Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009

DRUGS AFFECTING INTERMEDIARY MECHANISM

Examples, Sulfonamides, Pyrimethamine, Trimethoprim. These drugs are only bacteriostatic. They inhibit synthesis of folic acid by the bacteria, which in turn will affect synthesis of nucleic acid and protein. As human cells get folic acid from the diet these are not affected. This action will be inhibited by drugs containing PABA. The sulfonamides will not act in the presence of pus and necrotic tissue.

Sulfonamides: Are active against gram positive, gram negative organisms, actinomyces, chlamydia, plasmodia, pneumocystis and toxoplasma. But many organisms are resistant now.

Topically sulfonamides are applied as eye drops. In toxoplasmosis, sulphadiazine with pyrimethamine or sulfamethoxazole and trimethoprim combination is used.

Side effects: Anorexia, nausea, vomiting, diarrhoea, urticaria, rash and the dreaded Steven Johnson's syndrome. Blood dyscrasias like haemolytic anemia, aplastic anemia and agranulocytosis also are seen. Transient myopia can occur during treatment.

Locally it can cause irritation, burning and photosensitisation leading on to sunburn of lid margins and eye lid skin. As sulfonamides will increase the hypoglycaemic effect of tolbutamide and chlorpropamide, and anticoagulant effect of coumarin, it should be used with caution in, patients taking these drugs.

Pyrimethamine and trimethoprim: Act by inhibiting folic acid synthesis at a different level. Hence, they have an additive effect when given along with sulfa. They are used in the treatment of Pneumocystis carini infection in AIDS patients. A combination of trimethoprim and polymyxin B is used topically for Pneumococcal and H. influenza conjunctivitis.

Side effects: Depression of white blood cells, red blood cells and platelets causing megaloblastic anemia due to folic acid deficiency. To counteract this folic acid must be added during treatment with these drugs.

DRUGS ACTING ON BACTERIAL DNA SYNTHESIS

Examples, Fluroquinolones like ciprofloxacin, ofloxacin, levofloxacin, norfloxacin, sparfloxacin.

They prevent replication of the bacteria by inhibiting bacterial DNA gyrase. They have a broad spectrum of action against gram positive and negative organisms including pseudomonas and H. influenza. They are active to some extent on M. Chelonae and M. fortuitum. But many organisms have become resistant to these drugs.

Ciprofloxacin and ofloxacin are effective against gonococci. Cipro flox and Norflox are effective against E.coli, Salmonella, Shigella and Campylobacter.

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Antivirals

ANTIVIRALS

Viruses contain either RNA or DNA with a capsid a protein coat. They are intracellular which makes it difficult for the drugs to kill the organisms as that will affect the human cells also. The antivirals now available affect the viral nucleic acid synthesis thereby preventing their replication. The commercially available drugs are useful against Herpes group of viruses like Herpes zoster, Herpes simplex, Epstein Barr virus and Cytomegalovirus and the human immunodeficiency virus.

Drugs active against herpetic infections:

Pyrimidine analogs: Iodoxuridine, vidarabine and trifluridine. Idoxuridine: Is a nucleoside analog of thymidine. It inhibits thymidine kinase, thymidilate kinase and DNA polymerase. It is incorporated into the viral DNA, which alters the character of the DNA. This in turn will prevent further replication of the viruses. Human epithelial cells also can take up iodoxuridine, which is the reason for its toxicity. It is effective only for epithelial involvement and not for uveitis.

Dose: 0.1% drops every hour and 0.5% ointment at night for 2 weeks by which time improvement will be noticed. Then the drug is tapered off.

Side effects are burning, diffuse punctate keratitis, subepithelial infiltrates, stromal ulceration and obliteration of the canaliculus. All these complications will mimic worsening of the disease inducing the treating surgeon to increase the dosage and prolong the treatment, which is detrimental to the corneal epithelium. This must be avoided.

Vidarabine: An adenosine arabinoside also inhibits viral DNA. As it is not soluble in water it is available only as an ointment. It is metabolized to arabinoside hypoxanthine, which is more soluble in water but less effective.

Dose: 3% ointment five times daily for 2 to 3 weeks. The side effects are similar to IDU.

Trifluridine: Triflurothymidine inhibits thymidylate synthetase and gets incorporated into viral DNA. This affects the transcription and translation of viral genome. It is more effective than IDU and can act against resistant strains. As it penetrates the epithelium it can be used in uveitis cases also.

Dose: 1% drops 9 times daily.

Drugs like (S)-1-(3 hydroxy-2 phosphonyl methoxy propyl) cytosine (HPMPC, cidofovir is a DNA polymerase inhibitor and active against adenovirus and ribavirin and fluoro-deoxy-arabino furanosyl-isocytosine (FIAC) are being investigated for use against viral infections in human beings.

Dihydroxy propoxy methyl guanine (DHPG) is used for CMV retinitis and HSV keratitis.

Fomivirsen: Is an antisense oligonucleotide that blocks viral proteins necessary for replication. It can be given intravitreally for CMV retinitis along with foscarnet and gancyclovir. One injection is given on the first day followed by the second on the fifteenth day and then once every month.

Antiviral drugs for HIV infections

Zidovudine is a thymidine analog. It has to be phosphorylated by the cellular enzymes to active triphosphate form. This will inhibit reverse transcriptase and terminate viral DNA elongation. It is used in iridocyclitis due to HIV infection. Side effects: Bone marrow depression, nausea, vomiting, hepatitis, malaise and myositis.

Didanosine, Zalcitabine, Stavudine and Lamivudine are nucleoside reverse transcriptase inhibitors. These drugs can cause pancreatitis and peripheral neuropathy.

Nevirapine and delaviridine are nonnucleoside inhibitors, which act by disrupting reverse transcriptase by binding to it.

Side effects: Nausea, vomiting, fever, headache and rashes.

Protease inhibitors: E.g. Saquinavir, Indinavir, Ritonavir, Relfinavir inhibit HIV specific protease. This will result in immature HIV particles, which are non-infectious.

Side effects: Nausea, vomiting, diarrhea, anemia, hepatitis, renal stones and renal failure.

Combination of reverse transcriptase inhibitors and protease inhibitors (HAART therapy) can reduce HIV levels in the blood.

INTERFERONS

Are substances produced by cells infected with virus to protect other cells. This can be used along with other drugs for better healing as it has an additive effect.

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Antifungal Agents

ANTIFUNGAL AGENTS

There are three groups of antifungal drugs. They are polyenes (amphotericin, natamycin and nystatin), imidazoles (miconazole, ketaconazole, etc.) and flucytosine.

Polyenes act by binding to the sterols in the cell membrane of the fungi but not the human cells. This will damage the cell wall and cause leakage of the cellular contents and electrolyte imbalance. As cell wall is damaged other antifungal agents also enter the cell causing further damage. Thus, they will have an additive effect.

Amphotericin B binds to ergosterols of the fungal cell membrane. It is effective against candida, cryptococcus, aspergillus and to some extent against fusarium. It is an unstable compound and is affected by water and light. So, it can be stored only for a short time and that too only in a dark container away from light and heat. It is available as a powder, which should be dissolved in distilled water and diluted with glucose solution. Sodium chloride will cause precipitation.

0.1-0.2% i.e. 1 to 2 mg per ml is used as drops. The drug can bind with cholestrol in the human cell. This makes it very toxic. Drops will cause irritation, chemosis and corneal erosion. It is used systemically for involvement of other organs with fungal infections.

Natamycin: Is less toxic compared to amphotericin and more effective as it can penetrate intact epithelium to some extent. It is active against both candida and filamentous fungi. It is also more effective against fusarium compared to amphotericin.

It is available as 5% suspension to be applied every hour. White deposits form after a few applications, which causes irritation. But these deposits mixed with the mucus secretion form a depot, which acts for a longer time.

Nystatin is available for dermatologic candida infections. It can be used for candida infection of the cornea.

Imidazoles: Inhibit synthesis of ergosterol and are fungistatic. Ketaconazole is water-soluble and is absorbed well when taken orally. It can be given topically as 1-2% drops. Ketaconazole tablet is mixed with artificial tears to get these drops.

Micanazole is also active against yeasts and some filamentous fungi. It is effective to a limited extent against fusarium and aspergillus. It can be used topically, sub conjunctivally and systemically.

Clotrimazole is active against Aspergillus and is given as 1-% suspension. Flucytosine is a fluorinated pyrimidine. When absorbed by fungi it is converted to flurouracil which will prevent thymidine synthesis. It is effective against Candida, Cryptococcus, Aspergillus, Penicillium and Cladosporium. It is not effective against fusarium. It is better to use it along with amphotericin as the fungi develop resistance to the drug and is not useful when used alone. Available as 1% solution (10 mg/ml). Orally 50-150 mg/kg/day is given in

divided doses. It is toxic to bone marrow and liver.

Antiamebic Drugs

Diamidines like propamidine is used along with polymyxin B, neomycin and gramicidin. It has antifungal and antibiotic activity. Treatment should be continued for a long time. It should be applied every hour and tapered off to four times daily which should be continued for 1 year.

Polymeric biguanides: Polyhexamethylene biguanide (PHMB) is used to disinfect swimming pools. It is effective against both cysts and trophozoites when used as 0.02% solution. It should be combined with propamidine and neomycin for better effect.

Chlorhexidine solution also is effective against acanthamoeba when given as drops. 2.5 micrograms in one ml is used every hour.

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Antihypertensives

ANTIHYPERTENSIVES

Hypertension (HT) is defined as the presence of a blood pressure elevation to a level that places patients at increased risk for target organ damage in several vascular beds including the retina, brain, heart, kidneys, and large arteries. Of all hypertensive patients 90 % have essential HT, the remaining have HT secondary to causes such as renal parenchymal disease, renovascular, pheochromocytoma and Cushing syndrome, etc.

Classification of B.P for adults

Measurement of BP should be done on multiple occasions. This or more abnormal readings are required to start treatment. Hypertension is diagnosed if patient’s systolic BP is greater than 140 and diastolic BP is greater than 90 mm Hg. The main aim of treatment is to prevent long term target organ damage. Another entity called as malignant hypertension occurs when systolic BP exceeds 210 and diastolic BP exceeds 130 mm Hg, and presents as papilledema.

Nonpharmacological therapy should be practiced initially. It includes lifestyle modification including reduction in body weight, cessation of smoking and adequate mineral and vitamins.

Antihypertensive agents commonly used

I Diuretics:-

Diuretics are effective by causing natriuresis and reduce intravascular volume. They produce vasodilatation by inhibiting sodium entry into smooth muscles. They are subclassified depending on the site of action.

a)Thiazides block Na+ reabsorption in distal convoluted tubule by inhibiting Na/K+ cotransporter. e.g. Hydrochlorthiazide and chlorthalidone.

b)Loop diuretics - block Na reabsorption in thick ascending loop of Henle. e.g., Frusemide, ethacrynic acid.

c)Potassium sparing agents–act competitively by inhibiting actions of aldosterone. E.g. spironolactone, triamterene.

Side effects of diuretics include weakness, cramps and impotence. They cause hypokalemia, hypomagnesemia, hyperlipidemia and some cause ototoxicity ( loop diuretics).

IISympatholytic agents:-

a)β antagonist:

They act by competitive inhibition of catecholamines at beta receptors and thereby decrease heart rate and cardiac output. They also have CNS mediated antihypertensive effect.

They can be classified as cardioselective( affects ß1) and non-selective (β1and β2 blocker). Some agents have intrinsic sympathomimetic

effects—cause less bradycardia.

1)Cardio selective - Atenolol, Betaxolol, Metoprolol.

2)Non-selective - Propranolol, Timolol.

3)ISA - Carteolol, Pinodolol.

Side effects include AV block, heart failure, Raynaud's and impotence. Those drugs which cross CNS cause insomnia and depression. They also increase triglyceride level.

b)Selective α antagonist:

They block post synaptic α receptors producing arterial and venous vasodilatation. e.g., Prazosin, terazosin.

They cause postural hypotension, dizziness, headache and drowsiness. They decrease triglyceride level.

c)Both α and β blockers:

They block the effects of catecholamines at beta receptors and alpha1 receptors. e.g., Labetolol, carvedilol.

Side effects include liver damage, postural hypotension and tremors.

d)Centrally acting:

They stimulate pre synaptic α2 receptors in CNS and decrease the sympathetic tone and reduce vascular resistance. E.g. Clonidine, Methyl

Dopa.

Side effects include bradycardia, dry mouth, postural hypotension, and galactorrhea. Acute withdrawal (rebound hypertension) may occur on abrupt cessation of drug.

IIICalcium channel antagonist:-

Calcium channel antagonists cause arteriolar vasodilatation by blockade of calcium channels in vascular smooth muscle. E.g. Verapaamil, Diltiazem. Nifedipine. Verapmil and Diltiazem should be used cautiously in cardiac conduction abnormalities and this can worsen cardiac failure.

Side effects include nausea, head ache, postural hypotension, constipation. Sublingual Nifedipine produces wide fluctuation and excessive reduction in BP and should be avoided in acute management of hypertension.