PHARMACOLGICAL TERMSAND

ANTIBIOTICSBY

IBRAHIM AL SHARABI

• Pharmacology is the study of the manner in which the function of living system is affected by chemical agents.

• Pharmacokinetics is the study of the kinetics of drug absorption, biotransformation, and excretion or the processes to which the drug is subjected in the body.

• Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their mechanism of action.

PHARMACOLOGY OF ANTIMICROBIAL THERAPY

Concentrations Pharmacologic

in tissues and and toxicologic

body fluids effect

Dosing Concentrations

Regimen in Serum

Concentrations Antimicrobial

Absorption at site of infection effect Distribution

Elimination

Pharmacokinetics Pharmacodynamics

Passage of a drug from the site of administration into the blood.Absorption is affected by : 1-Physicochemicalproperties of the drug solubility ionization valency 2-Dosage form 3-Route of administration skin mucous membrane parental site 4-Area and vascularity of the absorption surface 5- Specific factors

ABSORPTION

There are four patterns for drug distribution

1-Drugs with high m. wt that present only in plasma e.g. heparin.

2-Drugs that can pass capillary wall but can not pass the cell membrane ( extracellularlly only) e.g. Na, Cl.

3-Drugs that pass freely across cell membrane with no affinity for special tissues e.g. alcohol.

4-Drugs with affinity for special tissues e.g. Iodide in the thyroid gland.

N.B. PLASMA PROTEIN BINDING

DISTRIBUTION

Chemical alteration to which a drug is undergoes within a living organism.

Hepatic enzyme activators e.g. phenobarbiton.

Hepatic enzyme inhibitors e.g. erythromycin.

BIOTRANFORMATION

Through kidneys, lungs, skin and the gut.

EXCRETION

Time (hours)

Con

cent

ratio

n

AUCAUC

MIC

PHARMACOKINETIC/PHARMACODYNAMIC PREDICTORS OF EFFICACY

Craig W. Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men. Clin Infect Dis. 1998; 26:1-12.

Cmax (Peak)

Time > MIC

Area under the curve:

Parameters of Interest:

• Time > MIC

• Cmax/MIC ratio

• AUC/MIC ratio

ANTIBIOTIC

• Chemical substance produced by a microorganism which

has capacity to

inhibit growth

Kill other microorganisms.

IDEAL ANTIBIOTIC

Inhibit growth of bacteria without harming the host.

Penetrate body tissues to reach the site of infections with sufficient concentration to inhibit or kill pathogen

BACTERIOSTATIC VS. BACTERICIDAL

BACTERIOSTATIC

Arrests the growth and replication of bacteria

BACTERICIDAL

Actually kills the bacteria

HOWEVER THESE TERMS ARE NOT THE CONCERN THE FAST ELIMINATION AND CLINICAL OUTCMES ARE MOST IMPORTANT.

MIC

Seen with all beta-lactams, clindamycin, macrolides.

GOAL: optimize duration of exposure

Seen with aminoglycosides, quinolones, ketolides and amphotericin B.

GOAL: maximize concentrations

Time >MIC(time-dependent killing)

MIC

CONC. >MIC(concentration-dependent killing)

PHARMACOKINETIC/PHARMACODYNAMIC PROFILES

MIC

AUC24 /MIC(time-dependent killing)

PHARMACOKINETIC/PHARMACODYNAMIC PROFILES

tetracyclines, azithromycin.GOAL: optimize amount of drug

SPECTRUM

range of bacteria a specific drug will treat

-Narrow spectrum

Effective against a limited type/number of bacteria

Mostly gram-positive organisms

-Moderate spectrum

Generally effective against the gram-positives

Most systemic, enteric and urinary tract gram-negative pathogens

-Broad spectrum:

Effective against all prokaryotic cells except mycobacteria and pseudomonas

RESISTANCE

ABILITY OF BACTERIA TO RESIST THE EFFECTS OF THE ANTIBIOTIC

ATTRIBUTED TO– PROPERTIES OF THE DRUG– MISUSE OF ANITBIOTICS BY CONSUMERS

ANTIBIOTIC RESISTANCE RELATED TO THE SITES OF ANTIMICROBIAL ACTIVITY– ALTERED RECEPTORS FOR THE DRUG– DECREASED CONC. IN THE CELL– DESTRUCTION OR INACTIVATION OF THE DRUG

Antibiotic-resistant BacteriaAntibiotic-resistant Bacteria

INFLUX PUMP

ALTERATION OF THE TARGETS ORGANS

CLASSES OF ANTIBIOTICS

SULFONAMIDES

PENICILLINS

CEPHALSPORINS

MACROGLIDES

AMINOGLYCOSIDES

FLOUROQUINILONES

TETRACYCLINES

MISCELLANEOUS

DRAWBACKS OF THE MAIN COMPETITORS

USUAL PENICILLINSNarrow spectrum.

Low penetration (low intracellular conc.).

Common resistance.

Allergic reactions.

Low patient compliance.

Most are parentral

Frequent dosing regimen

AMOXICILLIN / CLAVULANATE ( AUGMENTIN )Cost

Lack of atypical pathogens coverage .

Low intracellular concentration.

Low success rate .

Sever liver toxicity.

GI upsets.

Dosage regimen.

New resistance pattern

Affected by heat, light and humidity.

CEFUROXIME ( ZINNAT ) Cost

Lack of atypical pathogens coverage .

Low intracellular concentration.

Low success rate .

Cross allergy and cross resistance with penicillins.

AZITHROMYCIN ( ZOCIN )BACTERIOSTATIC ACTIVITY

LOWER ANTI-G +ve ACTIVITY

LOW PATIENT COMPLIANCE

FOOD INTERACTION

GI UPSETS

DELAYED ACION

LOW CLINICAL SUCCESS

VERY HIGH INTRACELLULAR LEVEL

LOW SERUM LEVEL

DIFFICULT CONTROL

FLOUROQUINOLONES

spectrum: broad coverage. effective vs. G +, G -, atypicals, and pseudomonas.

RESPIRATORY QUINOLONES (Levofloxacin): ACTIVE vs. S. Pneumo (Including penicillin-resistant forms), S. aureus (Including MRSA), H. Influ., And M. Catarrhalis (including penicillin-resistant strains).

ANTIPSEUDOMONAS QUINOLONES (Ciprofloxacin): effective vs. pseudomonas and G-ve bacteria.

NEW FLOXINS (Gati, Moxi, Gemi): Similar to respiratory quinolones but less activity vs. Pseudomonas and addition of anerobic activity

HISTORY• Erythromycin was introduced in 1952 and has remained

the prototype of the macrolides. • The limitations of erythromycin include variable

absorption, instability in gastric acid, poor tissues penetration, short elimination half life, GI irritation, and a narrow spectrum of activity.

• Modifications of the macrolide structure are designed to improve the chemical, biological and pharmacokinetic properties of erythromycin.

• Clarithromycin (KLACID) is a14-membered macrolide known as 6-O-methyl-erythromycin which overcomes all of the above limitations and introduced in 1991.

PERFECT SPECTRUM

KLACID covers almost the whole spectrum of important pathogens in RTIs (Typical as S.pneumoniae ,H.influenzae, moraxella catarrhalis, S.aureus and atypical as C.pneumoniae, M.pneumoniae, L.pneumophila) with bactericidal activities. Therefore KLACID is the ideal antibiotic to be used empirically in the treatment of CAP.

BALANCED DISTRIBUTION

• Pneumonia caused by pneumococci leads to bacteremia in about 30% of the patients. Only with sufficient serum antibiotic levels the circulating micro-organisms can be eliminated

Concentration of different antibiotics in

serum ,soft tissues and macrophagesAntibiotic Serum level Extracellular levels

Conc. in macrophages

clarithromycin + + + + + +

Roxithromycin

+ + + +

Azithromycin + + + + + +

Β-lactams + + + + ▬

EXCELLENT SAFETY PROFILE

0

2

4

6

8

10

12

14

16

6% 15%

KLACID

Amoxicillin/clavulanate

• Significantly less GI upset than amoxicillin/clavulanate

EXCELLENT PATIENT COMPLIANCE

• KLACID XL improves patients compliance so reducing the risk of resistance

010203040506070

8090

100

OD TID

NO FOOD INTERACTION

Misadministration rate

01020304050607080

90100

0% 89% 94%

KLACID

Azithromycin

Roxythromycin

HIGH CLINICAL SUCCESS RATEPharyngitis

Sinusitis

AECB

CAP

Peptic ulcer

100%

97%

99%

97%

94%

ADDITIONAL ANTI-INFLAMMATORY

AND MUCOLYTIC ACTIVITY