lec3 sem5 ifmwk2 20121221(antidiarrheal and antimicrobial drugs)

7/27/2019 Lec3 Sem5 Ifmwk2 20121221(Antidiarrheal and Antimicrobial Drugs)

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SEMESTER 5

INFECTIOUS DISEASES MODULE

PHARMACOLOGY

ANTIDIARRHEAL AND ANTIMICROBIAL DRUGS

Learning Objectives:

At the end of the lecture, students should be able to:

Know the classification of antiamoebics. Know the pharmacokinetics, mechanism of actions, adverse effects, drug interactions)

of these drugs.

Metronidazole. Idoquinol Diloxanide Furoate. Describe the antibiotics. Give different antimicrobial agents. Explain Drug resistance and Complication of antibiotic therapy. Describe the Patient factors.

Classification of Antiamoebics

Luminal amoebicides: act in the bowel lumen Direct amebicides

1. Diloxanide

2. Iodoquinol

3.Paromomycin

Indirect amoebicides1. Erythromycin &tetracyclines

Tissue amoebicides: effective against trophozoites in tissues Emetine &dehydroemetine


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Chloroquine; effective against trophozoites in liver only. Mixed (luminal & tissue amebicides): Metronidazole &tinidazole

Treatment of amebiasis

Aim of treatment: Eradication of tissue invading trophozoites Eradication of the cyst in intestinal lumen

METRONIDAZOLE

Metronidazole Pharmacokinetics (1)

It is rapidly & completely absorbed from intestine.

Low intra-intestinal concentration. Route of administration: oral & parenteral. Widely distributed into tissues.

Metronidazole Actions

Activity against protozoa: Anti-amebic activity: mixed luminal & tissue amebicidal Less effect as lumen amebicidal. Anti-giardiasis. Antitrichomoniasis

Powerful activity against anerobic bacteria: e.g. Bacteroidsfragilis& Clostridium difficileMetronidazole Mechanism of Action

Enters bacteria via cell diffusion Activated via single reduction step by bacteria forms radicals reacts with

nucleic acid cell death.

Metronidazole Adverse effects

GI: Nausea, Vomiting, epigastric distress


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Metallic taste Darkening of urine Peripheral neuropathy Pancreatitis Hepatitis Fever Reversible neutropenia

MetronidazoleContraindications

Neurological diseases,

blood dyscrasias,

First trimester of pregnancy, Chronic alcoholism.MetronidazoleDrug interactions

Antacids CyclosporinA / tacrolimus Lithium Phenytoin Rifampin Warfarin

MetronidazoleResistance

Resistance is Rare.

Mechanism: decreased activation

( redox reaction) of drug.

MetronidazoleAntimicrobial Spectrum

Anaerobic bacteria Microaerophilic bacteria


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ProtozoaMetronidazoleIndications

1. Amebiasis Drug of choice for :EntamoebaHistolytica

i. Intestinalamebiasis

ii. Hepatic amebic abscess

iii. Extra-intestinal amebic disease

2. Trichomoniasis3. Giardiasis4.

H. Pylori

5. Anaerobic infectioni. Pseudomembranous colitis: clostridium difficile

ii. Sepsis caused by anerobic bacteria: e.g. intraabdominal infection caused by bacteroidsfragilis

iii.Bacterialvaginosis

IDOQUINOL

Idoquinol - Properties

Effective against parasites in intestinal lumen. Ineffective against tissue parasites. It is used in asymptomatic and mild to moderate cases of intestinal amoebiasis.Idoquinol Clinical Application

Indication:

Luminal amoebiasis.Contraindications:

Intolerance to drug. Renal and thyroid diseases. Liver disease.


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Infants.

Idoquinol - Adverse Effects

Idoquinol may cause nausea, vomiting, diarrhea abdominal discomfort and enlargementof thyroid.

It may interfere with thyroid function tests. Drug produces severe neurotoxicity when given in large doses for prolonged periods. Optic atrophy, visual loss and peripheral neuropathy are common. When given in standard dosage of 650 mg TDS for 21 days, it does not produce

neurotoxicity.

DILOXANIDE FUROATE

DiloxanideFuroate - Properties

Highly effective luminal amoebicide Drug of Choice for mild intestinal / asymptomatic amoebiasis

Directly kills trophozoites

No systemic antiamoebic activity seen despite absorption No anti bacterial action

DiloxanideFuroate - Clinical Uses

Luminal amoebiasis. Given in combination with metronidazole or tinidazole. Given after tissue amoebicide to eradicate cysts. DiloxanideFuroate - Adverse Effects

Troublesome flatulence Pruritis Urticaria.


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ANTIBIOTICS

These are substances produced by microorganisms,which suppress the growth of or kill other

microorganisms at very low concentrations.

Anti microbial agent (AMA)

Anti microbial agent (AMA) are synthetic as well asnaturally obtained drugs that attenuate microorganisms.

The central concept of antimicrobial action is that of selective toxicitythat is, growthof the infecting organism is inhibited or the organisms is killed without damage to

cells of the host. All antimicrobials are selectively toxic to microorganisms.

Anti microbial agent (AMA)

The antimicrobials agents exert their antibacterialeffects through one of the following mechanisms.

inhibition of cell-wall synthesis

Beta-lactam Antibiotics Vancomycin Cycloserine.

Inhibition Of Protein Synthesis


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o Aminoglycosides,o Erythromycin,o Clindamycin,o Chloramphenicol,o Tetracyclines.

Inhibition of nucleic acid synthesis or function

Sulfonamides Trimethoprim Metronidazole Quinolones Rifampin

Inhibition of outer and/or cytoplasmic membrane function

Polymyxins.

COMBINATIONS OF

ANTI-MICROBIAL DRUGS

It is therapeutically advisable to treat with the single agent that is most specific for theinfecting organisms.

Specific single agent strategy reduces the possibility of super infection, decreases theemergence of resistant organisms and minimizes toxicity.

However, situations in which combinations of drugs are employed do exist. For e.g. the Treatment of tuberculosis benefits from drug combinations.

ADVANTAGE

Certain combinations of ABs, such as B-lactam and amino glycosides, show synergism. Because such synergism among anti-microbial agents is rare they should only be used

in special situation.

DISADVANTAGE

A number of ABs act only when organisms are growing. Thus concomitant administration of a second agent that results in bacteriostatic may

interfere with the action of the first drug that is bactericidal.


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DRUG RESISTANCE

Bacteria are said to be resistant, if their growth is not halted by the maximal level ofan AB, that is tolerated by the host.

Some organisms are inherently resistant, to an AB. For e.g. gram negative organismsare resistant to vancomycin.

However, microbial species normally responsive to a particular drug may developresistant strains.

Many organism have adapted, through spontaneous mutation or acquired resistance. selection and developed more virulent strains many of which resistant to multiple

ABs.

The emergence of these resistant strains has been ascribed to the imprudent andinappropriate use of ABs in condition that might resolve with out Treatment or which

are not amenable to AB therapy for e.g. the common cold.

PROPHYLACTIC ANTI-BIOTICS

Certain clinical situations require the use of ABs for the prevention rather than theTreatment of infections.

Since the indiscriminate use of anti-microbial agents can result in bacterial resistanceand super infection, prophylactic use is restricted to clinical situations in which

benefits outweigh the potential risks.

The duration of prophylaxis is dictated by the duration of the risk of infection.

COMPLICATIONS OF ANTI-BIOTIC THERAPYo Hypersensitivity.o Direct toxicity.o Super infections

EFFECT OF THE SITE OF INFECTION ON THERAPY:

The blood-brain barrier. Lipid solubility of the drug. Molecular weight of the drug. Protein binding of the drug. Patients Factors.

PATIENT FACTORS

In selecting an antibiotics, attention must be paid to the condition of the patient. For example, the status of the patient,s immune systems, kidneys, liver circulation,

and age must be considered.


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In women, pregnancy or beast-feeding an infant also affects selection of theantimicrobial agent.

IMMUNE SYSTEM Elimination of infecting organisms from the body depends on an intact immune

system.

Antibacterial drugs decrease the microbial population (bactericidal) or inhibit furtherbacterial growth (bacteriostatic).

The host defense system must ultimately eliminate the invading organisms. Alcoholism, diabetes, infection with the human immunodeficiency virus, malnutrion,

or advanced age can affect a patient,s immunocompetency, as can therapy with

immunosuppressive drugs.

Higher-than-usual doses of bactericidal agents or longer courses of treatment arerequired to eliminate infective organisms in these individuals.

RENAL DYSFUNCTION

Poor kidney function (ten percent or less of normal) causes accumulation in the bodyof antibiotics that ordinarily are eliminated by this route.

This may lead to serious adverse effects unless drug accumulation is controlled byadjusting the dose or the dosage schedule of the antibiotic.

Serum creatinine levels are frequently used as an index of renal function foradjustment of drug regimens.

However, direct monitoring of serum levels of someantibiotics (for example, aminoglycosides) is a preferred to

identify maximum and minimum values.

Rising minimum values alert the physician to potential. The number of functioning nephrons decreases with age.

Thus, elderly patients are particularly vulnerable to

accumulation of drugs eliminated by the kidneys.

Antibiotics that undergo extensive metabolism or areexcreted via the biliary route may be favored in such patients

HEPATIC DYSFUNCTION

Antibiotics that are concentrated or eliminated by the liver (for example,erythromycin and tetracycline) are contraindicated in treating patients with liver

disease.

POOR PERFUSION

Decreased circulation to an anatomic area, such as the lower limbsof diabetic, reduces the amount of antibiotics that reaches that

area, and makes infections notoriously difficult to treat.


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AGE

Renal or hepatic elimination processes are often poorlydeveloped in newborn, making neonates particularly vulnerable

to the toxic effects of chloramphenicol and sulfonamides.

Young children should not be treated with tetracyclines, whichaffect bone growth.

PREGNANCY

All antibiotics cross the placenta. Adverse effects to the fetus are rare, except fortooth dysplasia and inhibition of bone growth encountered with the tetracyclines.

However, some anthelmintics are embryotoxic and teratogenic. Aminoglycosides should be avoided in pregnancy because of their ototoxic effect on

the fetus.

LACTATION

Drugs administered to a lactating mother may enter the nursing infant via the breastmilk.

Although the concentration of an antibiotic in breast milk is usually low, the total doseto the infant may be enough to cause problems.

SAFETY OF THE AGENT

Many of the antibiotics, such as the penicillins, are among the least toxic of all drugs,because they interfere with a site unique to the growth of microorganisms.

Other antimicrobial agents (for example, chloramphenicol) are less microorganism-specific, and are reserved for life-threating infections because of the drug,s potential

for serious toxicity to the patient, safety is related not only to the inherent nature of

the drug, but also to patient factors that can predispose to toxicity.

ROUTE OF ADMINISTRATION

The route of adminstration is chosen for infection that are mild and can be treated onan outpatient basis.


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In addition, economic pressures have promoted the use of oral antibiotic therapy in allbut the most serious infectious diseases.

In patients requiring a course of intravenous therapy initially, the switch to oralagents occurs as soon as possible.

However, some antibiotics, such as Vancomycin, the aminoglycosides, andamphotericin are so poorly absorbed from the gastrointestinal tract that adequateserum levels cannot be obtained by oral administration.

Parenteral administration is used for drugs that are poorly absorbed from thegastrointestinal tract, and for treatment of patients with serious infections, for whom

it is necessary to maintain higher serum concentrations of antimicrobial agents than

can be reliably obtained by the oral route.

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lec3 sem5 ifmwk2 20121221(antidiarrheal and antimicrobial drugs)

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