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Practical Pharmacology
Dr. Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Assistant Professor, Dept of Family Medicine, University of Ottawa
Clinical Pharmacist, Bruyere Academic Family Health Team
March 2013
[email protected]
(Partially adapted from slides by Marc Riachi, R.Ph.)
Objectives
• Review all pharmacology in an abnormally short
amount of time in preparation for LMCC
• List the four steps of rational prescribing
• Understand 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 use
• Highlight clinical pearls in the proper use of these
agents in practice.
Topics to be covered
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Antibacterials
Antimycobacterials
Antifungals
Narcotic analgesics
Autonomic nervous system
Anti seizure drugs
Migraines
Antidepressants
Antianxiety agents
Agents for insomnia
Antidiabetics
Antilipemics
Antihypertensives
Diuretics
Nitrates
Ref: Marc Riachi, RPh
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Antiplatelets and anticoagulants
Antiasthmatics
BPH
Erectile dysfunction
Dementia
Parkinson’s disease and
schizophrenia
Dyspepsia, GERD and PUD
Antiemetics
IBD
IBS
Osteoporosis
Gout
OTC drugs
Appendix I & II
Topics to be covered in this lecture
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Antibacterials
Antimycobacterials
Antifungals
Narcotic analgesics
Autonomic nervous system
Anti seizure drugs
Migraines
Antidepressants
Antianxiety agents
Agents for insomnia
Antidiabetics
Antilipemics
Antihypertensives
Diuretics
Nitrates
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Antiplatelets and anticoagulants
Antiasthmatics
BPH
Erectile dysfunction
Dementia
Parkinson’s disease and
schizophrenia
Dyspepsia, GERD and PUD
Antiemetics
IBD
IBS
Osteoporosis
Gout
OTC drugs
Appendix I & II
A Process for
Rational Prescribing
(your new best friend)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
Objectives
• To promote an efficient process for selecting
optimal drug therapy for patients
• To promote a process for applying population
level evidence based medicine to individual
patients.
A Structure Requires Process
To prescribe or not to prescribe?
That is the question…
•
Rational prescribing requires a process for
selecting therapy: (in order)
1.
2.
3.
4.
Efficacy
Toxicity
Cost
Convenience
1. Efficacy – Ask About…
1. Which HARD Outcomes
a) Mortality benefit?
b) Morbidity benefit?
2. Which SURROGATE Outcomes
•
Clinically relevant?
3. THEN “What is the quality of the evidence to
prove this?”
•
•
•
•
Meta-analysis?
Randomized Controlled Trial?
Case series?
Anecdotal evidence?
Efficacy
• If 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.
2. Toxicity – Ask About…
Bothersome
Severe
Common
Rare
Not legal
Who cares
• Age?
•
•
Newer agents
Older agents
=
=
Less Safety Data
More Safety Data
3. Cost – Ask About…
• Patient cost vs Societal cost
• Covered under provincial formulary?
– Covered under private plans?
4. Convenience – Ask About…
• What is the likelihood of compliance?
1. Frequency of administration?
– Daily vs QID?
2. Special restrictions? (eg. bisphosphonates)
– PO vs IV?
– Home vs Office vs Hospital therapy?
3. Many interactions?
4. Special monitoring requirements?
A simple example:
Metformin
Januvia®
VS
Why is Metformin first line
therapy?
Efficacy
1. HARD Outcomes
–
Mortality benefit
» Metformin – reduction in CV events (UKPDS-34 trial)
–
Morbidity benefit
» Metformin – reduction in microvascular complications
2. SURROGATE Outcomes
a) Hgb-A1c reduction
a) Metformin ~ 1% - 2%
b) Januvia® ~ 0.5% - 0.8%
b) Insulin Sparing Effects
a) Metformin
Toxicity
• Metformin
– Very rare risk of lactic acidosis?
• 0.03 cases / 1000 pt-yrs (~ 50%
fatal)
• Never clearly implicated
– GI upset / diarrhea
• Start low, go slow!
– B12 / folate deficiency /
anemia (6 - 8/100)
• Reduced absorption – easy to
supplement
– Anorexia
• usually transient
• Januvia®
– ?Unknown - too new
• ?Pancreatitis
– Too few patients examined
– GI upset
– edema
– ?elevated risk of
infection?
Cost & Convenience
• Metformin
• Januvia®
– Ontario Drug Benefit:
– Ontario Drug Benefit:
• $ 0.0587 / tab
• Covered by ODB
• $ 2.8050 / tab
• Covered by ODB
– Rxfiles 2012:
• ~ $33 / 100 days
– QD to TID po
– Rxfiles 2012:
• ~ $315 / 100 days
– Once daily po
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Antibiotic Review
(80% of the knowledge, 80% of the time)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
Objectives
• Review clinically relevant pathogens in human
disease in an ambulatory care setting
• Review antibiotic classes and spectra of
activity
– Focus on bread and butter examples of each
• Review treatment recommendations for
common infections in primary care
Process
1. Map the Bugs
– “Know your enemy”
2. Map the Drugs
– “Save your ammo”
3. Map the Battlefield
Part 1 - Map the (Clinically Important) Bugs
“Know your enemy”
Gram Negative
Aerobic
β-Lactamase Negative
Cocci (spheres)
Bacilli (rods)
Gram Positive
Anaerobic
β-Lactamase Positive
Map the Bugs
Aerobes
Anaerobes
Gram Positive Gram Negative
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-]
b-L[+] b-L[-]
1 2 3
4
b-L[+] b-L[-] b-L[+] b-L[-]
5 6
7 8
b-L[+] b-L[-] b-L[+] b-L[-]
b-L[+] b-L[-] b-L[+] b-L[-]
9 10 11 12 13 14 15 16
Anaerobes
Above & below the diaphragm
Oral
• Simple organisms
• Easily handled by
penicillins (beta-lactams)
– Eg. Actinomyces
Bifidobacterium
Fusobacterium
Lactobacillus
Peptococcus
Peptostreptococcus
Propionibacterium
etc
Gut
• Approx the same, except:
• Human pathogens:
• Bacteroides fragilis
(B.frag)
• Clostridium difficile
(C.diff)
– More virulent bugs
requiring ‘bigger guns’…
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
Bacilli
Above & Below
diaphragm
Bacilli
B.Frag
C.Diff
b-L[+] b-L[-]
b-L[+] b-L[-]
1 2
3 4
b-L[+] b-L[-]
5
6
b-L[+] b-L[-]
7 8
9
.
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
Bacilli
Below
diaphragm
Bacilli
B.Frag
C.Diff
b-L[+] b-L[-]
b-L[+] b-L[-]
1 2
3 4
b-L[+] b-L[-]
5
6
b-L[+] b-L[-]
7 8
9
.
Gram[+] Bacilli
• Not usually pathogenic
– Major Exception: Listeria monocytogenes
• Listeriosis – enteritis, sepsis, meningitis +/- encephalitis
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
Bacilli
Below
diaphragm
Bacilli
B.Frag
C.Diff
(Listeria)
β-L[+] β-L[-]
1 2
b-L[+] b-L[-]
3
4
β-L[+]
β-L[-]
5 6
7
.
Gm[-] Cocci
• Not usually pathogenic
– Major Exceptions:
• Neisseria gonorrhea
• Neisseria meningitidis
and
• Moraxella catarrhalis
– (formerly thought to be a type of Neisseria)
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
(Neisseria &
Moraxella)
β-L[+] β-L[-]
1 2
Bacilli
(Listeria)
Below
diaphragm
Bacilli
B.Frag
C.Diff
β-L[+]
3
β-L[-]
4
5
.
β-Lactamase Enzymes
• First 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 strep
give Penicillin
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Cocci
(Neisseria &
Moraxella)
Bacilli
(Listeria)
β-L[+] β-L[-]
1
(GrpAStrep)
Below
diaphragm
Bacilli
B.Frag
C.Diff
β-L[+]
2
β-L[-]
3
4
.
Map the Bugs
Anaerobes
Aerobes
Gram Positive
Gram Negative
Cocci
Below
diaphragm
Bacilli
B.Frag
C.Diff
β-L[+]
1
both β-L[+]&[-]
2
3
.
Map the Clinically Important Bugs
Atypicals
Aerobes
Gram [+]
Gram [-]
Cocci
Bacilli
1
2
1. Legionella
pneumonia
2. Chlamydia
pneumonia
3. Mycoplasma
pneumonia
3
.
Anaerobes
(esp. Gut
organisms)
Eg. C-Diff
& B-frag
4
.
1 - Gram [+] Cocci
Staphylococcus
• S. aureus
– Methicillin resistant (MRSA)
– Methicillin sensitive (MSSA)
• S. epidermidis
– Methicillin resistant (MRSE)
– Methicillin sensitive (MSSE)
– Skin commensal
– Rarely pathogenic
Streptococcus
• Group A (pyogenes) (β-Lact[-])
• Group B (agalactiae)
•
Neonates, v. elderly, obstetrics
• S. pneumonia
etc. etc.
Enterococcus
• (Formerly thought to be ‘Strep D’)
• E. faecalis
• E. faecium
2 - Gram [-] Bacilli
•
•
•
•
•
•
Easy to Kill
Proteus mirabilis
Escherichia coli
Klebsiella pneumonia
Salmonella
Shigella
Haemophilus influenza
•
•
•
•
•
Hard to Kill
Serratia
Pseudomonas
Acinetobacter
Citrobacter
Enterobacter
– (Moraxella catarrhalis)
(actually a Gm[-] coccus)
PEcKSS-HiM
SPACE bugs
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;
Atypicals:
• Mycoplasma pneumo
• Chlamydia pneumo
• Legionella pneumo
Map the Bugs
• Gram positive aerobes:
– Cocci
Summary
Anaerobes:
• Oral
• Gut – Bfrag & Cdiff
• Gram negative aerobes:
– Bacilli
• Staph
– Aureus
» MRSA (~8-10%)
» MSSA
– Epiderimidis
» MRSE (~65%)
» MSSE
• Easy to Kill
– PEcKSS (Proteus, Ecoli,
Klebsiella, Salmonella, Shigella)
– HiM (H.flu and Moraxella
(actually a Gm[-]coccus))
• Hard to Kill
– SPACE bugs (Serratia,
Pseudomonas, Acinetobacter,
Citrobacter, Enterobacter)
• Strep
–
–
–
–
Group A strep (pyogenes)
Group B strep (agalactiae)
Strep Viridans
Strep pneumo etc.
• Enterococcus
– Faecalis
– Faecium
– Bacilli
• Listeria
– Cocci
• Neisseria
– gonorrhaea
– meningitidis
• Moraxella catarhallis
Part 2 - Map the Drugs
(Save your Ammo)
Map the Drugs
• Arms race!
– Remember: “Bigger guns
breed higher walls”
• Older drugs tend to be
simpler drugs
– More narrow spectrum
– Broad spectrum drugs
breed resistance
– Superbugs develop
• MRSA, VRE, ESBL, etc
• Older drugs have more
safety data
– Tend to be less toxic
– Learn their history
– Learn their
pharmacology
Part 2 - Map the Drugs
“Save your Ammo”
Fluoroquinolones
Penicillins
Tetracyclines
Aminoglycosides
Vancomycin
Macrolides
Carbapenems
Cephalosporins
Clindamycin
Metronidazole
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Beta-Lactams - Penicillins
Penicillin
Anti-Staph
Anti-Strep
Amoxicillin / Ampicillin
(po)
(iv)
Amox + Clavulanic acid
Cloxacillin / Methicillin
(clinic)
(lab)
Beta-Lactams - Cephalosporins
– Cephalexin (Keflex™)(or Cefadroxil) (po)
– Cefazolin (Ancef™) (iv)
• 2nd Generation
– Cefuroxime (po & iv)
• 3rd Generation
– Ceftriaxone, Cefotaxime, Ceftazidime (iv)
– Cefixime (Suprax™) (po)
• 4th Generation
– Cefepime (iv)
Increasing Gram[-] coverage
• 1st Generation
Beta-Lactams – Other (FYI)
(IV only, inpatient use only)
• Piperacillin (plus tazobactam)
– big gun, tazo = suicide substrate, like clavulanic acid
• Carbapenems
– Meropenem
– Imipenem
– Ertapenem
• Monobactams
– Aztreonam
Broad spectrum, big gun antibiotics
that cover Gm[+], both easy and hard
to kill Gm[-] bugs, even some
anaerobes.
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Fluoroquinolones
• 2nd generation
– Ofloxacin
– Ciprofloxacin
– Norfloxacin
• 3rd generation
– Levofloxacin
• 4th generation
– Moxifloxacin
• Covers: strep & Gm[-]’s
– PEcKSS-HiM & SPACE bugs
• Ofloxacin
• Ciprofloxacin
– Anti-pseudomonal – the
only PO option!
– Norfloxacin
• Same spectrum as Cipro
(even anti-Pseudomonal) –
but only for cystitis UTI.
• Concentrates in the G.U.
system only
• N.B. Not good enough for
pyelonephritis or systemic
infection
Fluoroquinolones
• The “Respiratory FQs”
– Concentrate in alveolar
macrophages
– Greater than serum concn
1. Levofloxacin
– the more active Lenantiomer of Ofloxacin
– Renal clearance
2. Moxifloxacin
– Hepatic clearance
• Enhanced coverage of:
1. Strep pneumo
2. Oral Anaerobes
3. Atypicals
– N.B. only Moxi cover B.frag
– Neither covers C.diff
• (Both will cover Clostrium
non-difficile strains)
• Both have 100% oral
bioavailability
– Therefore PO = IV dose
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Macrolides
• Coverage of:
– Atypicals, Strep pneumo, &
Hi.M. (Hflu & Mcat)
• So, good for respiratory
infections!
– N.B. But doesn’t cover
PEcKSS or SPACE bugs
• Erythromycin
– Efficacy: Poorer coverage of
H.flu, MSSA
– Toxicity:
• Prokinetic – diarrhea!
• Worse for QTc prolongation
– Convenience: QID dosing
• Clarithromycin
– Better Hflu &MSSA coverage
– Less QTc prolongation vs E
– Shorter half-life vs Azithro
• BID dosing x 7-10days
• New daily ‘XL’ formulation
• Azithromycin
– An azalide, (not a macrolide)
• Same spectrum of activity
• Less QTc prolongation vs E & C!
– Long t1/2 – QD dosing x 5d
• BUT can breed resistant
S.pneumo (since below [MIC]
for long periods of time)
Antibiotics – Mechanisms of Action
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Aminoglycosides
1. Gentamicin
2. Tobramycin
– Reserved for Pseudomonas
aeruginosa
3. Amikacin
• Efficacy: excellent Gm[-]
• Toxicity:
– Nephrotoxicity
– Ototoxicity
– Less now with daily dosing
• Cost:
• All excellent Gram[-]
coverage:
– PEcKSS-HiM and SPACE
bugs
– Cheap, old meds
• Convenience
– Now Once daily IV/IM
Pharmacodynamics
Relationship between Abx Concentration & Effect
Concentration Dependent
Killing
• Higher the peak, better the
kill
• i.e. Ratio of peak drug
concentration and M.I.C.
determines rate of kill.
• Eg. FQs, AGs
Log
[Conc]
Time Dependent Killing
• Time over MIC matters
• i.e. Independent of peak
concentration. Determined
by length of time over MIC
• Eg. B-lactams (Pen, Ceph etc)
Log
[Conc]
Peak
MIC
MIC
Time (h)
Time (h)
Pharmacodynamics
Relationship between Abx Concentration & Effect
Concentration Dependent
Killing
• With renal impairment:
– Maintain the peak,
lengthen the interval
– This ensures good rate of
killing while allowing
enough time to eliminate
the drug and avoid
toxicities
– For eg:
• Higher the peak, better the
kill
• i.e. Ratio of peak drug
concentration and M.I.C.
determines rate of kill.
• Eg. FQs, AGs
Log
[Conc]
Peak
Log
[Conc]
Peak
MIC
Time (h)
MIC
Time (h)
• If CrCL = 90mL/min Levofloxacin 750mg q24h po
• If CrCL = 30mL/min –
Levofloxacin 750mg q48h po
Pharmacodymamics
Bactericidal vs Bacteriostatic
• Bactericidal Abx
–
–
–
–
–
–
B-lactams (Pen, Ceph)
Aminoglycosides (AGs)
Fluoroquinolones (FQs)
Rifampin
Metronidazole
Vancomycin
• Bacteriostatic Abx
–
–
–
–
Tetracyclines
Macrolides
Clindamycin
Chloramphenicol
Rarely a clinically important characteristic, unless the
patient is immunocompromised or the risk of death with
delayed/incorrect therapy is high.
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
Map the Drugs
Pharmacology Summary
• Many antibiotic classes
– Beta-lactams generally safest agents.
• Even at high doses
– Some have overlapping mechanisms of action
– Avoid combining similar mechanisms of action
• Competing effects may reduce effectiveness of one agent
• Eg. Penicillins + vancomycin – cell wall synthesis inhibitors
• Eg. Tetracyclines + aminoglycosides –protein synthesis
inhibitors via 30-S subunit of the ribosome
Map the Drugs – Summary
For: TB, MRSA
For: skin,
dental
infx
(staph,
strep, &
anaerobes)
From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12
Part 3 – Map the Battlefield
Map the Battlefield
Rational Prescribing
Individual
Population
1. Efficacy
1. Efficacy
– Could be reduced, BUT:
– Empiric tx still effective if
it is well chosen
– Maintained long term with
lower resistance rates
2. Toxicity
• (Lower risk infections,
properly dosed, clinically
stable, true indication etc.)
– Reduced since lifespan of
older drugs is maintained
3. Cost
2. Toxicity
– Reduced with narrow
spectrum tx
3. Cost
– Reduced with older tx
4. Convenience
– Usually less convenient
VS.
– Reduced insurance costs,
economic losses, hospital
costs dealing with
superbugs
4. Convenience
Map the Battlefield
Map the Battlefield
Otitis media: S.pneumo, Hi,M
Conjunctivitis: viral – no tx
(Amox +/- Clav, Cef2, Septra)
Sinusitis: viral – no tx
AECOPD: S.pneumo, Hi,M
Oral anaerobes: abscess
drainage – no tx
(Amox +/- Clav, Cef2, Septra)
(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))
Cellulitis: MSSA, S.pneumo
– (Clox, Cef1, Clinda)
Pyelonephritis: PEcK –
(Septra, Amox/Clav, FQ (not Norflox)
UTI (Cystitis): PEcK – (Septra,
Macrobid, Amox, Norflox)
Pharyngitis: viral – no tx
(Group A Strep – Pen VK)
Bronchitis: viral – no tx
Skin abscess:
drainage – no tx
H.pylori: triple po tx
PPI + (Clarithro +/Amox +/- Metro)
Cdiff / Bfrag: Metro / po
Traveller’s Diarrhea: (80% bacterial): EcSS, Vanco
(camphlyobacter) - Septra, FQ, (Azithro)
Map the Battlefield
Penicillin
(Group A Strep, oral anaerobes, Neisseria)
Amoxicillin / Ampicillin
(Strep & Enterococcus plus
Easy-to-Kill Gm[-](ie. PEcKSS))
Cloxacillin
(Staph aureus, Staph epi)
Amox/Clav
(Vancomycin)
(for Strep & Entero & PEcKSS-HiM)
(H.flu & Moraxella can be ~35% amox resistant)
(for MRSA / MRSE)
(~8-10% / ~ 65% resistant)
Beta-Lactams - Cephalosporins
– Cephalexin (Keflex™) or Cefadroxil (po)
– Cefazolin (Ancef™) (iv)
• 2nd Generation
– Cefuroxime (po & iv)
• 3rd Generation
To boost: for PEcKSS-HiM
(same as Amox/Clav)
SPACE bugs: The Big Guns
– Ceftriaxone, Cefotaxime, Ceftazidime (iv)
– Cefixime (Suprax™) (po)
• 4th Generation
– Cefipime (iv)
Increasing Gram[-] coverage
• 1st Generation
MSSA and Strep & PEcKSS
(same as Amox)
N.B. never Enterococcus!
SPACE bugs
• The Big Guns:
– 3rd and 4th generation Cephalosporins
– Carbapenems (Meropenem)
– Piperacillin/Tazobactam
– Aminoglycosides (Gentamicin, Tobramicin)
– Fluoroquinolones (Levofloxacin, Moxi, Cipro)
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/Tazobactam
Meropenem
Need for Bigger guns
• There is a higher risk of Gram negative SPACE bugs
with:
– More risk factors / comorbidities
– COPD, HIV, Diabetes, CKD etc
– More institutionalized settings
• Community  Retirement Home  Nursing Home 
Hospital ward  ICU  ventilated pt in ICU.
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 strep
• N.B. NOT Enterococcus (Cef’s never cover enterococcus!)
– How to boost? Cef2 (cefuroxime) for HiM-PEcKSS
• What 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)
Antibiotics contraindicated in
pregnancy (category X)
•
•
•
•
•
•
•
•
•
Tetracyclines (also in children < 9 y.o.): are incorporated into fetal
skeleton/unerupted teeth
Fluoroquinolones
Erythromycin estolate (may cause toxic liver reaction), clarithromycin
TMP: in 1st trimester because it is a folate antagonist
Sulfonamides: 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 kernicterus
Nitrofurantoin (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
fetuses
Aminoglycosides: nephrotoxic and ototoxic to the fetus
High (>2 grams) single dose metronidazole
Chloramphenicol (at term or during labour): limited glucuronidating capacity
of the newborn’s liver
Ref: Marc Riachi, RPh
Antibiotics Preferred in Pregnancy
•
Penicillins
•
•
•
•
•
•
Including those in combination with ß-lactamase
inhibitors (clavulanic acid, sulbactam, and
tazobactam)
Cephalosporins
Erythromycin base
Azithromycin
Clindamycin
Metronidazole
•
Ref: Marc Riachi, RPh
(regular dose 250-500 mg BID)
Summary
• This is far from an exhaustive review
• Some parts have been highly simplified for use
in clinical practice
• Some memorization is needed with regular
review of the material to retain this
knowledge
• Doing so will allow you to choose empiric
antibiotics with greater comfort in difficult
situations and unfamiliar settings.
Penicillin:
BL-ve aer obic GPC
oral anaer obes
N.meni ngitidi s
Lacking Activity Vs.
Atypical Organis m s
BL+ Ae robic GPC
Ae robic GNB
Gut anaerobe s
(B. fragilis)
95% of Staph. specie s are BL +ve
MRSA(7%)/ MRSE (>65%)
MSSA/MSSE
TMP/SM X
Clindam ycin
Easy to Kill GNB
Macrolide s :
Erythromycin
Clarithromycin
Azithromycin
TMP/SM X
Tetracyclines
Res pirator y Fluor oquinolone s
Gatif loxacin
Levofloxacin
Moxif loxacin
Vancom ycin
Rifam pin
Fus idic Acid
Line zolid
Syner cid
Me tronidazole
Am picillin/Am oxicillin:
HiPEELSS
Isoxazoyl PCNs :
e g. Cloxacillin, Nafcillin
1st Ge ne ration Cephs :
(Cefazolin iv / Ce phalexin po)
PEcKSS
Second Gener ation Ce phs
Am oxicillin/Clavulanic acid
Am picillin/Sulbactam
Ce furoxim e
Ce furoxim e axetil
Ce faclor
B. fragi li s
H. i nfluenza e
Ce fote tan
Ce foxitin
Difficult to Kill GNB
3rd Gener ation Ce phs.
Ce ftriaxone
Ce fotaxim e
Ce ftazidim e
4th Ge ne ration Cephs :
Ce fe pim e
No Ce phalos porin cover s:
MRSA / MRSE
enterococcus sp.
Listeri a monocytogenes
AM Gs:
Ge ntam icin
Tobram ycin
Am ik acin
Pipe racillin:
(P.aerugi nosa , Enter obacter)
Never Us e Alone !
Pipe racillin/Tazobactam
Ticarcillin/Clavulanic Acid
FQs :
ciprofloxacin
ofloxacin
norf loxacin
Carbape ne m s :
Im ipenem
Me rope ne m
Adapted fr om : Wins lade N. On Continuing Practice 1990-1, volum es 17-18.
Prepare d By:
Sandr a A.N. Tailor, Pharm .D.
Clinical Coor dinator - Infectious Dise as e s
Sunnybrook Health Science Ce ntre
Depar tm e nt of Pharm acy
11/11/02
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
TB drugs
Adapted from: Marc Riachi, RPh
Mycobaterium tuberculosis
The Consumption
• Mostly latent, asymptomatic infection (90-95%)
–
–
–
–
Activation risk ~ 10%
Usually pulmonary; can occur anywhere
Spreads via air droplet
One 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 wall
– Acid-fast bacilli
– Combinations of drugs needed to treat
• Slow growing
– Therefore requires extended treatment period
• Treatment:
– Multiple side effects = reduced compliance by patient = further emergence
of resistant strains
– MDR, XDR strains
Adapted from: Marc Riachi, RPh
Available antimycobacterials
• First-line:
– Isoniazid (INH)
– Rifampin (RIF) or Rifampicin (RMP)
– Pyrazinamide (PZA)
– Ethambutol (ETB)
• Second-line:
– Amikacin
– FQs (Ciprofloxacin / Levofloxacin / Moxifloxacin)
– Clarithromycin / Azithromycin
Ref: Marc Riachi, RPh
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. 2007 p. 130 http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf Access March 14, 2013.
Treatment – Latent TB
• INH – monitor LFTs
– Hepatitis (rare < 20y.o.; >2% in >50y.o.)
– Drug interactions!
• RIF – GI toxicities, major drug interactions!
– Huge inducer of cytochrome P450
Ref: PHAC. Canadian Tuberuclosis Standards, 6th Ed. 2007 p. 148 http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf Access March 14, 2013.
Which agents to use in active disease?
• Pulmonary or extrapulmonary disease:
– INH+RIF+PZA+ETB
• If resistant to INH:
– RIF+PZA+ETB (+FQ if severe)
• If resistant to RIF:
– INH+PZA+ETB+FQ
• if resistant to INH and RIF:
– PZA+ETB+FQ+amikacin
• If resistant to INH, RIF and PZA or ETB
– ETB (or PZA)+FQ+amikacin+two 2nd line agents
Ref: Marc Riachi, RPh
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Anti-fungals
Adapted from: Marc Riachi, RPh
Drug info
•
•
INH (inhibits formation of fatty acids found in the
cell wall):
– Bactericidal; penetrates cavitations
– Hepatotoxicity (↑ with alcohol & rifampin)
 monitor LFTs
– peripheral neuropathy (give vit B6)
– GI symptoms, skin rash
– ↑ phenytoin, carbamazepine &
benzodiazepine blood levels
RIF (inhibits mRNA synthesis):
– Bactericidal; penetrates cavitations
– Hepatotoxicity (↑ with alcohol)  monitor
LFTs
– GI symptoms, skin rash
– Pancytopenia
– Colours urine, feces, saliva, tears orange 
may permanently stain contact lenses
– Induces CYP450
Ref: Marc Riachi, RPh
•
•
PZA (may inhibit mycobacterial
metabolism):
– Bactericidal in acid environment (in
macrophages)
– Hepatotoxicity (↑ with alcohol &
rifampin)  monitor LFTs
– Hyperuricemia  monitor uric acid
– GI symptoms and arthralgias
ETB (may inhibit cell wall synthesis):
– Bacteriostatic
– GI symptoms, hyperuricemia
– Ocular toxicity and change in color
perception  monitor at high doses
Antifungals
• Topical
• Oral
– Azole anti-fungals
•
•
•
•
•
•
Itra- (Sporanox),
flu- (Diflucan),
vori-,
posaketoconazole (Nizoral)
active vs. yeast and
dermatophytes
– Terbinafine (Lamisil)
• active vs. yeast and
dermatophytes
– Nystatin
• active vs. yeast only
Ref: Marc Riachi, RPh
– Ciclopirox
• (cream, lacquer, shampoo),
– nystatin
• (cream, pv, oral suspension),
– clotrimazole
• (cream, pv),
– miconazole
• (cream, pv),
– ketoconazole
• (cream shampoo),
– terbinafine
• (cream, spray),
– tolnaftate
• (powder  suitable for skin folds)
• Injectables
– usually require I.D. consult
Which agents to use?
• Onychomycosis:
– 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, ketoconazole
• Oral 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
•
•
Drug info
Terbinafine po:
– Very active vs dermatophytes
– headache, GI diarrhea, dyspepsia, abdominal pain
– taste disturbance (may persist post treatment)
– CYP2D6 inhibitor:
• Decreases formation of active metabolites of tamoxifen
• May ↓ breakdown of TCA’s, fluoxetine, paroxetine, fluvoxamine, sertraline,
tamsulosin, mirtazapine, haloperidol, some beta blockers
Azole 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
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Hypertension and BP Meds
(The ABCD’s of HTN)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
Objectives
• List first line classes of medication for the
treatment of essential hypertension
• Explain how co-morbid indications may
change your choice in therapy
• Apply a rational approach in selecting therapy
• Understand the dosing, monitoring and
titration of key examples from each class of
medication
Rational Prescribing
•
Rational prescribing requires a process for
selecting therapy: (in order)
1.
2.
3.
4.
Efficacy
Toxicity
Cost
Convenience
A
A
B
C
D
ARB
ACEinh
B-blockers
CCB
Diuretics
(DHP-type)
(Thiazide type)
Angiotension Receptor
Blocker
Angiotensin Converting
Enzyme Inhibitor
Beta-Blocker
Calcium Channel Blocker
(dihydropyridine type)
-sartan
-pril
-olol
-dipine
Losartan
Valsartan
Candesartan
Etc
Ramipril
Enalapril
Perindopril
Etc
Bisoprolol
Metoprolol
Atenolol
Etc
Amlodipine
Nifedipine
Felodipine
Etc
Chlorthalidone
Hydrochlorothiazide
Indapamide
Etc
Reduced
sympathetic
outflow, and
heart rate
Relaxation of
coronary &
peripheral
arterial smooth
muscle
(not AV node!)
Inhibits Na+ &
Cl- reabsorption
in the corticaldiluting segment
of the ascending
loop of Henle
= diuresis.
Reduction in
systemic
vascular
resistance
1st line
1st line
Blocks conversion of AT1 to ATII
(ACEinh) or blocks ATII receptors
(ARB) =
Inhibition of vasoconstriction,
aldosterone, catecholamine, and
arginine vasopressin release, water
intake, and hypertrophic responses
(b1 receptor – in heart)
(cardioselective ~ A-M)
(b2 receptor – in lungs)
(Non-selective ~ N-Z)
(“one heart; two lungs”)
Efficacy: 1st line
1st line
1st line (< 65y.o.)
A
A
B
C
D
Toxicity:
Toxicity:
Toxicity:
Toxicity:
Hypotension
HyperK+
Acute renal failure (ARF)
Angioedema
Hypotension
Bradycardia
Bronchoconstric
tion (in brittle
asthmatics with
noncardioselective
bbl’s)
Hypotension
Edema
Orthostatic
hypotension
Hypotension
HypoNa+
HypoK+
ARF
Monitor: SCr, K+, BP
Monitor: BP, HR,
RR
Monitor: SCr,
lytes, BP
Cost:
Generic - $$$
ODB covered
Cost:
Generic - $
ODB covered
Cost:
$
ODB covered
Cost:
Generic: $$$
ODB covered
Cost:
¢
ODB covered
Convenience:
QD
Losartan
25mg to 100mg
Convenience:
QD
Ramipril
2.5mg to 10mg
Convenience:
QD
Bisoprolol
2.5mg to 10mg
Convenience:
QD
Amlodipine
2.5mg to 10mg
Convenience:
QAM
Chlorthalidone
25mg
Choosing Therapy
• If 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 based
• Toxicities are individual.
• Some combos are additive others synergistic BP
lowering
– Rarely clinically relevant
– Can choose between groups A or B plus C or D
(synergistic)
• N.B. Choice will also be guided by various
comorbidites
Comorbidities
Indication
ARB
ACEinh
B
C
HTN
(ALLHAT)
MI
(HOPE trial)
CHF
(CONSENSUS,
SOLVD,
ATLAS)
DM2
(HOPE)
(IDNT, IRMA-2,
RENAAL)
CVA
(HOPE,
PROGRESS)
(LIFE,
SCOPE,
MOSES)
PVD
(HOPE)
Afib
D
(VALIANT)
(CAPRICORN,
BHAT)
(MERIT-HF,
CIBIS II,
COPERNICUS)
(ALLHAT,
PROGRESS)
(Diltiazem)
Second Line Therapy
• What if you have used all
available 1st line options?
• 2nd line options:
–
–
–
–
–
–
–
Alpha blockers
Spironolactone
Hydralazine
Nitrates
Clonidine
Beta-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.
Second Line Therapy
• Alpha blockers
– Eg. Terazosin, Prazosin, Doxazosin
– Toxicity: Risk of orthostatic
hypotension
– Cost: cheap, generic
– Convenience: only QD
• Good 1st choice of 2nd line tx
• Dual treatment of BPH & BP if
also needed in male patients
• Spironolactone
– Efficacy: mortality benefit in
late stage CHF (NYHA class III or IV)
– Toxicity: risk of hyperK+
• esp with ARBs or ACEinh’s
– Cost: cheap generic
– Convenience: only QD
• Hydralazine
– MOA: direct vasodilation of
arteries
– Toxicity: orthostatic
hypotension
– Cost: cheap, generic
– Convenience: QID dosing
• Nitrates
– eg. ISDN, ISMN, NTG
– MOA: smooth muscle
vasodilation of vasculature
(veins > arteries);
– Toxicity: headache, orthostatic
hypotension, dizziness
– Cost: cheap/ generic
– Convenience: BID- QID dosing;
Process
1. Start first drug
2. Increase to moderate
dose
3. Monitor for efficacy
(BP) and toxicity
• If close to target:
• Dose response curves
– Flatten at top half
– Less bang for your buck
BP
– increase dose
• If far from target:
– start new drug
mg
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Oral Anti-hyperglycemics
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
Objectives
• List 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 therapy
– Rationalize prescribing of oral hypoglycemics
• Describe the current approach to pharmacologic
management of type 2 diabetes.
Diagnosis of IFG, IGT
Category
FPG
2-hour
And/or after
OGTT
IFG
6.1-6.9
IFG (isolated)
6.1-6.9
IGT (Isolated)
< 6.1
7.8-11.0
6.1-6.9
7.8-11.0
IFG and IGT
N/A
AND
< 7.8
Can J Diabetes 2003;27(2);S11
Diabetes: complications
MACROvascular
Stroke
Heart disease
&
hypertension
MICROvascular
Diabetic eye
disease
(retinopathy &
cataracts)
Nephropathy
Peripheral
vascular disease
Neuropathy
Foot
problems
Foot problems
Kumamoto Study – HgbA1c & Complications
Intensive vs. conventional insulin therapy (n=110)
Median A1c - 7.1% vs. 9.4%
16
14
Retinopathy
16
14
12
Nephropathy
12
10
10
8
6
4
2
0
8
6
7%
5
6
7
7%
4
2
0
8
9
HbA1c (%)
10 11
5
6
7
8
9
HbA1c (%)
10 11
Prevention of Diabetes in IGT
• Lifestyle modification
– (see Finnish Diabetes Trial)
– Moderate weight loss (5%) (esp. abd fat)
– Regular physical activity
• > 150 minutes per week
– 58% RRR for type 2 Diabetes at four years
• Pharmacotherapy
– Multiple effective trials
• Eg. LIFE trial - Losartan  onset of new DM2
Can J Diabetes 2003;27(2);S12
Pharmacological Prevention Studies
Study
Drug
DPP
Metformin
850mg BID
2.8
31
STOPNIDDM
Acarbose 100mg
TID
3.3
30
DREAM
Rosiglitazone
8mg daily
3.0
55
Orlistat 120mg
TID
4.0
37
XENDOS
Duration
(years)
RRR (%)
Non-Pharmacologic Tx
Mainstay of therapy!
• Nutrition therapy
– ↓ A1c 1-2%
– CDA recommends counseling by a dietician for
all type 2 diabetics
– www.cvtoolbox.com diet for Type 2 diabetes
Can J Diabetes 2003;27(2);S27
Pharmacotherapy
Comparison of antihyperglycemics
Drug Classes
Sensitizers
Secretagogues
Other
Drug Classes
Sensitizers
Secretagogues
• Metformin
• Glitazones
• Sulfonylureas
– Eg. Glyburide, Gliclazide
• Meglitinides
– Rosiglitazone (AVANDIA)
– Pioglitazone (ACTOS)
– Eg Repaglinide (GLUCONORM)
Other
• Alpha glucosidase inhibitors (Acarbose)
• DPP4 inhibitors (Gliptins)
• Sitagliptin
(JANUVIA)
• Saxagliptin
(ONGLYZA)
Incretin Analogues
* Liraglutide
(VICTOZA) (sc inj)
* Exenatide
(BYETTA) (sc inj)
Drug Classes
Sensitizers
• Metformin
• Glitazones
– Rosiglitazone (AVANDIA)
– Pioglitazone (ACTOS)
• Sensitizers – reduce
insulin resistance
• Increase glucose uptake &
utilization in muscle and
adipose tissue
• Reduce hepatic glucose
output
Drug Classes
• ↑Basal & prandial insulin
secretion, ↓hepatic
gluconeogenesis
• Doesn’t correct impaired
1st phase insulin
secretion; primarily
affects 2nd phase
• Beta-cell sensitizer –
primes glucose mediated
insulin secretion (1st
phase)
Secretagogues
• Sulfonylureas
– Eg. Glyburide, Gliclazide
• Meglitinides
– Eg Repaglinide
(GLUCONORM)
Drug Classes
Other
• Alpha glucosidase inhibitors (Acarbose)
• Competitive inhibitor of pancreatic α-amylase and intestinal brush border αglucosidases, 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 fructose
• DPP4 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
Rational Prescribing
•
FOUR steps to Rational Prescribing:
1. EFFICACY
2. TOXICITY
3. COST
4. CONVENIENCE
EFFICACY – Ask…
1. HARD Outcomes
a) Any mortality benefit?
b) Any morbidity benefit?
Then,
2. SURROGATE Outcomes
a) Clinically relevant?
EFFICACY
1. HARD Outcomes
– Mortality benefit
» Metformin – UKPDS-34 trial
– Morbidity
2. SURROGATE Outcomes
a) Hgb-A1c
•
Blood glucose levels
– Fasting or Prandial
b) Insulin Sparing Effects
Effect of Metformin on Event Rates in the
UKPDS
• Diabetes-related endpoint 32% p=0.002
• All-cause mortality  36% p=0.011
•  MI / CVA
• Diabetes-related death  42% p=0.017
– But.. When added early to sulfonylurea
 risk of DM-related death (?statistical anomaly?)
EFFICACY
A) Surrogate Outcome - Hgb-A1c
– ~ 1% to 2%
•
•
•
•
METFORMIN
SULFONYLUREA’s
REPAGLINIDE
GLITAZONE’s
(1% - 2%)
(1% - 2%)
(1% - 1.5%)
(0.4% - 1.5%)
– ~ 0.5% to 0.8%
•
•
•
ACARBOSE
DPP4 inhibitors (‘GLIPTINS)
NATEGLINIDE
Nathan DM, et al. Diabetes Care 2008 (Dec);31:1-11.
EFFICACY
B) Surrogate Outcome - Insulin Sparing Effect
– METFORMIN
– ACARBOSE
– GLITAZONE’s (Pioglitazone)
– Gliptins (Sitagliptin, Saxagliptin)
– Incretin Analogies (Liraglutide, Exenatide)
= Weight neutral or weight negative
= Reduction of hyperinsulinemia
TOXICITY – Ask…
1. Serious / Fatal Side Effects
2. Bothersome / Common s.e.
3. Age?
•
•
Newer agents = Less Safety Data
Older agents = More Safety Data
TOXICITY – Serious / Fatal
•
Glitazones
• Secretatgogues
– CHF
– Fractures
– M.I.
(Sulfonylureas &
Meglitinides)
•
(rosiglitazone)
– Bladder Cancer
•
(pioglitazone)
– Severe Hypoglycemia
TOXICITY – Serious / Fatal
• Metformin
• ?Risk of Lactic Acidosis
– 0.03 cases / 1000 pt-yrs
– ~ 50% fatal
– When implicated:
• Metformin plasma levels are usually >5 μg/mL
• Cases - primarily diabetics w/ significant renal
insufficiency, both intrinsic renal disease and renal
hypoperfusion, w/ multiple medical/surgical problems
and multiple medications.
Metformin Dosing
• Dosing recommendations with renal insufficiency:
– (CONTROVERSIAL)
• CrCl 60ml/min→
– 1700 mg/day (Rxfiles)
– 2.5g/day (Roland)
• CrCl 30ml/min→
– 850mg/day (Rxfiles)
– 2.5g/day (Roland)
• CrCl < 30ml/min→
– Contraindicated (Rxfiles)
– 1g/day (>20mL/min) (Roland) If NO other risk factors, else D/C.
– Take home: assess OTHER RISK FACTORS for L.A.
Risk Factors - Lactic Acidosis
• Severe renal impairment
– (caution if CrCl < 30ml/min)
and
•
•
•
•
•
•
•
Hepatic disease
alcoholism
CHF
COPD
CRF
Pneumonia
Ongoing acidosis
– Lactic, keto etc.
TOXICITY - Bothersome
1) METFORMIN
– GI upset / diarrhea – Start low, go slow!
• Initial dose 250mg QDaily to BID
– B12 / folate deficiency / anemia (6 - 8/100)
• Reduced absorption – so, supplement
– Anorexia – usually transient
– Metallic taste
TOXICITY - Bothersome
2) Sulfonylureas:
– Sulfa skin reactions
• Rash / photosensitivity ~1%
– Weight gain (2-3kg)
– Mild Hypoglycemia:
• Most with glyburide. Least w/ glimepiride & gliclazide
• Requires consistent food intake
• Major episodes 1-2% (esp. in elderly)
TOXICITY - Bothersome
3) Glitazones:
–
Edema
4) Meglitinides:
–
Hypoglycemia
5) Acarbose:
–
GI upset / diarrhea / bloating
6) Gliptins:
•
GI upset, edema, ?infection
7) Incretin analogues
•
N/V/D, ?infection
Cost – Ask…
• Patient cost vs societal cost
• Rx cost?
• ODB coverage?
• Covered under other plans?
Cost/tab – ODB covered?
• Metformin
• Glyburide
• Gliclazide
- $ 0.0587 - ODB
- $ 0.0574 - ODB
- $ 0.0931 - ODB
– Gliclazide MR $ 0.1405 - ODB
•
•
•
•
•
Repaglinide
Acarbose
Sitagliptin
Saxagliptin
Pioglitazone
- $ 0. - Section 8 (EAP)
- $ 0.3584 - ODB
- $ 2.8050 - ODB
- No
- $ 0. - Section 8 (EAP)
Cost
• From Rxfiles May 2010
• Cost per 100 days therapy
(in Sask.)
Convenience
• PO vs IV?
• QD vs QID?
Convenience
•
•
•
•
•
•
Gliptin’s
- QD
Glitazones
- QD
Sulfonylureas – QD to BID
Metformin
- QD to TID
Meglitinides
– QD to TID
Acarbose
– QD to TID
with meals
• 1st line – METFORMIN
• 2nd line - SULFONYLUREA or INSULIN
– Meglitinide – if poor CrCL or irregular eating
• 3rd line - GLIPTINs or ACARBOSE if patients
absolutely REFUSE insulin
NEVER USE GLITAZONEs!
Did I say, never? I meant NEVER!
www.rxfiles.ca
Individualization of Drug Therapy
Patient Factor
Consider→ Possibly preferred drugs
Renal Failure
Repaglinide (Gluconorm)
Also: gliclazide, insulin
Hepatic Disease
Insulin, repaglinide, acarbose
Caution: glyburide, metformin, glitazones
Hyoglycemia
Metformin, Acarbose
Also, repaglinide, nateglinide, gliclazide,
glimepiride;
Obese
Metformin, Acarbose
Irregular Mealtimes
Repaglinide (may be preferred over SU)
PPBG >10mmol/L and
FBG minimally ↑’d
Repaglinide or Acarbose
Insulin lispro (Humalog) if PPBG very high
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Insulins
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
New Drugs/Drug News vol 24 (3):
May/June 2006
Insulins - Simplified
• Long = Basal
• Short = Prandial
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 10/90, 20/80, 40/60, 50/50)
• Humalog Mix-25, NovoMix-30
Which to choose?
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 & HS
– So, go after AM first!
1. ?Any hypo’s?- fix ‘em!
then,
2. FBS AM
3. FBS Noon
4. FBS PM
5. FBS HS
then,
6. 2h PPG AM
7. 2h PPG Noon
8. 2h PPG PM
Insulins
• Long – Basal
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
• Short – Prandial
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 10/90, 20/80, 40/60, 50/50)
• Humalog Mix-25, NovoMix-30
(R + NPH)
(Rapid + NPH)
Now, which to choose?
Rational Prescribing
•
FOUR steps to Rational Prescribing:
1. EFFICACY
2. TOXICITY
3. COST
4. CONVENIENCE
Long – Basal Insulins
• Efficacy:
– NPH = Lantus = Levemir = NPH
– Equivalent
• Morbidity benefits, A1c lowering effect
– Despite 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 BID
• NPH can be used QHS for some
Long – Basal Insulins
• Toxicity:
– All:
• Hypoglycemia
– NPH:
• Peak effect at ~ 8hrs (4-10hrs)
– Risk of hypoglycemia (~ 5%? vs “peakless” insulins)
– Lantus / Levemir:
• Insulin analogues
• Increased breast cancer risk?
– more research needed
Long – Basal Insulins
• Cost:
– All: covered under ODB
• N.B. No Rx required for any insulins – all OTC
– NPH: ~ $40
– Lantus: ~ $90
– Levemir: ~ $100
• Convenience:
– All sc injections, via penfills
– All QD – BID
Bottom Line – Basal Insulins
• All equivalent
• Choose 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.
Starting Basal Insulin
• Fancy Way:
– calculate unit/kg dose = 0.1 - 0.2u/kg/day sc
• Risk hypoglycemia on first dose – lose your patient’s buy-in
forever.
• Primary Care Method:
– Initiate 5u or 10u qhs sc
– Titrate by 1-2u q3-4d until AM FBS = 4 - 7 mmol/L
• 10% titrations
– If dose = 30’s – increase by 3 units
– If dose = 40’s – increase by 4 units
– etc. etc.
Rx
1. NPH
– Sig: 5u qhs sc or ud
– M: 1 box penfills
– Repeat x 12
2. Needle tips – 28G - 6mm
– Sig: ud
– M: 1 box
– r x 12
•
N.B. (Please teach pt pen
technique)
Insulins
• Long = Basal
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
• Short = Prandial
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 10/90, 20/80, 40/60, 50/50)
• Humalog Mix-25, NovoMix-30
(R + NPH)
(Rapid + NPH)
Short – Prandial Insulins
• Efficacy
– Equivalent reduction in morbidity, HgbA1c
Short – Prandial Insulins
• Toxicity
– Hypoglycemia
– Rapid insulins
better reflect
physiological
effect of
pancreatic insulin
(vs Regular insulin)
• More important
in CKD (=longer
insulin t½ )
Short – Prandial Insulins
• Cost
– All covered under ODB
•
•
•
•
Regular (R) / Toronto ~ $40
NovoRapid (aspart) ~ $56
Humalog (lispro) ~ $55
Apidra (glulisine) ~ $48
• Convenience
– All injected with meals
– Regular insulin injected 30-45 min before meal
– Rapid insulin can be taken with meal
• Reduced risk of hypo if pt injects, then forgets to eat
Bottom Line – Prandial Insulins
• All equivalent
• Choose therapy based on cost / familiarity
– Rapid insulins reflect pancreatic insulin release
better than [R]/Toronto.
– The worse the CrCL, the more important this fact
becomes.
Starting Prandial Insulin
• Fancy Way:
– Total dose: 0.5u/kg
– 40% of total dose - basal insulin qHS
– 20% of total dose TID with meals (60%) – prandial insulin 1530 min before meals
• Eg. 80kg pt – 0.5u/kg = 16u basal (40%); 8u TID (20% x 3 = 60%)
• Primary Care Method:
– Start 5u sc with meals
• Titrate AM to HS to target
– Monitor 2h PPG
• Start injection TID or only single meal as required
– If poor control: inj TID sc; If mediocre control: inj qAM sc
• Still aim for ~ 2/3rds split (40% basal / 60% prandial)
Insulins
• Long = Basal
– NPH, (N)
– Glargine (Lantus)
– Detemir (Levemir)
• Short = Prandial
– Short
• Regular (R)
• Toronto
– Rapid
• Lispro (Humalog)
• Aspart (NovoRapid)
• Glulisine (Apidra)
• Premixed
• 30/70 (and 10/90, 20/80, 40/60, 50/50) (Reg + NPH)
• Humalog Mix-25, NovoMix-30
(Rapid + NPH)
Pre-mixed Insulins
• NovoMix-30 = Humalog Mix25 (equivalent)
• Efficacy
– All ~ 30% short / 70% long
• Toxicity
– Hypoglycemia (less with Rapid vs Regular insulin)
• Cost: ~$53 (Rapids) ~$40 (Regular 30/70)
• Convenience ~ Rapids can be injected with meal
Starting Pre-mixed Insulins
• Fancy Way:
– Estimate total starting daily dose
• (0.3-0.6 units/kg)
– Divide daily dose:
• 2/3 before breakfast; 1/3 before supper
• Primary Care Method:
– From scratch: Start 5-10u QD-BID and titrate
– From other insulins: Calculate approximate
amount of basal and prandial units and divide
2/3rd - 1/3rd AM and PM
Pearls
• Insulin is 2nd line after metformin
– No need to save it for last!
• Better than adding a 3rd PO drug
– Better efficacy, lower toxicity, better studied
• Improve buy-in from patient:
– “Natural” supplement
– Only BID glucochecking at alternating times required:
•
•
•
•
•
•
•
FBS AM + PPG AM, then
FBS AM + FBS noon, then
FBS AM + PPG noon, then
FBS AM + FBS PM, then
FBS AM + PPG PM, then
FBS AM + FBS HS
repeat
Pearls (cont’d)
• D/C secretagogues after starting insulin to
reduce risk of hypo’s.
– Eg. Sulfonylureas, meglitinides
– Black box warning against combo with glitizones!
(Actos, Avandia)
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD
Anti-Dyslipidemic Drugs
(So simple it hurts)
Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD
Pharmacist, Bruyere Academic FHT
Assistant Professor, Dept Family Medicine, U of Ottawa
March 2013
Objectives
• List 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.
Rational Prescribing Process
•
FOUR steps to Rational Prescribing:
1. EFFICACY
2. TOXICITY
3. COST
4. CONVENIENCE
Choosing Anti-dyslipidemics
• First, define your options:
1. Statins (HMG-CoA Reductase inhibitors)
• Prava-, Fluva-, Simva-, Atorva-, Rosuva-statin
2. Fibrates
•
(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, & Gemfibrozil
3. Ezetimibe
•
(Inhibits absorption of cholesterol at the brush border of the small
intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1)).
4. Niacin
5. Cholestyramine
•
(Bile acid sequestrant)
Efficacy – Endpoints?
• Hard Endpoints
– Reduction in mortality
• Fatal MI, Fatal stroke
– Reduction in morbidity
• Non-fatal MI, non-fatal stroke, reduction in hospitalization
• Soft Endpoints
– Reduction in plaque size
– Reduction in lipid panel values
– etc
Efficacy
• Only statins have any proven reduction in hard
endpoints.
The End.
Who cares about lipid panel numbers going up
and down if they don’t affect morbidity or
mortality?
So….why bother with the
Toxicity,
Cost or
Inconvenience of any others?
Can J Cardiol Vol 25 No 10 October 2009
Cdn Dyslipidemia Guidelines 2009
Can J Cardiol Vol 25 No 10 October 2009
Cdn Dyslipidemia Guidelines 2009
Can J Cardiol Vol 25 No 10 October 2009
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
Correlation versus Causation
Why statins?
• Lipid lowering effects
vs
• Pleiotrophic effects
– Plaque stabilizing
– Anti-inflammatory
– Improved endothelial cell function
– Inhibition of thrombogenic response
Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118.
see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694580/?tool=pubmed Accessed Apr 25/12.
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.
Bottom Line
• Being 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.
Exceptions
• Gemfibrozil
– Two trials that show reduction in CVD events
• Helsinki Heart Study (HHS)
• Veterans Administration HDL Intervention Trial (VA-HIT)
– Never combine it with statins
• Serious risk of rhabdomyolysis
• N.B. Fenofibrate
– No effect on CVD events
• Fibrates for high TGs – reduce risk of pancreatitis
• Fibrates for high TGs – treatment of gout
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 2010. Accessed Apr 26/12.
Statin + Ezetimibe
(Lipid-ENHANCE Trial)
• No hard endpoints reported.
• Even intima-media thickness non-significant
– IMPROVE-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: http://www.theheart.org/article/1064755.do )
Rxfiles.ca. ENHANCE Trial Summary, June 2008. Accessed Apr 26/12.
Statin + Niacin
(AIM-HIGH Trial)
• “ …stopped early for futility.”
– 3414 patients
• Earlier Statin + Niacin studies had only showed reduction in soft endpoints.
– Eg. Regression of carotid atherosclerosis
Rxfiles.ca. AIM-HIGH Trial Summary, Dec 2011. Accessed Apr 29/12.
Michael O'Riordan. AIM-HIGH fell short, leaving experts looking for reasons in new review. Heart.org APR 19, 2012. Accessed Apr 25/12
Treatment Populations
• Who gets statins?
– Secondary prevention
– Primary prevention?
– Moderate risk??
– Put it in the water???
Secondary Prevention
• Clear efficacy
• Reduction of
mortality
• Reduction of
morbidity
• Benefit in as
little as one
year
– (usually 4-5
years)
Primary Prevention
• Clear efficacy
in High Risk
Framingham
• Reduction in
morbidity
• No effect on
mortality
Primary Prevention
(never had an MI or Stroke)
• High risk Framingham patients with history of:
– Diabetes
– CKD
– CHF
– Angina
– PVD
– CABG or PCI
– Metabolic syndrome
– Score > 20%
Moderate Risk
• Likely not worthwhile…
• BUT, the JUPITER trial = reduction in hard
endpoints!
– Patients with low/normal cholesterol and high CRP
– Relative Risk Reduction ~ 50%!
– But the Absolute Risk Reduction was tiny!
– hsCRP can differentiate between higher- and lowerrisk Moderate Category Framingham patients
Ridker 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. 2008 Nov 9.
Rosuvastatin:
22/8901 (0.28%)
of non-fatal MI
JUPITER trial
N Engl J Med 2008;359:2195-207.
Placebo:
62/8901 (0.70%)
of non-fatal MI
Relative vs Absolute Risk
Time to Benefit
• How old is too old to start therapy?
– Upper ages of trials ~ 80-83 yrs old.
– …Add time to divergence of survival curves
• ~ 4 to 6 years…
plus
• ?Prognosis
• Older than 85y.o, don’t start?
– Already on it, don’t stop, but don’t bother
checking LDL either.
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
“…Trials (were) Underway…”
• Statin + Niacin trials:
• AIM-HIGH trial
– Stopped early. No benefit from niacin in HDL
raising.
• See: http://www.theheart.org/article/1231453.do
– Known risk of hepatotoxicty with Niacin and
significant flushing.
• HPS2-THRIVE trial (statin + ER Niacin/Laropiprant)
– No benefit (n = 25673)
• See: http://www.theheart.org/article/1515533.do
Toxicity
• Statin
– Rare/Severe:
• Myopathy, even
Myositis/Rhabdomyolysis
• Hepatotoxicty
• Memory impairment
• ?Diabetes??
– discuss
– Common/Bothersome:
• Myalgias
• Fibrates
– Same as above
• Ezetimibe
– Same as above
• Niacin
– +++ flushing
– Hepatotoxicity (esp with
long acting form –
Niaspan)
Cost
• All statins covered under ODB
• All statins are generic
Convenience
• Older statins require QHS dosing
– Cholesterol synthesis mostly occurs late at night
• New statins last long enough to be dosed daily
at any time
• Lacking grapefruit juice interaction:
– Rosuvastatin, fluvastatin, pravastatin
• (non 3A4 P450 metabolism)
Comments, Questions & Requests?
• [email protected]
• Monday & Fridays:
– 613-230-7788 ext 238
• Tuesday, Wednesday,
Thursday:
– 613-241-3344 ext 327
• Twitter: @Roland Halil, PharmD