduction in morbidity, HgbA1c
148 Short – Prandial Insulins ToxicityHypoglycemiaRapid insulins better reflect physiological effect of pancreatic insulin (vs Regular insulin)More important in CKD (=longer insulin t½ )
149 Short – Prandial Insulins CostAll covered under ODBRegular (R) / Toronto ~ $40NovoRapid (aspart) ~ $56Humalog (lispro) ~ $55Apidra (glulisine) ~ $48ConvenienceAll injected with mealsRegular insulin injected min before mealRapid insulin can be taken with mealReduced risk of hypo if pt injects, then forgets to eat
150 Bottom Line – Prandial Insulins All equivalentChoose therapy based on cost / familiarityRapid insulins reflect pancreatic insulin release better than [R]/Toronto.The worse the CrCL, the more important this fact becomes.
151 Starting Prandial Insulin Fancy Way:Total dose: 0.5u/kg40% of total dose - basal insulin qHS20% of total dose TID with meals (60%) – prandial insulin min before mealsEg. 80kg pt – 0.5u/kg = 16u basal (40%); 8u TID (20% x 3 = 60%)Primary Care Method:Start 5u sc with mealsTitrate AM to HS to targetMonitor 2h PPGStart injection TID or only single meal as requiredIf poor control: inj TID sc; If mediocre control: inj qAM scStill aim for ~ 2/3rds split (40% basal / 60% prandial)
153 Pre-mixed Insulins NovoMix-30 = Humalog Mix25 (equivalent) Efficacy All ~ 30% short / 70% longToxicityHypoglycemia (less with Rapid vs Regular insulin)Cost: ~$53 (Rapids) ~$40 (Regular 30/70)Convenience ~ Rapids can be injected with meal
154 Starting Pre-mixed Insulins Fancy Way:Estimate total starting daily dose( units/kg)Divide daily dose:2/3 before breakfast; 1/3 before supperPrimary Care Method:From scratch: Start 5-10u QD-BID and titrateFrom other insulins: Calculate approximate amount of basal and prandial units and divide 2/3rd - 1/3rd AM and PM
155 Pearls Insulin is 2nd line after metformin No need to save it for last!Better than adding a 3rd PO drugBetter efficacy, lower toxicity, better studiedImprove buy-in from patient:“Natural” supplementOnly BID glucochecking at alternating times required:FBS AM + PPG AM, thenFBS AM + FBS noon, thenFBS AM + PPG noon, thenFBS AM + FBS PM, thenFBS AM + PPG PM, thenFBS AM + FBS HSrepeat
156 Pearls (cont’d)D/C secretagogues after starting insulin to reduce risk of hypo’s.Eg. Sulfonylureas, meglitinidesBlack box warning against combo with glitizones! (Actos, Avandia)
158 Anti-Dyslipidemic Drugs (So simple it hurts) Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHTAssistant Professor, Dept Family Medicine, U of OttawaMarch 2013
159 ObjectivesList the 4 steps in rationalizing drug therapy choices using evidence based medicine.List the important parameters in choosing anti-dyslipidemia drugs in a clinical setting.Identify clinically important differences in the efficacy, toxicity, cost and convenience of different anti-dyslipidemics.Recognize the inherent weaknesses of current guidelines.
160 Rational Prescribing Process FOUR steps to Rational Prescribing:EFFICACYTOXICITYCOSTCONVENIENCE
161 Choosing Anti-dyslipidemics First, define your options:Statins (HMG-CoA Reductase inhibitors)Prava-, Fluva-, Simva-, Atorva-, Rosuva-statinFibrates(The exact mechanism of action of gemfibrozil is unknown; Theories re: the VLDL effect; it can inhibit lipolysis and decrease subsequent hepatic fatty acid uptake as well as inhibit hepatic secretion of VLDL; together these actions decrease serum VLDL levels; increases HDL-cholesterol; the mechanism behind HDL elevation is currently unknown)Feno-, Beza-, Clo-fibrate, & GemfibrozilEzetimibe(Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)).NiacinCholestyramine(Bile acid sequestrant)
162 Efficacy – Endpoints? Hard Endpoints Soft Endpoints Reduction in mortalityFatal MI, Fatal strokeReduction in morbidityNon-fatal MI, non-fatal stroke, reduction in hospitalizationSoft EndpointsReduction in plaque sizeReduction in lipid panel valuesetc
163 EfficacyOnly statins have any proven reduction in hard endpoints.
167 Cdn Dyslipidemia Guidelines 2009 Can J Cardiol Vol 25 No 10 October 2009
168 Cdn Dyslipidemia Guidelines 2009 Can J Cardiol Vol 25 No 10 October 2009
169 Pharmacotherapy“The majority of patients will be able to achieve target LDL-C levels on statin monotherapy.”“Clinical outcome data on the incremental benefit of combination therapy with statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are lacking, although clinical trials are underway to examine this issue.”Can J Cardiol Vol 25 No 10 October 2009
170 Correlation versus Causation Example of sun rise and sun set and flag going up and down the flag pole– can’t make the sun set by taking down the flag….
171 Why statins? Lipid lowering effects vs Pleiotrophic effects Plaque stabilizingAnti-inflammatoryImproved endothelial cell functionInhibition of thrombogenic responseLiao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:see: Accessed Apr 25/12.
172 So?So….If equivalent LDL lowering with non-statin drugs have no effect on morbidity or mortality then LDL may only be a surrogate marker of the pleiotrophic effects of statins.
173 Bottom LineBeing on any statin at any dose is the most important thing.Being on the highest dose of statin that a patient can tolerate is secondary.Doubling the statin dose only lowers LDL by 6%Pushing the statin dose to levels that result in side effects is just not worth it. Non-compliance will result.The LDL target is just your guide.
174 Exceptions Gemfibrozil N.B. Fenofibrate Two trials that show reduction in CVD eventsHelsinki Heart Study (HHS)Veterans Administration HDL Intervention Trial (VA-HIT)Never combine it with statinsSerious risk of rhabdomyolysisN.B. FenofibrateNo effect on CVD eventsFibrates for high TGs – reduce risk of pancreatitisFibrates for high TGs – treatment of gout
175 Statin + Fibrate (ACCORD-Lipid Trial) No difference in vascular (hard) outcomes.Almost a difference in lipids values (ie. soft outcomes)?Possible vascular harm in women? [9.1% vs 6.6%]Rxfiles.ca ACCORD Lipid & BP Trial Overview Sept Accessed Apr 26/12.
176 Statin + Ezetimibe (Lipid-ENHANCE Trial) No hard endpoints reported.Even intima-media thickness non-significantIMPROVE-IT Trial still ongoing (expected 2013)“Dr Steven Nissen (Cleveland Clinic, OH) questioned whether the trial would be completed because more than 5000 hard clinical end points are needed for the study to reach statistical significance, an unusually high number given that past studies required a few hundred events.” (see: )Rxfiles.ca. ENHANCE Trial Summary, June Accessed Apr 26/12.
177 Statin + Niacin (AIM-HIGH Trial) “ …stopped early for futility.”3414 patientsEarlier Statin + Niacin studies had only showed reduction in soft endpoints.Eg. Regression of carotid atherosclerosisRxfiles.ca. AIM-HIGH Trial Summary, Dec Accessed Apr 29/12.Michael O'Riordan. AIM-HIGH fell short, leaving experts looking for reasons in new review. Heart.org APR 19, Accessed Apr 25/12
178 Treatment Populations Who gets statins?Secondary preventionPrimary prevention?Moderate risk??Put it in the water???
179 Secondary Prevention Clear efficacy Reduction of mortality Reduction of morbidityBenefit in as little as one year(usually 4-5 years)
180 Primary Prevention Clear efficacy in High Risk Framingham Reduction in morbidityNo effect on mortality
181 Primary Prevention (never had an MI or Stroke) High risk Framingham patients with history of:DiabetesCKDCHFAnginaPVDCABG or PCIMetabolic syndromeScore > 20%
182 Moderate Risk Likely not worthwhile… BUT, the JUPITER trial = reduction in hard endpoints!Patients with low/normal cholesterol and high CRPRelative Risk Reduction ~ 50%!But the Absolute Risk Reduction was tiny!hsCRP can differentiate between higher- and lower-risk Moderate Category Framingham patientsRidker PM, et al. the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med Nov 9.
183 JUPITER trial N Engl J Med 2008;359:2195-207. Rosuvastatin:22/8901 (0.28%) of non-fatal MIPlacebo:62/8901 (0.70%) of non-fatal MI
185 Time to Benefit How old is too old to start therapy? Upper ages of trials ~ yrs old.…Add time to divergence of survival curves~ 4 to 6 years…plus?PrognosisOlder than 85y.o, don’t start?Already on it, don’t stop, but don’t bother checking LDL either.
186 Pharmacotherapy“The majority of patients will be able to achieve target LDL-C levels on statin monotherapy.”“Clinical outcome data on the incremental benefit of combination therapy with statin plus ezetimibe, niacin or fibrate, versus statin monotherapy are lacking, although clinical trials are underway to examine this issue.”Can J Cardiol Vol 25 No 10 October 2009
187 “…Trials (were) Underway…” Statin + Niacin trials:AIM-HIGH trialStopped early. No benefit from niacin in HDL raising.See:Known risk of hepatotoxicty with Niacin and significant flushing.HPS2-THRIVE trial (statin + ER Niacin/Laropiprant)No benefit (n = 25673)See:
188 Toxicity Statin Fibrates Ezetimibe Niacin Rare/Severe: Myopathy, even Myositis/RhabdomyolysisHepatotoxictyMemory impairment?Diabetes??discussCommon/Bothersome:MyalgiasFibratesSame as aboveEzetimibeNiacin+++ flushingHepatotoxicity (esp with long acting form – Niaspan)
189 CostAll statins covered under ODBAll statins are generic
190 Convenience Older statins require QHS dosing Cholesterol synthesis mostly occurs late at nightNew statins last long enough to be dosed daily at any timeLacking grapefruit juice interaction:Rosuvastatin, fluvastatin, pravastatin(non 3A4 P450 metabolism)