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Pharmacology Therapeutics
= =
Mechanism of Action Pharmacology
+ +
Pharmacokinetics Pathophysiology
+
Pharmacodynamics
Antibiotic Review
Process
1. Map the Bugs
Know your enemy
Gram Negative
Aerobic
-Lactamase Negative
Cocci (spheres)
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)
give Penicillin
1 - Gram [+] Cocci
Staphylococcus Streptococcus
Group A (pyogenes) (-Lact[-])
S. aureus Group B (agalactiae) (-Lact[-])
Methicillin resistant (MRSA) Neonates, v. elderly, obstetrics
Sinusitis: viral
AECOPD: S.pneumo, Hi,M Oral abscess: oral anaerobes
Bronchitis: viral
Skin abscess:
anaerobes, staph,
Cellulitis: MSSA, GAS, GBS strep
N.B. Boils = Staph
Anti-Strep Anti-Staph
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)
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
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
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
For: skin,
dental
infx
(staph,
strep, &
anaerobes)
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!
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)
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*
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!
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
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
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
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
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
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