Pharm 100 - Lesson D.1 part 2
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The incidence of serious fungal infections continues to increase, particularly in patients who have AIDS or who are required to take immunosuppressive drugs. Unfortunately, only a few highlyeffective antifungal drugs are available.
This is the drug of choice for therapy of severe fungal infections. It binds to a steroid in the outer membrane of susceptible fungi. The combination of amphotericin B with the membrane steroid, ergosterol, results in pore formation in the fungal membrane and leakage across the membrane. Amphotericin B is poorly absorbed from the gastrointestinal tract and must therefore be administered intravenously for systemic fungal disease. The drug causes a variety of adverse effects and kidney toxicity is the major dose-limiting toxicity.
Imidazoles (or Azoles)
In contrast to amphotericin B, ketoconazole, fluconazole and itraconazole are effective whentaken orally for systemic fungal infections. The imidazole class of antifungal agents is leading to improvement in the therapy of fungal infections. The azole antifungals all act to inhibit ergosterol synthesis, which is required for proper formation of the fungal cell membrane. The enzyme that isinhibited is a fungal cytochrome P450, the selective toxicity of the azoles lies in their higher affinity for the fungal P450 than human P450s that are involved in drug metabolism. A number of these agents (miconazole) are available as over the counter drugs for the treatment of yeast infections.
There is a great need for additional and more effective antiviral drugs. For this reason, a greatdeal of effort is being directed to synthesizing and testing new antiviral agents. A particularly strongeffort is in progress to combat the virus responsible for HIV infection and AIDS. Some antiviralagents that are effective are the following
Amantidine is used for prevention of influenza due to the influenza A virus. It is 70 to 90% effective in achieving prevention.
Is a neurominidase inhibitor, an enzyme that allows the spread of the virus from cell to cell. Drugs of this class prevent neighbouring cells from being infected with the virus. Unfortunately resistance is a problem.
Acyclovir is the drug of choice for treatment of serious infections caused by herpes simplex virus(HSV). Long-term use of acyclovir by the oral route for prophylaxis (prevention) will markedly decrease the frequency of recurrence of genital herpes. Acyclovir is also useful in combatting infections due to varicella-zoster virus (VSV), a virus which causes chicken pox and shingles.
Antiviral Agents for Treatment of HIV Infection
- Students should read the SCIENTIFIC AMERICAN article, July 1998, entitled “Improving HIVTherapy” by Bartlett and Moore (pages 84-87), paying particular attention to the HIV life cycle and the role of reverse transcriptase and protease enzymes in this cycle. For a more detailed description see Katzung; Basic and Clinical Pharmacology. (Available on line at Queen’s library).
- Zidovudine (AZT), a nucleoside analogue which is a reverse transcriptase inhibitor, was introduced in 1987 for the treatment of symptomatic HIV-infected patients. It was shown to slowprogression to AIDS and to prolong survival. In 1996, the Food and Drug Administration approved five new drugs for individuals with HIV infection. There were two nucleoside analogues – lamivudine(3TC) and stavudine (d4T), and three protease inhibitors – saquinavir, ritonavir and indinavir.
- Optimal therapy for HIV infection is triple therapy with two nucleoside analogues and a proteaseinhibitor.
- The last decade has seen multiple drugs for HIV infections. Newer agents include entry inhibitors, which block the entry of the virus into cells, and integrase inhibitors that block thereplication of the virus. An example of such a drug is raltegravir.
Disadvantages of Using Antibiotics in Combination
- (a) Unnecessary additional cost if a single antibiotic is effective.
- (b) Increased chance of encountering toxicity. Moreover, when toxicity is encountered, the physician does not know which antibiotic is responsible and has to cease therapy with thecombination. This could lead to the patient being deprived of therapy.
- (c) Using a combination of antibiotics enhances the opportunity for resistant bacteria to arise and take over from susceptible bacteria.
- (d) A combination of antibiotics will decrease the number of normal populations of different bacteria and remove their inhibitory influence on potentially dangerous bacteria. Thus, a new dangerous infection, referred to as a superinfection, could arise.
Indications for Clinical Use of Antibiotic Combinations
- (a) Therapy of a severe infection where it is not known what microorganism is responsible. The infection is so dangerous that one cannot wait to determine by laboratory tests which microorganism is responsible.
- (b) Treatment of a mixed bacterial infection where no single antibiotic could eliminate all the different bacteria responsible for the infection.
- (c) When treating tuberculosis, emergence of resistant tubercle bacilli is an important hazard. Treatment, therefore, is always carried out with a combination of antitubercular drugs to decrease the change of emergence of resistant tubercle bacilli.
- (d) Two drugs may in some infections be effective where a single antibiotic may not. For example, acombination of a penicillin and an aminoglycoside is required to treat inflammation of the endocardium (inner lining of the heart) caused by bacteria known as entero cocci. The penicillin damages the cell wall of the enterococci, allowing the aminoglycoside to penetrate and inhibitbacterial protein synthesis.
General Principles in the Use of Antimicrobial Agents
Approximately one in five prescriptions are written for antibiotics and there is evidence thatconsiderable physician over-prescribing occurs. As a result of over-prescribing, resistantmicroorganisms arise, unnecessary adverse effects are induced, and unnecessary costs are incurred.
1. What are the reasons for over-prescribing by physicians?
- (a) A great deal of pressure is exerted on physicians by their patients to prescribe antibiotics when the physician does not believe that it is in the best interest of their patient. For example, parents will sometimes demand by telephone that a physician prescribe for a child without evenexamining the child.
- (b) A physician may be tempted to prescribe a broad spectrum antibiotic as a substitute for diagnostic judgement. This type of prescribing was often done with the tetracyclines so that this group of antibiotics is considerably less effective than when first introduced. Moreover, many infections are caused by viruses and not bacteria. It needs to be stressed that viruses are not susceptible to antibiotic
- (c) Physicians are visited on a regular basis by representatives of the pharmaceutical industry who market the new antibiotics introduced by their companies. Moreover, physicians will receive “educational” material on the drugs from these representatives. This type of promotion of antibiotics undoubtedly influences physician prescribing.
- (d) It is important for a physician to have laboratory assistance to assist in diagnosing bacterial infection and identifying the particular bacterium responsible. This may be difficult for the physician working in remote areas and who does not have any diagnostic laboratory facilities readily at hand.
2. Formulation of a specific diagnosis:
The physician makes the most intelligent guess on clinical grounds as to which microorganism is responsible for the infection.
3. Specimens taken and sent for laboratory examination:
Prior to administering an antibiotic, the physician will take a blood, urine or saliva specimen, a throat swab, or several of these, to send to a diagnostic laboratory. It is important to take these specimens prior to administering the antibiotic because the presence of the antibiotic in the specimen will increase the difficulty experienced by laboratory personnel in growing and identifying bacteria.
4. Selection of antibiotic most likely to be effective:
This places a heavy onus on the physician. She/he will require to keep up to date with the latest information on newer antibiotics and the changing susceptibility of bacteria to older and new antibiotics.
5. Antimicrobial susceptibility tests:
These tests enable laboratory workers to help the physician select the most effective antibiotic once the microorganism has been isolated and identified.
6. Prophylaxis (prevention) of infection with antibiotics:
Approximately 30-50% of antibiotics are administered to prevent infection. Clinical studies haveshown that, in some situations, prophylaxis with antibiotics is highly effective. On the otherhand, prophylaxis has been shown to be valueless in some situations and may be harmful. In certain situations, the use of antibiotics for prophylaxis is controversial and further clinical studies are required to resolve the controversies.
examples of successful use of antibiotics in prophylaxis are the following:
- (a) To prevent recurrent urinary tract infection caused by the gram-negative bacterium, Escherichiacoli. The antibacterial combination drug, co-trimoxazole, is used.
- (b) To prevent wound infections after surgery.
- (c) To prevent infections when dental procedures are carried out in patients with valvular heart disease. During dental procedures, bacteria in the mouth can enter the bloodstream and are particularly hazardous to patients with valvular heart disease
- Malaria affects over 200 million people and is responsible for more than two million deaths per year. Human malaria is caused by four species of protozoa of the genus Plasmodium. These four speciesare:
- Plasmodium falciparum
- Plasmodium vivax
- Plasmodium ovale
- Plasmodium malariae
The following is the life cycle of the malaria parasite Plasmodium:
- 1. An infected Anopheles mosquito bites an individual and injects the malaria parasite (at this stage the parasite is referred to as a sporozoite) into the bloodstream.
- 2. The sporozoites are carried by the bloodstream to the liver where they enter liver cells and change into schizonts.
- 3. The parasites then emerge from the liver into the bloodstream where they enter red blood cells rbc's, multiply, and rupture red blood cells. At this stage, the parasite (referred to as merozoites) repeat entry into red blood cells and the process is repeated.
- Some parasites change into a form called a gametocyte. If the gametocytes are picked up by a mosquito, they replicate and multiply, moving as sporozoites to the salivary glands of the mosquito. They are ready to infect other individuals that the mosquito will bite.
Chloroquine is used for prevention of malaria in areas of the world where the plasmodia are susceptible. Chloroquine is also used for treatment of malaria due to all species of plasmodia except chloroquine-resistant Plasmodium falciparum. The drug is suitable for use in pregnancy and in people of all ages. Adverse effects encountered are nausea, headache, and difficulty in focussing the eyes.
- Mefloquine is the drug of choice for prevention of malaria in areas where the plasmodia are resistant to chloroquine, e.g. Guyana, South America. The drug is contraindicated in pregnancy. Rarely, the following adverse effects may be observed: vertigo, seizures and psychosis. These adverse effects are more likely to be observed with the higher doses used in therapy than with the lower doses used for prevention.
- The following are contraindications to the use of mefloquine: (a) pregnancy – women should not become pregnant for three months following the last dose; (b) seizure disorder or history of severe depression or psychosis; and (c) activities in which vertigo may become important.
- Quinine is more toxic and less effective than chloroquine. It is especially of value for therapy of severe illness due to chloroquine- and multidrug-resistant strains of Plasmodium falciparum. It is available for oral use and by injection.
- Adverse effects associated with quinine are ringing in the ears,nausea, headache, and disturbed vision. The adverse effects are referred to as cinchonism. You will recollect from the first lecture on the History of Drug Usage that quinine was isolated from cinchonabark.
- For drug-resistant Plasmodium malaria, a second drug is recommended in addition to quinine. The choice is made from either: doxycycline, clindamycin, or a combination of pyrimethamine and sulfadoxine
Doxycycline, a member of the tetracycline group, is contraindicated during pregnancy and in children less than 12 years of age. It is also contraindicated in women who are breast feeding. It is photosensitizing and a sunscreen is used when doxycycline is being taken.
When an individual is infected with Plasmodium vivax or Plasmodium ovale, a persistent liver phase occurs which is responsible for relapses. After chloroquine therapy, primaquine is the agent of choice to prevent a relapse due to the persistent liver phase. Patients should be tested for glucose-6-phosphate dehydrogenase deficiency before prescribing primaquine since primaquine can cause hemolysis (destruction of red blood cells) in patients with this enzyme deficiency.
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