1. Back to Basics 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
(Partially adapted from slides by Marc Riachi, R.Ph.)

2. 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.

3. Topics to be covered Antiplatelets and anticoagulants Antibacterials
Antimycobacterials
Antifungals
Narcotic analgesics
Autonomic nervous system
Anti seizure drugs
Migraines
Antidepressants
Antianxiety agents
Agents for insomnia
Antidiabetics
Antilipemics
Antihypertensives
Diuretics
Nitrates
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
Ref: Marc Riachi, RPh

4. Topics to be covered in this lecture
Antibacterials
Antimycobacterials
Antifungals
Narcotic analgesics
Autonomic nervous system
Anti seizure drugs
Migraines
Antidepressants
Antianxiety agents
Agents for insomnia
Antidiabetics
Antilipemics
Antihypertensives
Diuretics
Nitrates
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

5. 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

6. 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.

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)
Efficacy
Toxicity
Cost
Convenience

8. 1. Efficacy – Ask About… Which HARD Outcomes Which SURROGATE Outcomes
Mortality benefit?
Morbidity benefit?
Which SURROGATE Outcomes
Clinically relevant?
THEN “What is the quality of the evidence to prove this?”
Meta-analysis?
Randomized Controlled Trial?
Case series?
Anecdotal evidence?

9. 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.

10. 2. Toxicity – Ask About… Age? Newer agents = Less Safety Data
Bothersome
Severe
Common
Not legal
Rare
Who cares
Age?
Newer agents = Less Safety Data
Older 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®

14. Efficacy HARD Outcomes SURROGATE Outcomes Mortality benefit
Metformin – reduction in CV events (UKPDS-34 trial)
Morbidity benefit
Metformin – reduction in microvascular complications
SURROGATE Outcomes
Hgb-A1c reduction
Metformin ~ 1% - 2%
Januvia® ~ 0.5% - 0.8%
Insulin Sparing Effects
Metformin

15. Toxicity Metformin Januvia® ?Unknown - too new
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?

16. Cost & Convenience Metformin Januvia® Ontario Drug Benefit:
$ / tab
Covered by ODB
Rxfiles 2012:
~ $33 / 100 days
QD to TID po
Januvia®
Ontario Drug Benefit:
$ / tab
Covered by ODB
Rxfiles 2012:
~ $315 / 100 days
Once daily po

17. Topics to be covered in this lecture
Antibacterials
Antimycobacterials
Antifungals
Narcotic analgesics
Autonomic nervous system
Anti seizure drugs
Migraines
Antidepressants
Antianxiety agents
Agents for insomnia
Antidiabetics
Antilipemics
Antihypertensives
Diuretics
Nitrates
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

18. 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

19. 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

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 Negative
Aerobic
β-Lactamase Negative
Cocci (spheres)
Gram Positive
Bacilli (rods)
Anaerobic
β-Lactamase Positive

22. Map the Bugs Aerobes Anaerobes 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Gram Positive Gram Negative Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

23. 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’…

24. Map the Bugs Aerobes Anaerobes Above & Below diaphragm 9
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]
Anaerobes
Above & Below
diaphragm
B.Frag
C.Diff 9 .

25. Map the Bugs Aerobes Anaerobes Below diaphragm 9 1 2 3 4 5 6 7 8
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 9 .

26. Gram[+] Bacilli Not usually pathogenic
Major Exception: Listeria monocytogenes
Listeriosis – enteritis, sepsis, meningitis +/- encephalitis

27. Map the Bugs Aerobes (Listeria) Anaerobes Below diaphragm 7
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
(Listeria)
β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 7 .

28. Gm[-] Cocci Not usually pathogenic Major Exceptions:
Neisseria gonorrhea
Neisseria meningitidis
and
Moraxella catarrhalis
(formerly thought to be a type of Neisseria)

29. Map the Bugs Aerobes Anaerobes Below diaphragm 5 1 2 3 4
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
(Listeria) (Neisseria &
Moraxella)
β-L[+] β-L[-] β-L[+] β-L[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 5 .

30. 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

31. Map the Bugs Aerobes Anaerobes Below diaphragm 4 1 (GrpAStrep) 2 3
Gram Positive Gram Negative
Cocci Bacilli Cocci Bacilli
(Listeria) (Neisseria &
Moraxella)
β-L[+] β-L[-] β-L[+] β-L[-]
1 (GrpAStrep)
Anaerobes
Below
diaphragm
B.Frag
C.Diff 4 .

32. Gram Positive Gram Negative
Map the Bugs
Aerobes
Gram Positive Gram Negative
Cocci Bacilli
β-L[+] both β-L[+]&[-]
Anaerobes
Below
diaphragm
B.Frag
C.Diff 3 .

33. Map the Clinically Important Bugs
Aerobes
Gram [+] Gram [-]
Cocci Bacilli
Atypicals
Legionella pneumonia
Chlamydia pneumonia
Mycoplasma pneumonia 3 .
Anaerobes
(esp. Gut organisms)
Eg. C-Diff
& B-frag 4 .

34. 1 - Gram [+] Cocci Staphylococcus S. aureus S. epidermidis
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

35. 2 - Gram [-] Bacilli Easy to Kill Proteus mirabilis Escherichia coli
Klebsiella pneumonia
Salmonella
Shigella
Haemophilus influenza
(Moraxella catarrhalis) (actually a Gm[-] coccus)
PEcKSS-HiM
Hard to Kill
Serratia
Pseudomonas
Acinetobacter
Citrobacter
Enterobacter
SPACE 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 pneumo
Chlamydia pneumo
Legionella pneumo
Map the Bugs Summary
Anaerobes:
Oral
Gut – Bfrag & Cdiff
Gram positive aerobes:
Cocci
Staph
Aureus
MRSA (~8-10%)
MSSA
Epiderimidis
MRSE (~65%)
MSSE
Strep
Group A strep (pyogenes)
Group B strep (agalactiae)
Strep Viridans
Strep pneumo etc.
Enterococcus
Faecalis
Faecium
Bacilli
Listeria
Gram negative aerobes:
Bacilli
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)
Cocci
Neisseria
gonorrhaea
meningitidis
Moraxella catarhallis

38. Part 2 - Map the Drugs (Save your Ammo)

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 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

40. Part 2 - Map the Drugs “Save your Ammo”
Fluoroquinolones
Penicillins
Tetracyclines
Aminoglycosides
Macrolides
Vancomycin
Carbapenems
Cephalosporins
Clindamycin
Metronidazole

41. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

42. Beta-Lactams - Penicillins
Amoxicillin / Ampicillin Cloxacillin / Methicillin
(po) (iv) (clinic) (lab)
Amox + Clavulanic acid
Anti-Staph
Anti-Strep

43. Beta-Lactams - Cephalosporins
1st Generation
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
Cefadroxil (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 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.

45. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

46. Fluoroquinolones 2nd generation 3rd generation 4th 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

47. Fluoroquinolones The “Respiratory FQs” Levofloxacin Moxifloxacin
Concentrate in alveolar macrophages
Greater than serum concn
Levofloxacin
the more active L-enantiomer of Ofloxacin
Renal clearance
Moxifloxacin
Hepatic clearance
Enhanced coverage of:
Strep pneumo
Oral Anaerobes
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

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 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)

50. Antibiotics – Mechanisms of Action
From: Accessed Dec 28/12

51. Aminoglycosides Gentamicin Tobramycin Amikacin
Reserved for Pseudomonas aeruginosa
Amikacin
All excellent Gram[-] coverage:
PEcKSS-HiM and SPACE bugs
Efficacy: excellent Gm[-]
Toxicity:
Nephrotoxicity
Ototoxicity
Less now with daily dosing
Cost:
Cheap, old meds
Convenience
Now Once daily IV/IM

52. 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
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
Log [Conc]
MIC
MIC
Time (h)
Time (h)

53. 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
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:
If CrCL = 90mL/min - Levofloxacin 750mg q24h po
If CrCL = 30mL/min – Levofloxacin 750mg q48h po
Peak
Peak
Log [Conc]
Log [Conc]
MIC
MIC
Time (h)
Time (h)

54. 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.

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 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

57. For: skin, dental infx (staph, strep, & anaerobes)
Map the Drugs – Summary
For: TB, MRSA
For: skin, dental infx (staph, strep, & anaerobes)
From: Accessed Dec 28/12

58. Part 3 – Map the Battlefield

59. Map the Battlefield Rational Prescribing
Individual
Efficacy
Could be reduced, BUT:
Empiric tx still effective if it is well chosen
(Lower risk infections, properly dosed, clinically stable, true indication etc.)
Toxicity
Reduced with narrow spectrum tx
Cost
Reduced with older tx
Convenience
Usually less convenient
Population
Efficacy
Maintained long term with lower resistance rates
Toxicity
Reduced since lifespan of older drugs is maintained
Cost
Reduced insurance costs, economic losses, hospital costs dealing with superbugs
Convenience
VS.

60. Map the Battlefield

61. Map the Battlefield
Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)
Conjunctivitis: viral – no tx
Sinusitis: viral – no tx
AECOPD: 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 tx
Skin abscess: drainage – no tx
Cellulitis: 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 Vanco
Traveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter) - Septra, FQ, (Azithro)

62. (Group A Strep, oral anaerobes, Neisseria)
Map the Battlefield
Penicillin
(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 Generation
Cephalexin (Keflex™) or Cefadroxil (po)
Cefazolin (Ancef™) (iv)
2nd Generation
Cefuroxime (po & iv)
3rd Generation
Ceftriaxone, Cefotaxime, Ceftazidime (iv)
Cefixime (Suprax™) (po)
4th Generation
Cefipime (iv)
To boost: for PEcKSS-HiM
(same as Amox/Clav)
Increasing Gram[-] coverage
SPACE bugs: The Big Guns
Cefadroxil (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/Tazobactam
Aminoglycosides (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/Tazobactam
Meropenem

66. 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.

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 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)

68. 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

69. Antibiotics Preferred in Pregnancy
Penicillins
Including those in combination with ß-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam)
Cephalosporins
Erythromycin base
Azithromycin
Clindamycin
Metronidazole
(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 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.

72. Adapted from: Marc Riachi, RPh
TB drugs
Adapted from: Marc Riachi, RPh

73. 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

74. 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

75. 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.

76. Treatment – Latent TB RIF – GI toxicities, major drug interactions!
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 p Access March 14, 2013.

77. 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

78. Adapted from: Marc Riachi, RPh
Anti-fungals
Adapted from: Marc Riachi, RPh

79. Drug info PZA (may inhibit mycobacterial metabolism):
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):
Hepatotoxicity (↑ with alcohol)  monitor LFTs
Pancytopenia
Colours urine, feces, saliva, tears orange  may permanently stain contact lenses
Induces CYP450
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
Ref: Marc Riachi, RPh

80. Antifungals Oral Topical Injectables Azole anti-fungals
Itra- (Sporanox),
flu- (Diflucan),
vori-,
posa-
ketoconazole (Nizoral)
active vs. yeast and dermatophytes
Terbinafine (Lamisil)
Nystatin
active vs. yeast only
Topical
Ciclopirox
(cream, lacquer, shampoo),
nystatin
(cream, pv, oral suspension),
clotrimazole
(cream, pv),
miconazole
ketoconazole
(cream shampoo),
terbinafine
(cream, spray),
tolnaftate
(powder  suitable for skin folds)
Injectables
usually require I.D. consult
Ref: Marc Riachi, RPh

81. 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, 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

82. 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

83. 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

84. 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

85. Rational Prescribing
Rational prescribing requires a process for selecting therapy: (in order)
Efficacy
Toxicity
Cost
Convenience

86. Reduced sympathetic outflow, and heart rate B C D
ARB
ACEinh
B-blockers
CCB
(DHP-type)
Diuretics
(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
Bisoprolol
Metoprolol
Atenolol
Amlodipine
Nifedipine
Felodipine
Chlorthalidone
Hydrochlorothiazide
Indapamide
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
Reduced 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 resistance
Efficacy: 1st line
1st line
1st line (< 65y.o.)

87. Toxicity: A B C D Hypotension HyperK+ Acute renal failure (ARF)
Angioedema
Monitor: SCr, K+, BP
Bradycardia
Bronchoconstriction (in brittle asthmatics with non-cardioselective bbl’s)
Monitor: BP, HR, RR
Edema
Orthostatic hypotension
HypoNa+
HypoK+
ARF
Monitor: SCr, lytes, BP
Cost:
Generic - $$$
ODB covered
Generic - $ $
Generic: $$$
Convenience: QD
Losartan
25mg to 100mg
Ramipril
2.5mg to 10mg
Bisoprolol 2.5mg to 10mg
Amlodipine 2.5mg to 10mg
QAM
Chlorthalidone 25mg

88. 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

89. 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)
PVD
Afib
(Diltiazem)

90. 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.

91. Second Line Therapy Alpha blockers Spironolactone Hydralazine Nitrates
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
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;

92. Process Start first drug Increase to moderate dose
Monitor for efficacy (BP) and toxicity
If close to target:
increase dose
If far from target:
start new drug
Dose response curves
Flatten at top half
Less bang for your buck BP mg

93. Comments, Questions & Requests?
Monday & Fridays:
ext 238
Tuesday, Wednesday, Thursday:
ext 327
Halil, PharmD