Back to BasicsPractical 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 2013rhalil@bruyere.org

(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• 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

• 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

Topics to be covered in this lecture• 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

• Antibacterials • Antimycobacterials• Antifungals• Narcotic analgesics• Autonomic nervous system• Anti seizure drugs• Migraines• Antidepressants• Antianxiety agents• Agents for insomnia• Antidiabetics• Antilipemics• Antihypertensives• Diuretics• Nitrates

A Process for Rational Prescribing

(your new best friend)

Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Pharmacist, Bruyere Academic FHTAssistant 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 ProcessTo prescribe or not to prescribe?

That is the question…

• Rational prescribing requires a process for selecting therapy: (in order)

1. Efficacy2. Toxicity3. Cost 4. Convenience

1. Efficacy – Ask About…

1. Which HARD Outcomesa) 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 Not legal

Rare Who cares

• Age? • Newer agents = Less Safety Data• Older agents = 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

VS

Why is Metformin first line therapy?

Januvia®

Efficacy1. HARD Outcomes

– Mortality benefit » Metformin – reduction in CV events (UKPDS-34 trial)

– Morbidity benefit» Metformin – reduction in microvascular complications

2. SURROGATE Outcomesa) Hgb-A1c reduction

a) Metformin ~ 1% - 2%b) Januvia® ~ 0.5% - 0.8%

b) Insulin Sparing Effectsa) 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– Ontario Drug Benefit:

• $ 0.0587 / tab • Covered by ODB

– Rxfiles 2012: • ~ $33 / 100 days

– QD to TID po

• Januvia®– Ontario Drug Benefit:

• $ 2.8050 / tab• Covered by ODB

– Rxfiles 2012:• ~ $315 / 100 days

– Once daily po

Topics to be covered in this lecture• 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

• Antibacterials • Antimycobacterials• Antifungals• Narcotic analgesics• Autonomic nervous system• Anti seizure drugs• Migraines• Antidepressants• Antianxiety agents• Agents for insomnia• Antidiabetics• Antilipemics• Antihypertensives• Diuretics• Nitrates

Antibiotic Review(80% of the knowledge, 80% of the time)

Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmD

Pharmacist, Bruyere Academic FHTAssistant 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”

Aerobic

β-Lactamase Negative

β-Lactamase Positive

Bacilli (rods)

Cocci (spheres)

Gram Negative

Gram Positive

Anaerobic

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[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Map the Bugs

AnaerobesAbove & 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’…

Aerobes

Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli

b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

1 2 3 4 5 6 7 8

Map the Bugs

Anaerobes

Above & Belowdiaphragm

B.Frag C.Diff

9.

Aerobes

Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli

b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-] b-L[+] b-L[-]

1 2 3 4 5 6 7 8

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

9.

Gram[+] Bacilli

• Not usually pathogenic– Major Exception: Listeria monocytogenes

• Listeriosis – enteritis, sepsis, meningitis +/- encephalitis

Aerobes

Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli

(Listeria)

β-L[+] β-L[-] b-L[+] b-L[-] β-L[+] β-L[-]

1 2 3 4 5 6

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

7.

Gm[-] Cocci

• Not usually pathogenic– Major Exceptions:

• Neisseria gonorrhea• Neisseria meningitidis and• Moraxella catarrhalis

– (formerly thought to be a type of Neisseria)

Aerobes

Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli (Listeria) (Neisseria &

Moraxella)

β-L[+] β-L[-] β-L[+] β-L[-]

1 2 3 4

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

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

Aerobes

Gram Positive Gram Negative

Cocci Bacilli Cocci Bacilli (Listeria) (Neisseria &

Moraxella)

β-L[+] β-L[-] β-L[+] β-L[-]

1 (GrpAStrep) 2 3

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

4.

Aerobes

Gram Positive Gram Negative

Cocci Bacilli

β-L[+] both β-L[+]&[-]

1 2

Map the Bugs

Anaerobes

Belowdiaphragm

B.FragC.Diff

3.

Aerobes

Gram [+] Gram [-]

Cocci Bacilli

1 2

Map the Clinically Important Bugs

Anaerobes

(esp. Gut organisms)

Eg. C-Diff& B-frag

4.

Atypicals

1. Legionella pneumonia

2. Chlamydia pneumonia

3. Mycoplasma pneumonia

3.

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. pneumoniaetc. 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

– (Moraxella catarrhalis) (actually a Gm[-] coccus)

PEcKSS-HiM

Hard to Kill• Serratia• Pseudomonas• Acinetobacter• Citrobacter• Enterobacter

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;

Map the BugsSummary

• 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

Anaerobes:• Oral• Gut – Bfrag & Cdiff

Atypicals:• Mycoplasma pneumo• Chlamydia pneumo• Legionella pneumo

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”

Penicillins

Tetracyclines

Clindamycin

Vancomycin

Aminoglycosides

Fluoroquinolones

Macrolides

Cephalosporins

Metronidazole

Carbapenems

Antibiotics – Mechanisms of Action

From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

Beta-Lactams - Penicillins

Penicillin

Amoxicillin / Ampicillin Cloxacillin / Methicillin(po) (iv) (clinic) (lab)

Amox + Clavulanic acid

Anti-Strep Anti-Staph

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) In

crea

sing

Gra

m[-]

cov

erag

e

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 L-

enantiomer of Ofloxacin– Renal clearance

2. Moxifloxacin– Hepatic clearance

• Enhanced coverage of:1. Strep pneumo2. Oral Anaerobes3. 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. Gentamicin2. Tobramycin

– Reserved for Pseudomonas aeruginosa

3. 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

PharmacodynamicsRelationship 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]

Time (h)

Peak

MIC

Log [Conc]

Time (h)

MIC

PharmacodynamicsRelationship 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

Log [Conc]

Time (h)

Peak

MIC

Log [Conc]

Time (h)

Peak

MIC

PharmacodymamicsBactericidal 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 DrugsPharmacology 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

From: http://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Accessed Dec 28/12

For: TB, MRSA

For: skin, dental

infx (staph, strep, &

anaerobes)

Part 3 – Map the Battlefield

Map the BattlefieldRational Prescribing

Individual1. Efficacy

– Could be reduced, BUT:– Empiric tx still effective if

it is well chosen • (Lower risk infections,

properly dosed, clinically stable, true indication etc.)

2. Toxicity– Reduced with narrow

spectrum tx

3. Cost– Reduced with older tx

4. Convenience– Usually less convenient

Population1. Efficacy

– Maintained long term with lower resistance rates

2. Toxicity– Reduced since lifespan of

older drugs is maintained

3. Cost– Reduced insurance costs,

economic losses, hospital costs dealing with superbugs

4. Convenience

VS.

Map the Battlefield

Map the BattlefieldConjunctivitis: viral – no tx

Sinusitis: viral – no tx

Oral anaerobes: abscess drainage – no tx (Amox 2g – pre dental sx?)

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 Vanco

Otitis media: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)

AECOPD: S.pneumo, Hi,M (Amox +/- Clav, Cef2, Septra)

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)

UTI (Cystitis): PEcK – (Septra, Macrobid, Amox, Norflox)

Pyelonephritis: PEcK – (Septra, Amox/Clav, FQ (not Norflox)

Traveller’s Diarrhea: (80% bacterial): EcSS, (camphlyobacter) - Septra, FQ, (Azithro)

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)

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– Cefipime (iv)

Incr

easi

ng G

ram

[-] c

over

age

MSSA and Strep & PEcKSS (same as Amox)

N.B. never Enterococcus!

To boost: for PEcKSS-HiM(same as Amox/Clav)

SPACE bugs: The Big Guns

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

• (regular dose 250-500 mg BID)

Ref: Marc Riachi, RPh

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.

BL+ Aerobic GPCAerobic GNB

95% of Staph. species are BL +ve

Penicillin:BL-ve aerobic GPC

oral anaerobesN.meningitidis

Isoxazoyl PCNs:eg. Cloxacillin, Nafcillin

Gut anaerobes(B. fragilis)

Ampicillin/Amoxicillin:HiPEELSS

Easy to Kill GNB

Lacking Activity Vs.

TMP/SMX

Atypical Organisms

MSSA/MSSE

Macrolides:ErythromycinClarithromycinAzithromycin

TMP/SMXTetracyclines

Respiratory FluoroquinolonesGatifloxacinLevofloxacinMoxifloxacin

MRSA(7%)/ MRSE (>65%)

VancomycinRifampin

Fusidic AcidLinezolidSynercid

Amoxicillin/Clavulanic acidAmpicillin/Sulbactam

Second Generation Cephs

1st Generation Cephs:(Cefazolin iv / Cephalexin po)

PEcKSS

H. influenzaeB. fragilis

CefotetanCefoxitin

Metronidazole

Clindamycin

3rd Generation Cephs.

CeftriaxoneCefotaxime

Ceftazidime

4th Generation Cephs:Cefepime

Piperacillin:(P.aeruginosa, Enterobacter)

Never Use Alone!

Piperacillin/TazobactamTicarcillin/Clavulanic Acid

Carbapenems:Imipenem

Meropenem

AMGs:GentamicinTobramycin

Amikacin

CefuroximeCefuroxime axetil

Cefaclor

No Cephalosporin covers:MRSA / MRSE

enterococcus sp.Listeria monocytogenes

Difficult to Kill GNB

FQs:ciprofloxacin

ofloxacinnorfloxacin

Adapted from: Winslade N. On Continuing Practice 1990-1, volumes 17-18.Prepared By:Sandra A.N. Tailor, Pharm.D.Clinical Coordinator - Infectious DiseasesSunnybrook Health Science CentreDepartment of Pharmacy11/11/02

TB drugs

Adapted from: Marc Riachi, RPh

Mycobaterium tuberculosisThe 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

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

• 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

Antifungals• Oral

– Azole anti-fungals• Itra- (Sporanox), • flu- (Diflucan), • vori-, • posa-• ketoconazole (Nizoral)• active vs. yeast and

dermatophytes

– Terbinafine (Lamisil)• active vs. yeast and

dermatophytes

– Nystatin• active vs. yeast only

• Topical– 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

Ref: Marc Riachi, RPh

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

Hypertension and BP Meds(The ABCD’s of HTN)

Dr Roland Halil, BSc(Hon), BScPharm, ACPR, PharmDPharmacist, Bruyere Academic FHT

Assistant Professor, Dept Family Medicine, U of OttawaMarch 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. Efficacy2. Toxicity3. Cost 4. Convenience

A A 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 -dipineLosartanValsartan

CandesartanEtc

RamiprilEnalapril

PerindoprilEtc

BisoprololMetoprolol

AtenololEtc

AmlodipineNifedipineFelodipine

Etc

ChlorthalidoneHydrochlorothiazide

Indapamide Etc

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

resistanceEfficacy: 1st line 1st line 1st line (< 65y.o.) 1st line 1st line

A A B C D

Toxicity: Hypotension

HyperK+Acute renal failure (ARF)

Angioedema

Monitor: SCr, K+, BP

Toxicity:HypotensionBradycardia

Bronchoconstriction (in brittle

asthmatics with non-

cardioselective bbl’s)

Monitor: BP, HR, RR

Toxicity:Hypotension

EdemaOrthostatic

hypotension

Toxicity:Hypotension

HypoNa+HypoK+

ARF

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

ComorbiditiesIndication ARB ACEinh B C D

HTN         (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 (HOPE)      

Afib     (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 drug2. Increase to moderate

dose3. 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

mg

BP

Comments, Questions & Requests?

• rhalil@bruyere.org• Monday & Fridays:

– 613-230-7788 ext 238

• Tuesday, Wednesday, Thursday: – 613-241-3344 ext 327

• Twitter: @Roland Halil, PharmD