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 anti- amoebics. 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 amoebicides 1. Erythromycin &tetracyclines Tissue amoebicides: effective against trophozoites in tissues Emetine &dehydroemetine

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 difficile

Metronidazole 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

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

Metronidazole Contraindications Neurological diseases, blood dyscrasias, First trimester of pregnancy, Chronic alcoholism.

Metronidazole Drug interactions Antacids CyclosporinA / tacrolimus Lithium Phenytoin Rifampin Warfarin

Metronidazole Resistance Resistance is Rare. Mechanism: decreased activation ( redox reaction) of drug. Metronidazole Antimicrobial Spectrum Anaerobic bacteria Microaerophilic bacteria

Protozoa

Metronidazole Indications 1. Amebiasis Drug of choice for :EntamoebaHistolytica

i. Intestinalamebiasis ii. Hepatic amebic abscess iii. Extra-intestinal amebic disease 2. Trichomoniasis 3. Giardiasis 4. H. Pylori 5. Anaerobic infection i. 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.

Infants.

Idoquinol - Adverse Effects Idoquinol may cause nausea, vomiting, diarrhea abdominal discomfort and enlargement of 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.

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 as naturally obtained drugs that attenuate microorganisms. The central concept of antimicrobial action is that of selective toxicitythat is, growth of 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 antibacterial effects through one of the following mechanisms.

inhibition of cell-wall synthesis Beta-lactam Antibiotics Vancomycin Cycloserine.

Inhibition Of Protein Synthesis

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 the infecting organisms. Specific single agent strategy reduces the possibility of super infection, decreases the emergence 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.

DRUG RESISTANCE Bacteria are said to be resistant, if their growth is not halted by the maximal level of an AB, that is tolerated by the host. Some organisms are inherently resistant, to an AB. For e.g. gram negative organisms are resistant to vancomycin. However, microbial species normally responsive to a particular drug may develop resistant 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 and inappropriate 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 the Treatment of infections. Since the indiscriminate use of anti-microbial agents can result in bacterial resistance and 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 THERAPY o 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.

In women, pregnancy or beast-feeding an infant also affects selection of the antimicrobial 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 further bacterial 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 are required to eliminate infective organisms in these individuals. RENAL DYSFUNCTION Poor kidney function (ten percent or less of normal) causes accumulation in the body of antibiotics that ordinarily are eliminated by this route. This may lead to serious adverse effects unless drug accumulation is controlled by adjusting the dose or the dosage schedule of the antibiotic. Serum creatinine levels are frequently used as an index of renal function for adjustment of drug regimens. However, direct monitoring of serum levels of some antibiotics (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 are excreted 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 limbs of diabetic, reduces the amount of antibiotics that reaches that area, and makes infections notoriously difficult to treat.

AGE Renal or hepatic elimination processes are often poorly developed in newborn, making neonates particularly vulnerable to the toxic effects of chloramphenicol and sulfonamides. Young children should not be treated with tetracyclines, which affect bone growth. PREGNANCY

All antibiotics cross the placenta. Adverse effects to the fetus are rare, except for tooth 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 breast milk. Although the concentration of an antibiotic in breast milk is usually low, the total dose to 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 microorganismspecific, 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 on an outpatient basis.

In addition, economic pressures have promoted the use of oral antibiotic therapy in all but the most serious infectious diseases. In patients requiring a course of intravenous therapy initially, the switch to oral agents occurs as soon as possible. However, some antibiotics, such as Vancomycin, the aminoglycosides, and amphotericin are so poorly absorbed from the gastrointestinal tract that adequate serum levels cannot be obtained by oral administration. Parenteral administration is used for drugs that are poorly absorbed from the gastrointestinal 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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