Ukrainian Medical Stomatological Academy Department of Experimental and Clinical Pharmacology

Lecture PHARMACOLOGY OF ANTIBIOTICS. ANTIMYCOBACTERIAL DRUGS

Prepared by Ye.Vazhnichaya ANTISPIROCHETAL DRUGS SPIROCHETAL INFECTIONS AND THEIR TREATMENT

Syphilis is one of the most widely spreading spirochetal infections caused by Treponema palidum. It is chronic infection developed in a few stages form the primary tissue affect to the systemic disorders in CNS and other organs. ANTISPIROCHETAL DRUGS: classification A. Antibiotics 1. Basis antibiotics – Benzylpenicillin sodium – Bicillin-1 – Bicillin-5 2. Alternative antibiotics – Cefaloridine – Erythromycin – Chloramphenicol (Laevomicetinum) B. Bismuth preparations – Bijochinolum. ANTISPIROCHETAL ANTIBIOTICS

 Benzyl penicillin sodium is the inhibitor of cell wall synthesis with shot duration of action and narrow spectrum. It is effective against Treponema palidum and used as the basis antibiotic in syphilis.  Bicillins are long acting natural penicillins which have narrow spectrum of action and are administered IM once a week (Bicillin-1) or once a month (Bicillin-5) for treatment of syphilis.  Cefaloridine is the 1st generation cephalosporin. It is the inhibitor of cell wall synthesis with wide spectrum of action. It is an alternative preparation in syphilis.  Erythromycin is macrolide antibiotic. It is protein synthesis inhibitor which spectrum of action is similar to the spectrum of benzylpenicillin. It is used as an alternative antibiotic in patients hypersensitive to basis antibiotics.  Chloramphenicol is wide spectrum antibiotic, protein synthesis inhibitor. It may be used as an alternative antibiotic in syphilis. PENICILLINS: MECHANISM OF ACTION MACROLIDES: MECHANISM OF ACTION CHLORAMPHENICOL: MECHANISM OF ACTION BISMUTH PREPARATIONS. BIJOCHINOL • is a compound between bismuth and quinine suspended in Oleum Persicorum • is administered IM once per 3 days, accumulates in the body; is excreted with urine and saliva • interacts with SH-groups of enzymes and has bacteriostatic action on Treponema palidum • is indicated for all stages of syphilis (together with benzylpenicillin), non-syphilitic encephalitis and myelitis • may cause grey spots on gums, stomatitis, renal disturbances • is contraindicated in patients with renal failure and diseases of oral mucosa. ANTI-TUBERCULAR DRUGS ANTIMYCOBACTERIAL DRUGS = Drugs for the treatment of tuberculosis (TB) TUBERCULOSIS AND ITS THERAPY Tuberculosis is chronic infection caused by Mycobacterium tuberculosis. The treatment of tuberculosis is a serious problem due to some peculiarities of mycobacteria, such as:  slow growth  ability to be dormant and completely resistant to many drugs  impermeability of cell wall to many agents  persistence in macrophages  development of resistance to any single drug. GENERAL PRINCIPLES OF CHEMOTHERAPY OF TUBERCULOSIS

 To begin the therapy with the 1st line drugs  To use the 2nd line preparations after the development of drug resistance in microbes  To apply 2-3 preparations together to delay or prevent the emergence of resistant strains  To carry out long lasting treatment (6-24 months)  To continue the regimen after the disappearance of clinical disease to eradicate any persistant organisms  To carry out laboratory monitoring of the efficacy of treatment. CLINICAL CLASSIFICATION OF ANTIMYCOBACTERIAL DRUGS

Antimycobacterial drugs

The 1st line preparations The 2nd line preparations

Isoniazid Aminosalicylic acid

Rifampin Cycloserine

Ethambutol Ethionamide

Streptomycin Pirazinamide ISONIAZID (INH): chemical structure

Isoniazid is the most potent anti- tubercular agent. It is the hydrazide of isonicotinic acid, a synthetic analog of pyridoxine. ISONIAZID (INH): pharmacokinetics

• is administered orally, IM, IV; absorption after the oral administration is impaired by food and antacids • diffuses into all the body: infected tissues tend to retain the drug longer • penetrates CNS • is metabolized in the liver by acetylation and hydrolysis; acetylation is genetically regulated: the fast acetylator trait is autosomal dominant • is excreted with urine, partly with saliva, sputum, and milk. ISONIAZID (INH): groups of patients on speed of isoniazid’s acetylation

N-acetylation

Rapid acetylators: Slow acetylators: half life of isoniazid is half-life of isoniazid is about 1 hr about 3 hrs ISONIAZID (INH): mechanism of action

• It disturbs the synthesis of mycolic acids which are an important constituent of mycobacterial cell wall. • It competes with vitamins B6, B1, PP. • For bacilli in the stationary phase, isoniazid is bacteriostatic; for dividing bacilli, it is bactericidal. • Isoniazid is effective against extracellular, as well as intracellular bacteria. • When it is used alone, resistant organisms rapidly emerge. ISONIAZID (INH): spectrum of action, indications, side-effects

Spectrum of action Mycobacterium tuberculosis Indications It is used for all forms of diagnosed tuberculosis. Side-effects • Hypersensitivity • Peripheral neuritis (paresthesia) • Mental abnormalities, psychotic episodes, euphoria, convulsions • Optic neuritis • Hepatitis Neurological side-effects are due to competition to B6 and pyridoxine deficiency. RIFAMICIN: chemical structure RIFAMICIN: SPECTRUM, INDICATIONS, SIDE-EFFECTS Spectrum of action Most Gram (+) and many Gram (-) microorganisms, Mycobacterium tuberculosis, Mycobacterium leprae. Indications . Tuberculosis (in combination with other agents) . Atypical mycobacterial infections . Leprosy . Bacterial infections caused by sensitive microbes: pneumonia, cholecystitis, osteomyelitis, etc (as alternative antibiotic). Side-effects  Red discoloration of urine, sweat, tears, and contact lenses  Changes in the half-life of a number of co-administered drugs metabolized by cytochrome P-450 system  Rash  Gastrointestinal disturbances  Renal damage  Jaundice and severe hepatic dysfunction. RIFAMICIN: mechanism of action PECULIARITIES OF OTHER ANTI- TUBERCULAR PREPARATIONS

 Streptomycin is aminoglycoside antibiotic, inhibitor of protein synthesis, is used in drug combination for treatment of life- threatening tuberculosis disease (meningitis, miliary dissemination, severe organ tuberculosis), is the 2nd line preparation  Ethambutol is taken orally and widely disrtributed in the body, penetrates into CNS; blocks nucleic acids synthesis and inhibits arabinozyl transferase involved in the synthesis of arabinogalactan, a component of mycobacterial cell wall; is bacteriostatic anti- tubercular agent; is the 1st line anti-tubercular preparation; may cause optic neuritis, loss of ability to discriminate between red and green.  Aminosalicylic acid is competitive inhibitor of PABA in folate metabolism, is bacteriostatic, is taken in high dose (10-15g per day) and causes many side-effects (dyspepsia, crystalluria, enlargement of thyroid gland), is used rarely as 2nd line preparation.  Ethionamide is structural analog of isoniazid, inhibits acetylation; is used as 2nd line preparation, may cause side-effects, such as hepatotoxicity, gastric irritation, peripheral and optic neuritis.

ANTIVIRAL AGENTS VIRAL INFECTIONS AND THEIR CHEMOTHERAPY

Viruses are obligate intracellular parasites. They are small particles, the main structure elements of which are nucleic acid (DNA or RNA) and protein coat (capsid), require the active participation of cell metabolism to survive. Life cycle of virus consists of adsorption and penetration, uncoating, early protein synthesis, nucleic acid synthesis, assembly and budding (release of virions). Viruses have some specific enzymes which are the targets for antiviral drugs (reverse transcriptase, HIV-specific protease, DNA polymerase). In the body there are natural antiviral substances interferons produced by immune competent cells. ANTIVIRAL AGENTS: classification according to mechanism of action 1. Inhibitors of attachment to or penetration of host cell – Remantadine 2. Inhibitors of DNA polymerase – Acyclovir 3. Reverse transferase inhibitors – Zidovudine (azidothymidine, AZT) 4. HIV protease inhibitors – Saquinavir 5. Neuroaminidase inhibitors – Zanamivir 6. Interferons – Laferonum (IFN-α-2β) ANTIVIRAL AGENTS: classification according to clinical use

1. For influenza and respiratory virus infections – Amantadine, Remantadine – Oxoline – Zanamivir and other neuroaminidase inhibitors 2. For herpes and cytomegalovirus infection – Acyclovir and other inhibitors of DNA polymerase – Oxoline 3. For HIV infection – Zidovudine and other reverse transferase inhibitors – Sanquinavir and other HIV protease inhibitors 4. Preparations with wide antiviral spectrum – Laferonum and other interferons INFLUENZA REPLICATION AND ANTIVIRAL TARGETS REMANTADINE: mechanism of action REMANTADINE: pharmacological properties Pharmacokinetics • is taken orally • does not penetrate into CNS • is excreted by cells of epithelium of upper respiratory pathways • is metabolized in the liver • is excreted with urine as parent drug and metabolites. Spectrum of action Virus of influenza A2, virus of encephalitis. Indications • Treatment of influenza A2 • Prevention of influenza • Prophylaxis of epidemic encephalitis. Side-effects • Headache • Hallucinations • Ataxia • Disturbances of speech • Insomnia • Confusion, seizures. HERPETIC INFECTION ACYCLOVIR: mechanism of action (at the top – synthesis of normal viral DNA guanine nucleotide; at the bottom – synthesis of false viral DNA nucleotide with acyclovir) ACYCLOVIR: pharmacological properties

It is synthetic purine nucleoside analog (acycloguanosine). Pharmacokinetics • is administered orally, IV, or topically • is widely distributed through the body • penetrates into CNS • is partially metabolized and excreted with urine. Spectrum of action Herpes simplex virus types І and ІІ, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus. Indications • Primary mucocutaneous herpes infection • Recurrent mucocutaneous herpes infection • Herpes genitalis • Herpes simplex encephalitis • Prophylaxis of herpes infection before and after tissue transplantation (in seropositive patients). Side-effects • Local discomfort, pruritus (after the topical application) • Nausea, vomiting • Headache, encephalopathy (after IV administration) • Nephrotoxicity. SPREAD OF HIV / AIDS ACUTE HIV INFECTION DRUG THERAPY OF HIV INFECTION TARGETS FOR ANTI-HIV / AIDS PREPARATIONS ZIDOVUDINE (AZT): mechanism of action ZIDOVUDINE (AZT): mechanism of action (scheme) ZIDOVUDINE (AZT): pharmacological properties Pharmacokinetics • is taken orally • has bioavailability of 60% • is widely distributed through the body • penetrates CNS • is metabolized in the liver • is excreted with urine in the form of metabolites • has a half-life of 1-3 hrs. Indications • AIDS • Prophylaxis of HIV infection through accidental needle sticks • Prevention of vertical HIV transmission from mother to neonate. Side-effects • Anemia, neutropenia • GI distress • Headache, agitation, insomnia, myalgia • Hepatitis and cholestasis. INTERFERONS They are glycoproteins produced by leukocytes (INF-α), fibroblasts (INF- β) and immune cells (INF-γ), nowdays are synthesized by recombinant DNA technology. Mechanism of action Interferons interact with receptors on host cell membrane and induce the formation of protein kinase that leads to phosphorilation and blockage of peptide chain initiation They also induce phosphodiesterase activation that leads to degradation of terminal nucleotides of tRNA. Spectrum of action Interferons have wide antiviral spectrum of action. They also have anti-cancer, anti-toxic, and immune stimulating properties. Indications • INF-α is used to treat viral hepatitis A and B, Kaposi’s sarcoma, papillomatosis, hairy cell leukemia. • INF- β is applied for treatment of multiple sclerosis. • INF-γ is used for chronic granulomatous disease. Side-effects • Fever • Lethargy • Bone marrow suppression • Heart failure, hypersensitivity. THE END

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