Pharmacology

Pharmacology Therapeutics
= =
Mechanism of Action Pharmacology
+ +
Pharmacokinetics Pathophysiology
+
Pharmacodynamics
Antibiotic Review
 Process
1. Map the Bugs
Know your enemy

2. Map the Drugs

Save your ammo
Part 1 - Map the (Clinically Important) Bugs
Know your enemy

Gram Negative
Aerobic

-Lactamase Negative
Cocci (spheres)

Gram Positive Bacilli (rods)

Anaerobic

-Lactamase Positive
 Anaerobes
Above & below the diaphragm
Oral Gut
Simple organisms Approx the same, except:
Easily handled by
penicillins (beta-lactams) Human pathogens:
Eg. Actinomyces Bacteroides fragilis
Bifidobacterium (B.frag)
Fusobacterium
Clostridium difficile
Lactobacillus
(C.diff)
Peptococcus
Peptostreptococcus
Propionibacterium
etc More virulent bugs
requiring bigger guns
 Gram[+] Bacilli
Not usually pathogenic
Major Exception: Listeria monocytogenes
Listeriosis enteritis, sepsis, meningitis +/- encephalitis
 Gm[-] Cocci
Not usually pathogenic
Major Exceptions:
Neisseria gonorrhea
Neisseria meningitidis
and
Moraxella catarrhalis
(formerly thought to be a type of Neisseria)
 -Lactamase Enzymes
First penicillinase described in 1940s even
before penicillin was clinically available.
Most bugs produce some type of -lactamase
enzyme that destroys -lactam antibiotics
(pens, cephs, carbapenems)

Gm[+] cocci & -lactamase [-]: Group A & B streps

give Penicillin
 1 - Gram [+] Cocci
Staphylococcus Streptococcus
Group A (pyogenes) (-Lact[-])
S. aureus Group B (agalactiae) (-Lact[-])

Methicillin resistant (MRSA) Neonates, v. elderly, obstetrics

Methicillin sensitive (MSSA) S. pneumonia

S. epidermidis etc. etc.
Methicillin resistant (MRSE) Enterococcus
Methicillin sensitive (MSSE) (Formerly thought to be Strep D)
Skin commensal E. faecalis
Rarely pathogenic E. faecium
A mean hospital organism
 2.5 - Gram [-] Bacilli
Easy to Kill Hard to Kill
Proteus mirabilis Serratia
Escherichia coli Pseudomonas
Klebsiella pneumonia Acinetobacter
Salmonella Citrobacter
Shigella Enterobacter
PEcKSS bugs SPACE bugs
?Moderate To Kill
Haemophilus influenza
(Moraxella catarrhalis) (actually a Gm[-] coccus)
HiM bugs
Atypicals:
Mycoplasma pneumo Map the Bugs Anaerobes:
Oral
Chlamydia pneumo Summary
Legionella pneumo Gut Bfrag & Cdiff

Gram positive aerobes: Gram negative aerobes:

Cocci Bacilli
Staph Easy to Kill
Aureus
PEcKSS (Proteus, Ecoli,
MRSA (~8-10%) Klebsiella, Salmonella, Shigella)
MSSA
HiM (H.flu and Moraxella
Epiderimidis
(actually a Gm[-]coccus))
MRSE (~65%)
MSSE Hard to Kill
Strep SPACE bugs (Serratia,
Group A strep (pyogenes) Pseudomonas, Acinetobacter,
Group B strep (agalactiae)
Citrobacter, Enterobacter)
Strep Viridans Cocci
Strep pneumo etc. Neisseria
Enterococcus gonorrhaea
Faecalis
meningitidis
Faecium
Moraxella catarhallis
Bacilli
Listeria
 Map the Bugs - Summary
Otitis media: S.pneumo, Hi,M Conjunctivitis: viral

Sinusitis: viral
AECOPD: S.pneumo, Hi,M Oral abscess: oral anaerobes

C.A.P: S.pneumo, atypicals

CAP+comorb./risk factors, or Pharyngitis: viral
NHAP: also HiM bugs (Group A Strep)

Bronchitis: viral
Skin abscess:
anaerobes, staph,
Cellulitis: MSSA, GAS, GBS strep
N.B. Boils = Staph

Pyelonephritis: PEcK H.pylori:

Cdiff / Bfrag:
UTI (Cystitis): PEcK
Travellers Diarrhea: (80% bacterial): EcSS,
(camphlyobacter)
Part 2 - Map the Drugs
(Save your Ammo)
 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-Strep Anti-Staph

Amoxicillin / Ampicillin Cloxacillin / Methicillin

(po) (iv) (clinic) (lab)

Amox + Clavulanic acid

Increasing Gram[-] coverage

 Beta-Lactams - Cephalosporins
1st Generation
Cephalexin (po)

Increasing Gram[-] coverage

Cefazolin (iv)

2nd Generation
Cefuroxime (po & iv)

3rd Generation
Ceftriaxone, Cefotaxime, Ceftazidime (iv)
Cefixime (po)

4th Generation
Cefepime (iv)
 Beta-Lactams Other
(IV only, inpatient use only)

Piperacillin (plus tazobactam)

Carbapenems
Meropenem
Broad spectrum, big gun antibiotics
Imipenem that cover Gm[+], both easy and hard
to kill Gm[-] bugs, even some
Ertapenem anaerobes.

Monobactams
Aztreonam
 Antibiotics Mechanisms of Action

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

 Fluoroquinolones
2nd generation Ofloxacin
Ofloxacin
Ciprofloxacin
Ciprofloxacin
Norfloxacin Anti-pseudomonal the
3rd generation only PO option!
Levofloxacin Norfloxacin
4th generation Same spectrum as Cipro
(even anti-Pseudomonal)
Moxifloxacin but only for cystitis UTI.
Concentrates in the G.U.
Covers: Gm[-]s system only
PEcKSS-HiM & SPACE bugs N.B. Not good enough for
3rd and 4th gen. FQs cover pyelonephritis or systemic
strep pneumo. well too infection

N.B. New FDA warnings on FQ safety (neuropathies, tendon rupture, hallucinations etc)
By Kristin J. Kelley. FDA Calls for More Restrictions on Fluoroquinolone Use. NJEM Journal Watch. May 16, 2016.
http://www.jwatch.org/fw111568/2016/05/16/fda-calls-more-restrictions-fluoroquinolone-use?query=pfw&jwd=000013533416&jspc=
 Fluoroquinolones
The Respiratory FQs Enhanced coverage of:
Concentrate in alveolar 1. Strep pneumo
macrophages 2. Oral Anaerobes
Greater than serum concn 3. Atypicals
1. Levofloxacin N.B. only Moxi cover B.frag
the more active L- Neither covers C.diff
enantiomer of Ofloxacin (Both will cover Clostrium
Renal clearance non-difficile strains)

2. Moxifloxacin
Both have 100% oral
Hepatic clearance
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 doesnt 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 Efficacy: excellent Gm[-]
2. Tobramycin Toxicity:
Reserved for Pseudomonas Nephrotoxicity
aeruginosa Ototoxicity
3. Amikacin Less now with daily dosing
Cost:
All excellent Gram[-] Cheap, old meds
coverage: Convenience
PEcKSS-HiM and SPACE Now Once daily IV/IM
bugs
 Pharmacodynamics
Relationship between Abx Concentration & Effect
Concentration Dependent Time Dependent Killing
Killing Time over MIC matters
Higher the peak, better the i.e. Independent of peak
kill concentration. Determined
i.e. Ratio of peak drug by length of time over MIC
concentration and M.I.C. Eg. B-lactams (Pen, Ceph etc)
determines rate of kill.
Eg. FQs, AGs
Log
Peak [Conc]
Log
[Conc]

MIC
MIC

Time (h)
Time (h)
 Pharmacodynamics
Relationship between Abx Concentration & Effect
Concentration Dependent
With renal impairment:
Killing
Maintain the peak,
Higher the peak, better the lengthen the interval
kill
This ensures good rate of
i.e. Ratio of peak drug killing while allowing
concentration and M.I.C. enough time to eliminate
determines rate of kill. the drug and avoid
Eg. FQs, AGs toxicities
Log
Peak
Log
Peak For eg:
[Conc] [Conc]
If CrCL = 90mL/min -
Levofloxacin 750mg q24h po
MIC MIC
If CrCL = 30mL/min
Levofloxacin 750mg q48h po
Time (h) Time (h)
 Pharmacodymamics
Bactericidal vs Bacteriostatic
Bactericidal Abx Bacteriostatic Abx
B-lactams (Pen, Ceph) Tetracyclines
Aminoglycosides (AGs) Macrolides
Fluoroquinolones (FQs) Clindamycin
Rifampin Chloramphenicol
Metronidazole
Vancomycin

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

 Map the Bugs - Summary
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
(Amox +/- Clav, Cef2, Septra)
drainage +/- tx
(Amox 2g pre dental sx?)
C.A.P: S.pneumo, atypicals
(Amox, Macrolides (Clarithro/Azithro)) Pharyngitis: viral no tx
CAP+comorb./risk factors, or (Group A Strep Pen VK)
NHAP: also HiM bugs (Combine
AmoxClav or Cef2 + Macrolide (or use
Bronchitis: viral no tx
FQ))
Skin abscess:
Cellulitis: MSSA, GAS, GBS - drainage +/- tx
(Clox, Cef1, & Clinda (more resistant)

H.pylori: triple po tx
Pyelonephritis: PEcK
PPI + (Clarithro +/-
(Septra, Amox-Clav, FQ (not Norflox)
Amox +/- Metro)
Cdiff / Bfrag: Metro / po Vanco

UTI (Cystitis): PEcK (Septra, Travellers Diarrhea: (80% bacterial): EcSS, (campylobacter)
Macrobid, Amox+/-Clav, Norflox) - Septra, FQ, (Azithro)
 Beta-Lactams - Cephalosporins
MSSA and Strep & PEcKSS
1st Generation (same as Amox)
N.B. never Enterococcus!

Increasing Gram[-] coverage

Cephalexin (Keflex) or Cefadroxil (po)
Cefazolin (Ancef) (iv)
2nd Generation To boost: for PEcKSS-HiM
(same as Amox/Clav)
Cefuroxime (po & iv)
3rd Generation SPACE bugs: The Big Guns

Ceftriaxone, Cefotaxime, Ceftazidime (iv)

Cefixime (Suprax) (po)
4th Generation
Cefipime (iv)
 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)(3rd line)
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.
 Keypoints
PEN for b-lact[-] Gm[+] cocci (GAS, GBS), oral anaerobes, Neisseria (meningitidis)
?What to do for Strep pneumo /Enterococcus?
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 (Cefs 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))
Hypertension and BP Meds
(The ABCDs of HTN)
 Essential Hypertension
A A B C D
(B-bl) beta- DHP-CCB
ACEinh ARB blockers (dihydropyridine) Thiazide Diuretic
"-pril" "-sartan" "-olol" "-dipine"
enalapril valsartan bisoprolol nifedipine hydrochlorothiazide
lisinopril irbesartan metoprolol amlodipine
ramipril candesartan propranolol felodipine
Blocks conversion of AT1 to ATII
(ACEinh) or blocks ATII receptors Reduces
Reduction in
(ARB) = sympathetic Relaxes
systemic vascular
Inhibition of vasoconstriction, outflow & heart peripheral
resistance (not
aldosterone, catecholamine, and rate & renal smooth muscle
diuresis)
arginine vasopressin release, water AT2 production
intake, and hypertrophic responses
1st line 1st line 2nd line 3rd line
 Essential Hypertension
A (ACEinh) A (ARB) B C D

Efficacy 1st line 1st line 2nd line 3rd line

Hypotension Hypotension Hypotension Hypotension Hypotension

Orthostatic
hyperK+ hyperK+ Bradycardia hypoK+, hypoNa+
hypotension

Bronchoconstric
Toxicity tion in brittle
Acute renal
asthmatics
failure ARF (esp high dose,
Edema ARF
(ARF) esp non-cardio-
selective)

BP, OH,
Monitor BP, SCr, K+ BP, SCr, K+ BP, HR, RR BP, SCr, K+, Na+
edema
 Hypertension with Comorbidities
A (ACEinh) A (ARB) B C D
HTN (ALLHAT)

(CAPRICORN,
MI (HOPE) (VALIANT)
BHAT)

(MERIT-HF,
(CONSENSUS,
CHF CIBIS II,
SOLVD, ATLAS)
COPERNICUS)

(IDNT, IRMA-2,
DM2 (HOPE)
RENAAL)

(HOPE, (LIFE, SCOPE, (ALLHAT,

CVA
PROGRESS) MOSES) PROGRESS)

PVD (HOPE)
Angina
 RAAS system
Pharmacology of ACEinh / ARBs
 Second Line Therapy
What if you have used all ~ Equivalent benefit
available 1st line options? choose based on potential
harm, cost or convenience
factors.
Options:
Ensure that you balance
Alpha blockers
these factors in their order
Spironolactone
of importance.
Hydralazine
Nitrates
Clonidine
Beta-blockers (> 60 y.o.)
etc.
 Second Line Therapy
Alpha blockers Hydralazine
Eg. Prazosin, Doxazosin MOA: direct vasodilation of
Harm: Risk of orthostatic arteries
hypotension Harm: orthostatic
Convenience: only OD hypotension
Good 1st choice of 2nd line tx QID dosing
Dual treatment of BPH & BP if
also needed in male patients
Nitrates
eg. ISDN, ISMN, NTG
Spironolactone
MOA: smooth muscle
Benefit: mortality benefit in vasodilation of vasculature
late stage CHF (NYHA class III or IV) (veins > arteries);
Harm: risk of hyperK+ Harm: headache, orthostatic
esp with ARBs or ACEinhs hypotension, dizziness
Convenience: only OD BID- QID dosing;
Dyslipidemia
 Choosing Anti-dyslipidemics
First, define your options:
1. Statins (HMG-CoA Reductase inhibitors)
Prava-, Simva-, Atorva-, Rosuva-statin
2. Fibrates
(The exact mechanism of action of gemfibrozil is unknown; Theories are: 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-, 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 (raises HDL)
5. Cholestyramine
(Bile acid sequestrant)
6. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor
Increases LDL-receptors to reduce serum LDL
 Dyslipidemia
Statins 1. Efficacy:
Fibrates 1. Mortality Benefit
Niacin 2. Morbidity Benefit
Ezetimibe (reduction in non-fatal
Cholestyramine MI, CVA, hospitalizations
etc)
PCSK9 inhibitor
3. Reduction in Surrogate
Markers
Eg. LDL
 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.
 Toxicity
Statin Fibrates
Rare/Severe: Same as statins (Additive)
Myopathy, even Ezetimibe
Myositis/Rhabdomyolysis
Hepatotoxicty Same as statins (Additive)
Memory impairment Niacin
?Diabetes?? +++ flushing
discuss
Common: Hepatotoxicity (esp with
long acting form
Myalgias Niaspan)
PCSK9 inhibitor
?????
Coronary Artery Disease &
Acute Coronary Syndromes
 CAD / ACS
All on a spectrum of Basic Principles:
ischemic damage: 1. BP control
2. Plaque
Stable Angina stabilization
Unstable Angina 3. Clot prevention
NSTEMI
STEMI
 CAD / ACS
1) BP control 2) Plaque Control
Mortality benefit with: Mortality benefit with:
ACEinh or ARB Statin
plus
Beta-blocker*

N.B. HTN accelerates atherosclerosis!

(see: HTN section) (see: Dyslipidemia section)

(*) b-blocker benefit may end between 1 month to 3 years post-MI
Anthony G. Nappi, William E. Boden. Should Beta-Blockers Continue to Be Used in Post-Percutaneous Coronary Intervention Patients Without Myocardial
Infarction? JACC: Cardiovascular Interventions Aug 2016, 9 (16) 1649-1651; http://www.interventions.onlinejacc.org/content/9/16/1649 Accessed Feb 27/16
Bangalore S. et al. Clinical outcomes with -blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med. 2014 Oct;127(10):939-53. doi:
10.1016/j.amjmed.2014.05.032. PMID: 24927909 https://www.ncbi.nlm.nih.gov/pubmed/?term=24927909
 Antiplatelets
Options

Primary prevention ACS Primary prevention CVA

ASA ASA
Clopidogrel Clopidogrel

Secondary prevention ACS Secondary prevention CVA

ASA ASA
+ Clopidogrel
Clopidogrel or ASA + Dipyridamole
Prasugrel or
Ticagrelor
 Mechanisms of Action
ASA Thienopyridines
Irreversible inh of COX-1 Clopidogrel
(thromboxane reduction) Prodrug activated by P450-2C19
Platelet lifespan: 7-10 days N.B. 2% - 14% of population are
poor metabolizers
Dipyridamole MR Prasugrel
inhibits the uptake of Prodrug activated by ester bond
adenosine & breakdown of hydrolysis

cGMP via:
Ticagrelor Irreversible inhibition of
Reversible inhibition of ADP platelet receptor
ADP platelet receptor subtype P2Y12
subtype P2Y12
 Summary CAD / ACS
N.B. Remember which modifiable risk factors
need management
Remember which medications offer a mortality
benefit in treated those risk factors; Use them 1st!

BP control with ACEinh (or ARB) + b-blocker

(For stroke: ACEinh (or ARB) + Thiazide)
Plaque stabilization with statin
Clot prevention with ASA (+/- Clopidogrel)
 Heart Failure
Several types: Basic Principles:
Left vs Right sided 1. BP control
Systolic vs Diastolic
2. Plaque
Preserved ejection stabilization
fraction vs not
3. Clot prevention
 CHF Systolic, Poor LVEF

1) BP control 2) Plaque Control

Mortality benefit with: Mortality benefit with:
ACEinh or ARB Statin
plus
Beta-blocker

(see: HTN section) (see: Dyslipidemia section)

 CHF Systolic, Poor LVEF
3) Clot Prevention Other forms of CHF less
well studied.
Mortality Benefit with:
Benefits of these
ASA 81mg qd
interventions are not as
If ASA allergic: clear
Clopidogrel 75mg qd But offered anyway.
Pay closer attention to
benefit/risk ratio since
benefit is smaller /
(see: Primary prevention of unknown
ACS & CVA section)
 Chronic Kidney Disease (CKD)
Vascular damage to renal beds
Is BP control required?
If so, what is the best agent?
ACEinh or ARB first!
Is prevention of atherosclerosis required?
If so, what is the best agent?
Statin at any dose tolerated
Is CKD a vascular risk?
If so, are anti-platelets required?
ASA (low dose, every day)
 Overall Summary
Vascular problems throughout the body require similar
approaches to management.
Understanding the pathophysiology and pharmacology
of preferred agents will inform your therapeutics.
ACEinh
Anti-inflammatory and modulation of RAAS
Statin
Anti-inflammatory and other pleiotrophic effects
ASA
Anti-inflammatory and anti-platelet
Beta-blocker
(If cardiac involvement) to reduce MVO2
Hypoglycemic Drugs
 Diabetes: complications
MACROvascular MICROvascular
Stroke Diabetic eye
disease
Heart disease (retinopathy &
& cataracts)
hypertension
Nephropathy
Peripheral
vascular disease
Neuropathy
Foot problems Foot problems
Kumamoto Study HbA1c & Complications
Intensive vs. conventional insulin therapy (N=110)
Median A1c - 7.1% vs. 9.4%
16 Retinopathy 16 Nephropathy
14 14
12 12
10 10
8 8
6 6
4 7% 4 7%
2 2
0 0

5 6 7 8 9 10 11 5 6 7 8 9 10 11
HbA1c (%) HbA1c (%)
 Drug Classes
Sensitizers Secretagogues
Metformin Sulfonylureas
Glitazones Eg. Glyburide, Gliclazide
Rosiglitazone Meglitinides
Pioglitazone Eg Repaglinide

Other
Alpha glucosidase inhibitors (Acarbose) SGLT2 inhibitors (Cana-, Dapa, Empa-gliflozin)
DPP4 inhibitors (Gliptins) Incretin (GLP1) Analogues
Sitagliptin, Linagliptin * Liraglutide (sc inj)
Saxagliptin, Alogliptin * Exenatide (sc inj)
 Drug Classes
Sensitizers Sensitizers reduce
Metformin insulin resistance
Glitazones Increase glucose uptake &
Rosiglitazone (AVANDIA) utilization in muscle and
Pioglitazone (ACTOS)
adipose tissue
hepatic
gluconeogenesis
 Drug Classes
Basal & prandial insulin Secretagogues
secretion
Sulfonylureas
Doesnt correct impaired Eg. Glyburide, Gliclazide
1st phase insulin
secretion; primarily
affects 2nd phase Meglitinides
Beta-cell sensitizer Eg Repaglinide
primes glucose mediated
insulin secretion (1st
phase)
 Drug Classes: Other
Alpha glucosidase inhibitors (Acarbose)
Competitive inhibitor of pancreatic -amylase and intestinal brush border -glucosidases,
resulting in delayed hydrolysis of ingested complex carbohydrates and disaccharides and
absorption of glucose; Dose-dependent reduction in postprandial serum insulin and
glucose peaks; inhibits the metabolism of sucrose to glucose and fructose

SGLT2 inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin)

Inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, reducing
reabsorption of filtered glucose from the tubular lumen and lowering the renal threshold for
glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered
glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose,
thereby reducing plasma glucose concentrations.

DPP4 inhibitors (Gliptins) (Sitagliptin, Lingliptin, Saxagliptin, Alogliptin)

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 (GLP1) Analogues (Liraglutide, Exenatide )

sc injection

mimic endogenous incretin hormones

 Harm Serious / Rare
Glitazones Secretatgogues
CHF (Sulfonylureas &
Fractures Meglitinides)
M.I.
(rosiglitazone) Severe Hypoglycemia
Bladder Cancer
(pioglitazone)
 Harm Serious / Rare
Metformin
?Risk of Lactic Acidosis
0.03 to 0.06 cases / 1000 pt-yrs
~ 50% fatal
When implicated:
Metformin plasma levels are usually >5 g/mL
Cases - primarily diabetics w/ significant renal
insufficiency, both intrinsic renal disease and renal
hypoperfusion, w/ multiple medical/surgical problems
and multiple medications.
 Harm Common / 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
 Harm Common / 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)
 Harm Common / Bothersome
3) Glitazones: 7) Incretin analogues
Edema N/V/D, ?infection
4) Meglitinides: 8) SGLT2 inhibitors
Hypoglycemia HyperK+, ARF (AKI)
UTI (includes bacteriuria [asymptomatic],
5) Acarbose: cystitis: 9%; females: 4%-18%;
GI upset / diarrhea / males: 4%),
bloating Genitourinary fungal infection
(4%; females: 5% to 11% [includes
6) Gliptins: bacterial vaginosis, cervicitis, vulvitis,
vulvovaginal candidiasis, vulvovaginal
GI upset, edema, infection, vulvovaginitis];
?infection males: 2% to 3% [includes balanitis,
balanoposthitis, genitourinary fungal
infection, penile infection, scrotal abscess])
GI Meds
 Dyspepsia, GERD, PUD: Options
Buffer antacids H2 receptor blocker (H2RA)
MOA: raise gastric pH Eg. Ranitidine, Famotidine,
Immediate effect, short lived Nizatidine, Cimetidine
Efficacy: relieves mild MOA: competitively inhibit
histamine H2 receptors on
GERD sxs in ~20% of parietal cells thereby decrease
patients gastric acid secretion
Calcium carbonate: Efficacy: all equivalent
most potent, chew 2-3 tabs prn, useful in
Tox: constipation treatment/prevention of mild
Sodium bicarb GERD
Tox: flatulence, belching. C.I. in CHF, Not effective enough for
edema, renal dysfunction NSAID prophylaxis of PUD
Magnesium/Aluminum Toxicity: well tolerated
hydroxide Cimetidine: ++ interactions
Tox: diarrhea . C.I. in CKD, ARF Convenience: BID dosing
Eg. Ranitidine 75-150mg QD-BID
 Dyspepsia, GERD, PUD: Options
Proton Pump Inhibitors Efficacy: (all equivalent)
Superior to H2RAs for dyspepsia,
(PPI) GERD, & PUD (esp meal-induced
Eg. Omeprazole 20mg, acid secretion)
(esomeprazole 20mg), Toxicity:
rabeprazole 20mg, Rebound hypersecretion
pantoprazole 40mg, Reduced calcium absorption
lansoprazole 30mg, Elevated risk of VIT B12 deficiency
(dexlansoprazole 30mg)
MOA: suppresses gastric
acid secretion by
inhibiting the parietal
cell H+/K+ ATP pump
 Peptic Ulcer Disease
H.pylori-Induced NSAID-Induced
90% of DU, 70% of GU Cause most H.pylori-
Once diagnosed, treat negative PUD
with at least triple therapy Assess risk factors!
Single and dual therapy are Previous Hx (OR=13.5x)
not effective enough High dose NSAID (OR=7x)
14 day tx more effective Anticoagulants (OR=6.4x)
than 7-10 day tx SSRI use (OR=4.8x)
Age > 60y.o. (OR=3.1x)
Steroids (OR=2.2x)
 Helicobacter pylori
1-2-3: one week, twice daily, 3 drugs
14d versus 7-10d Rx:
Superior efficacy, but elevated toxicity & cost
Triple therapy (all BID):
PPI + Clarithromycin + Amoxicillin
PPI + Clarithromcyin + Metronidazole
N.B. PPI + Amox + Metro inferior regimen
Quadruple therapy: (also 1st line)
PPI BID plus Metronidazole + Tetracyline +
Bismuth subsalicylate all QID
 Laxatives
1. Stool Softeners Increasing potency =
Eg. Docusate sodium
Increasing efficacy and
Not a laxative
Increasing side effects
2. Bulk laxatives:
Water absorption; peristalsis Cramps, pain, diarrhea
Eg. Psyllium, fibre, calcium
polycarbophil
3. Osmotic laxatives
Narcotic induced
Osmotic + colonic acidification
Eg. Milk of magnesia, mag
constipation requires at
citrate, sorbitol, lactulose, PEG least an osmotic laxative,
solution, sodium phosphate, (usually stimulant
glycerin suppositories
laxative)
4. Stimulant laxatives
Direct effect on mucosa
Bisacodyl, sennosides
Analgesics
 Pain: Somatic vs Neuropathic
Somatic Neuropathic
WHO Pain Ladder: TCA
1. Acetaminophen Nortriptyline
2. NSAID Amitriptyline
3. Acetaminophen or NSAID + Gabapentin
weak opioid (eg. Codeine)
Pregabalin
4. Pure strong opioid
Hydromorphone Anti-epileptics
Oxycodone CBZ
Morphine VPA
Codeine
Phenytoin
 Acetaminophen
MOA: unknown
(NAPQI metabolite may interfere w/ TRPA1 mediated pain transmission in the spine)
Efficacy
Equivalent analgesia and antipyresis to NSAIDs
Eg. OA, non-inflammatory pain
Toxicity
Much less GI upset vs NSAIDs, no PUD, no ARF
Liver toxicity in overdose N.B. combo OTC products!
 Choosing NSAIDs

EFFICACY: What are the endpoints of interest?

1. Analgesia
2. Anti-inflammation
3. Antipyresis

All NSAIDs are generally considered

equivalent for each endpoint.
Few useful comparative trials published
 Toxicity 1) Renal
Additive pharmacodynamic Direct nephrotoxicity
effects on renal vasculature Antibiotics Aminoglycosides,
Sulfonamides, Amphotericin B,
ACEinh
Foscarnet, Fluoroquinolones,
ARBs Rifampin, Tetracycline, Acyclovir
Aliskiren (only IV), Pentamidine,
Diuretics Vancomycin
NSAIDs Immunosuppressants Cisplatin,
Methotrexate, Mitomycin,
Cyclosporine, Ifosphamide
NSAIDs equivalent Heavy Metal Poisoning Mercury,
Lead, Arsenic, Bismuth
Lithium
 Toxicity Renal Triple Whammy!
3) ACEinh / ARBs vasodilate
1) Diuretics efferent arterioles (blockade of
reduce ATii effects)
forward
flow into
kidney

Result:
2) NSAIDs
vasoconstrict Reduced
afferent arterioles GFR &
(inh of PG Acute
synthesis) Renal
Failure!
Katarzyna K Loboz and Gillian M Shenfield. Drug combinations and impaired renal function the triple whammy. Br J Clin
Pharmacol. 2005 February; 59(2): 239243. see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884747/ Accessed Oct 31/11
 Toxicity 2) Gastrointestinal
Mechanism
Direct (local) Indirect (systemic)
Contact with GI mucosa Inhibition of PG synthesis
Acidic
Toxic to epithelia
Reduction of mucus and
bicarb secretion
Enterohepatic circulation
of some NSAIDs (repeated
exposure)

JOHN L. WALLACE Physiol Rev 88: 15471565, 2008 Accessed Nov 11/11 http://physrev.physiology.org/content/88/4/1547.full.pdf+html
 Toxicity - Gastrointestinal
Risk Factors: Drugs:
Age > 60 Antiplatelets
Hx of PUD Anticoagulants
GI cancer Corticosteroids
GERD Alcohol
esophageal varices ASA 81mg too!
liver disease
recent MI or CVA

N.B. There is no correlation between symptoms of dyspepsia

and GI mucosal damage as seen on endoscope.
 Toxicity 3) Cardiac
COX-2 selectivity seems to increase cardiac risk
Dose and duration dependent
Ratio of COX-2 : COX-1 inhibition:
Rofecoxib 80 : 1
Celecoxib 9:1
Ibuprofen 0.4 : 1
Naproxen 0.3 : 1
 Summary
1. Efficacy equivalent at equipotent doses
2. Toxicity Renal equivalent risk
GI dose and duration dependent
Higher with some NSAIDs (eg. Ketorolac)
With more risk factors add a PPI or Misoprostol
CV - COX-2 inhibitors > NSAIDs
AVOID COX-2 inh.
 Opioids
Efficacy:
All equivalent analgesia at equipotent doses
Bioavailability PO:IV = 2:1
Toxicity: (many!)
Constipation: ~ equivalent
(?codeine more than others)
Respiratory depression: ~ equivalent
Sedation: ~ equivalent
Pruritis / Histamine release:
Morphine > Hydromorphone > Fentanyl
 Neuropathic Agents
Efficacy: ~ the same; but additive
Presumed inhibition of fast, neuronal Na+ channels
1. Antidepressants
TCAs: Nortriptyline, Amitriptyline, etc.
SNRIs: Duloxetine, Venlafaxine
2. Anticonvulsants
Gabapentin, Pregabalin, VPA, CBZ, phenytoin,
topiramate
3. Topicals
Lidocaine 5%, capscaicin, NSAIDs, compounded
agents above etc.
 Neuropathic Agents
If Efficacy is ~ equivalent; choose based on potential
toxicity, cost, and convenience factors
Toxicity:
TCAs: anticholinergic, sedation, QTc prolongation
Gabapentin & Pregabalin: sedation, edema, dizziness
Duloxetine & Venlafaxine : CNS effects, GI effects
Anti-epileptics: hepatitis, GI effects, CBC alterations, drug
interactions
Drug-Drug Interactions
 Drug Interactions
Nature
Synergistic
Additive
Antagonistic
Consequence
Beneficial
Increased therapeutic effect
Reduced toxicity
Adverse
Reduced therapeutic effect
Increased toxicity
 Drug Interactions Mechanism
1. Pharmacokinetic (PK)
What the body does to the drug
1. Absorption
2. Distribution
3. Metabolism
4. Excretion
2. Pharmacodynamic (PD)
What the drug does to the body
 PK 1) Absorption Interactions
Important in practice:
Chelation (binding interactions)
Less commonly clinically relevant:
Alteration of gastric pH
Alteration of GI motility
 PK 1) Absorption Interactions
Chelation
1. Fluoroquinolones or Tetracyclines plus minerals
[Minerals = calcium (Ca2+) , magnesium (Mg2+) , iron (Fe3+) , aluminum (Al3+)]
[Almost all buffering antacids as well as MVITs, iron tabs etc.]
Risk of treatment failure!
2. Bisphosphonates plus minerals
Risk of osteoporotic fracture
3. Phenytoin plus minerals
Potential loss of seizure control

Separate administration by 2 hours

 PK 1) Absorption Interactions
Alteration of gastric pH
Increased pH
Eg. Iron / Ketoconazole / Vit B12 absorption is reduced
Administer with orange juice or Coca-cola
Alteration of GI motility
Decreased motility
Eg. Decreased absorption of Levodopa
Increased metabolism at intestinal brush border
Increased motility
Eg. Decreased absorption of Digoxin
 PK 2) Distribution Interactions
Displacement Reaction
(from protein binding sites)
Rarely significant
Often need:
Highly bound drug
(98% bound to 96% bound = 100% increase in free concentration)
 PK 3) Metabolism Interactions
Metabolism occurs in many places
Skin, lung, intestine, serum, kidney, liver
Most metabolism occurs in the liver
Genetic variability becoming more important
Isoniazid, codeine
 PK 3) Metabolism Interactions
Inducers of 3A4: Substrates of 3A4:
Rifampin / Rifabutin Clarithro / Erythromycin
Efavirenz / Nevirapine Alpraz / Diaz / Midazolam
Glucocorticoids CSA / Tacrolimus
Indinavir / Nelfinavir
Phenytoin
Ritonavir / Saquinavir
Carbamazepine
Amlodipine / Felodipine
Barbiturates Nifedipine / Verap / Dilt
St. John's Wort Atorva / Simvastatin
Pioglitazone Estrogen
etc etc
 PK 3) Metabolism Interactions
Inhibitors of 3A4: Substrates of 3A4:
Clarithro / Erythro Alpraz / Diaz / Midazolam
Ciprofloxacin CSA / Tacrolimus
Fluco / Itra / Ketoconazole Amlodipine / Felodipine
Nifedipine / Verap / Dilt
Grapefruit juice
Atorva / Simvastatin
Amiodarone
Clarithro / Erythromycin
Indinavir / Nelfinavir Indinavir / Nelfinavir
Ritonavir /Saquinavir Ritonavir / Saquinavir
Delaviridine Estrogen
Verapamil / Diltiazem Carbamazepine
Cimetidine etc

Flockhart D.A. P450 Table www.medicine.iupui.edu/flockhart/table.htm Accessed Sept 19/04.

 PK 4) Excretion Interactions
Rarely significant, but
Enterohepatic circulation:
Bile acid sequestrants + Warfarin or L-T4 or Estrogen
Alteration in urine pH
Ion trapping
Eg. Management of ASA overdose with bicarb
Eg. Methamphetamine overdose with Vit C / NH4Cl
Competition for tubular transporters
Anion: Probenecid + beta-lactams (osteomyelitis)
Cation: Itraconazole /cimetidine + digoxin / quinidine
 PD - CNS
Eg. CNS depression
Alcohol
Opioids
Benzodiazepines
Antihistamines
Diphenydramine, hydroxyzine, etc
Antipsychotics (typical & atypical)
Antidepressants (TCAs, SSRIs etc)
Barbiturates
Etc.
 PD - CV
Bradycardia Hypertension
Beta blockers NSAIDs & COX-2 inh
Diltiazem, Verapamil Corticosteroids
Digoxin EPO
Amiodarone Estrogens
Cyclosporine
Sympathomimetics
phenylephrine
caffeine
pseudoephedrine
 PD
Respiratory Depression Constipation
Opioids Loperamide
Barbiturates Opioids
Calcium / antacids
Benzodiazepines Anticholinergics
Alcohol Metamucil
Etc

PD interactions are
Diarrhea
common and best Laxatives
prevented by Erythromcyin
Antibiotics
understanding the Magnesium
MOA of drugs used in So many more!
practice.
 QTc Prolongation
Recent cases:
Domperidone, Citalopram, Escitalopram
Macrolides
Erythromycin > Clarithromycin > Azithromycin
Fluoroquinolones
Ciprofloxacin, Levofloxacin, Moxifloxacin, Norfloxacin
Miscellaneous
Clindamycin, Trimethoprim/Sulfamethoxazole
Azole Antifungals
Fluconazole, Itraconazole, Ketoconazole
Antipsychotics
SSRIs
TCAs
Etc.
Oral Anti-Thrombotics
 Anticoagulants
Warfarin Apixaban
Vitamin K antagonist
Rivaroxaban
(clotting factors 2,7,9,10,
protein C & S) Edoxaban (new)
For: Afib, VTE prophylaxis & Factor Xa inhibitor
tx, valvular disease
For:
Dabigatran Afib (all)
Direct thrombin inhibitor Recurrent VTE (all)
(factor 2) VTE prophylaxis post-op
TKR/THA
For: Afib, VTE prophylaxis
N.B. Edoxaban not indicated
post-op TKR/THA
(N.B. Ximelagatran withdrawan
due to hepatotoxicity)
Anti-depressants & Anxiolytics
 Anti-depressants & Anxiolytics
Selection of therapy: SSRIs:
Fluoxetine, sertraline, (es)citalopram,
Efficacy: All fluvoxamine, paroxetine
equivalent! SNRIs:
Therefore, tailor (des)venlafaxine, duloxetine
therapy based on Mirtazapine
potential toxicities! Bupropion
TCAs:
Amitriptyline, nortriptyline, despramine,
imipramine, clomipramine, doxepin

MAOis: (+++ types)

Moclobemide (reversible)
Phenelzine (irreversible) etc. etc.
 Toxicities
Anti-cholinergic effects Sedation
Paroxetine TCAs
Mirtazipine Fluvoxamine
(des)Venlafaxine Paroxetine (less extent)
TCAs: Mirtazapine
amitriptyline > nortriptyline > Trazodone
desipramine
N.B. Anti-cholinergic, anti- Activation
histaminergic & weight Fluoxetine
gain effects often go hand-
Bupropion
in-hand.
(des)Venlafaxine
Wt gain is usually minimal
Moclobemide
Some subpopulations gain++
 Toxicities
GI side effects Sexual dysfunction
Nausea - SSRIs SSRIs (>30% !)
Constipation - TCAs TCAs
Diarrhea - sertraline, N.B. More serotonin = less
fluoxetine, paroxetine, libido
duloxetine More dopamine = more libido

Drug/disease interactions
QTc prolongation (TdP)
Least with: (es)citalopram,
TCAs mirtazapine, moclobemide,
Citalopram > 40mg/day sertraline, (des)venlafaxine
Escitalopram > 20mg/day Moclobemide:
no tyramine restrictions
(unlike irrev MAOis!)
Anti-psychotics
 Anti-psychotics
Typical (1st gen / conventional) (Relative terms) Atypical (2nd gen)

Butyrophenones Clozapine
Haloperidol & Droperidol
Olanzapine
Phenothiazines
Chlorpromazine & Fluphenazine Quetiapine
Perphenazine & Prochlorperazine
Thioridazine & Trifluoperazine
Risperidone
Mesoridazine & Periciazine Aripiprazole
Promazine & Triflupromazine
Levomepromazine & Promethazine
Ziprasidone
Pimozide Paliperidone
Thioxanthenes Asenapine
Chlorprothixene & Clopenthixol
Flupenthixol & Thiothixene etc.
Zuclopenthixol
 Anti-psychotics
Toxicities:
Clozapine:
Agranulocytosis (10x higher risk vs other antipsychotics)
Hence, mandatory CBC q2-4weeks
Therefore, last line therapy, despite superior efficacy
 Toxicities
Sedation Tardive Dyskinesia
Quetiapine Typicals
Olanzapine Least: Clozapine (esp), all atypicals
Clozapine
Typicals Anticholinergic effects
Least: haloperidol, risperidone,
aripiprazole?, ziprasidone? Clozapine
Weight gain Typicals
Least: risperidone, quetiapine,
Clozapine haloperidol
Olanzapine
Quetiapine
Least: haloperidol, risperidone,
aripiprazole?, ziprasidone?
 Toxicities
EPS Hypotension
Typicals Clozapine
Least: atypicals Risperidone
QTc prolongation Typicals
Least: olanzapine, haloperidol,
Clozapine ziprasidone, paliperidone
Paliperidone
Ziprasidone
Pimozide
Asenapine
Thioridazine
Least: Risperidone, haloperidol,
aripiprazole, olanzapine, low dose
quetiapine
Gout
 Pathophysiology
Precipitation of monosodium urate crystals in
avascular tissues
(cartilage, epiphyseal bone, periarticular bone)
Hyperuricemia likely asymptomatic for years
The acute attack:
Crystals activate plasma proteases
Can activate factor XII & C5
Can adsorb opsonins in area, attracting phagocytes!
Pathophysiology Acute Attack
Inflammation lowers Phagocytosis fails.
pH in the joint Crystals lyse
Urate precipitates phagocytes.
out of solution = tophi Tophi are released

Enzymes released
MORE PHAGOCYTES
into synovial fluid
ARRIVE - Lactic acid
Damage tissue,
is a byproduct
activate
of phagocytosis
complement etc
 Principles of Management
1. Terminate acute attacks
2. Prevent recurrence
Eliminate urate crystals from joints & tissues
3. Address co-morbidities
Obesity
Hypertriglyceridemia
Hypertension
Diabetes mellitus
Excessive alcohol
 1) Treatment of Acute Attacks
Directed at WBC inflammatory response
Options:
1. NSAIDs
2. Colchicine
3. Corticosteroids
Choice depends on toxicity, cost & convenience since
efficacy is ~ equivalent
More importantly rapidity of treatment selection!
Keep agent close at all times; start PRN A.S.A.P.
 NSAIDs
No difference in Efficacy

Choose based on: Toxicity, Cost, Convenience

Toxicity:
N/V/D, GI bleeding, fluid retention, ARF, etc
So: avoid in PUD/GERD, CHF, peripheral edema, CKD etc
Convenience
Choose NSAID with a shorter half-life (t) (ss = 3 - 5 ts!)
Eg. Ibuprofen (2-4hrs); Diclofenac (2hrs); Indomethacin (4.5hrs);
 Colchicine
Used for centuries
Most specific agent in use
Decreases leukocyte motility
Binds to tubulin and inhibits microtubule
formation, arresting neutrophil motility Colchicum autumnale
Decreases phagocytosis in joints (autumn crocus)
Decreases lactic acid production (meadow saffron)

OVERALL EFFECT:
Interruption of inflammatory process
PO or IV
Avoid IV - Potentially fatal if mis-dosed!
Risk of arrhythmia
 Colchicine
Traditional dosing:
0.6mg q1-2hrs until:
Improved sxs
OR
GI distress
OR
10 doses with no effect

Too rigourous for most patients!

(Esp elderly) - GI distress in 50-80% of patients!
Narrow therapeutic window
 Corticosteroids
Reserved for:
Intolerant of NSAIDs or colchicine
Co-morbidities that prohibit use of other meds

Good alternative for elderly w/ poor renal function

 Summary
Treatment of Acute Attacks

Start treatment A.S.A.P.!

Do not change doses of any med that can alter urate
levels when treating acute attacks (ie. allopurinol)
Consider NSAIDs, colchicine, steroids at low doses and
in combination (different MOAs; additive benefits)
Avoid NSAIDs in CKD, CHF
Avoid / Reduce colchicine dose in CKD, liver dz,
neutropenia, on diuretics, statins, or cyclosporin
 2) Preventing Recurrence
Eliminate excess body urate
Else, tophi may continue to enlarge
Result: chronic arthritis due to chronic inflammatory
response destroying cartilage & bone
 Preventing Recurrence
Recall that: Lowering urate can precipitate a flare!

Start 2-3 weeks after flare resolved

Uricosuric agents increase UA excretion
Probenecid
Sulfinpyrazone
Xanthine Oxidase inhibitors decrease UA production
Allopurinol agent of choice
Febuxostat new agent
May consider prophylaxis before urate lowering
therapy (eg. low dose colchicine or NSAID daily)
Continue 3-6 months and/or [urate] < 360 umol/L
 Preventing Recurrence - Summary
Allopurinol
Most common
Febuxostat
New kid on the block!
Improved efficacy
Lacking sufficient safety data for some populations
Probenecid or Sulfinpyrazone: (unlikely)
only if CrcL > 50mL/min
No hx of kidney stones
No ASA > 2g/day
Interference with uricosuric effects
 3) Address Co-Morbid Conditions

Obesity
Hypertriglyceridemia
Hypertension and Diabetes Mellitus
Excessive Alcohol
 Excessive alcohol
Mechanisms:
1. Purine content of beverage
BEER! (lots of guanosine)
2. Chronic alcohol stimulates de novo purine biosynthesis in
liver
3. Binge drinking results in lactic acidemia, lowering renal
urate excretion
Moderate wine ok, but any alcohol is a risk factor
RR 1.32 (10 - 15 g/day)
RR 1.49 (15 - 30 g/day)
RR 1.96 (30 - 50 g/day)
> 30g/d in females; > 45g/d in males risk of liver disease
RR 2.53 (> 50 g/day)
TB drugs
 Mycobacterium 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

 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
Anti-fungals
 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