Pharmacology III L

The Saudi German Institute for Nursing& Allied Health Sciences Division of Academic Affairs Department of Pharmacy
SPOTLIGHT ON
PHARMACOLOGY
Volume III CHEMOTHERAPY & VITAMINS Pharma (4) Written by: Dr. Heba Abdelhamed
INDEX Antiprotozoal drugs Treatment of malaria Treatment of amoeba Antihelmintics Flat Worm 1 2 10 20 22
Flukes Chemotherapy of microbial disease Antimicrobial drug resistance .. Mechanism of resistance Penicillin Cephalosporin Trimethoprim .. Aminoglycosides Tetracyclines Macrolides Quinolones .. Sulfonamides .. Antiseptic disinfectant Drugs used for treatment of tuberculosis Agents used for treatment of Leprosy Antifungal drugs .. Antiviral drugs .. Respiratory virus infection Hepatic viral infection Herpes and cytomegalovirus infections . HIV infection Vaccines and Toxoid Cancer Classification of anticancer drugs Antimetabolite .. Immune response Vitamins .. Water soluble vitamins Fat soluble vitamins Locally acting drugs Psoriasis
23 25 30 32 36 40 43 45 47 50 52 55 56 60 61 69 70 72 73 74 75 76 77 82 79 87 88 93 95 96
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Pharmacology III
Dr..Heba Abdelhammed
Chapter 1
Antiprotozoal drugs
Antiprotozoal drugs are medicines that are used to treat a variety of diseases caused by protozoa Protozoa are single celled organisms and replicate, often rapidly, by various mechanisms within the infected host. Some are parasitic and cause infections in the body. African sleeping sickness, giardiasis, amebiasis, and malaria are examples of diseases caused by protozoa.
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Malaria
Malaria is an infectious disease caused by a one-celled parasite known as Plasmodium. Four species of Plasmodium: 1. 2. 3. 4. P. vivax P. falciparum (potentially fatal) P. malriae P. ovale The parasite is transmitted to humans by the bite of the female Anopheles mosquito.
The Plasmodium parasite spends its life cycle partly in humans and partly in mosquitoes.
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Mosquito infected with the malaria parasite bites human, passing cells Sporozoites travel to the liver. Each sporozoite undergoes asexual
called sporozoites into the humans bloodstream. reproduction, in which its nucleus splits to form two new cells, called merozoites. Merozoites enter the bloodstream and infect red blood cells. In red blood cells, merozoites grow and divide to produce more Some of the newly released merozoites go on to infect other red blood cells. Some merozoites develop into sex cells known as male and female gametocytes. merozoites, eventually causing the red blood cells to rupture.
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Ruptured blood cells release free parasites (gametocytes) into the
host's bloodstream. The human host shows the classic malaria symptoms at this stage. Another mosquito bites the infected human, ingesting the gametocytes. In the mosquitos stomach, the gametocytes mature. Male and female
gametocytes undergo sexual reproduction, uniting to form a zygote. The zygote multiplies to form sporozoites, which travel to the mosquitos salivary glands. If this mosquito bites another human, the cycle begins again.
Treatment of Malaria
Malaria is a preventable infection that can be fatal if left untreated. You cannot be vaccinated against malaria, but you can protect yourself Malaria can be a severe, potentially fatal disease (especially when
caused by Plasmodium falciparum) and treatment should be initiated as soon as possible. The severity of P. falciparum infections is due to the high percentage of red blood cells (RBCs) that are infected by this species.
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Classification
Anti malarial drugs can be classified according to anti malarial activity: a. Tissue schizonticides for preventing relapse: These drugs are effective against the hepatic forms of the parasite. the net result is ; 1. causal prophylaxis: Prevent invasion of erythrocytes and further transmission of maralria to mosquito pyrimethamine is extensively used for causal prophylaxis of P. falciparium 2. prevention of relapse: they act on hepatic forms of P.vivax and P.ovale that produce relapse after the primary attack If combined with appropriate blood schizonticide, they can achieve a radical cure of these infections. Include: Primaquine is the prototype drug; pyrimethamine and proquanil also. b. Blood schizonticides: These drugs act on the blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the most important drugs in anti malarial chemotherapy. Include: These include chloroquine, quinine, mefloquine, halofantrine, pyrimethamine, sulfadoxine, sulfones, tetracyclines etc.
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Comparison between blood schizonticidal drugs
Quinine
Chloroquine
Mefloquine
Pyr./Sulpha.
Efficacy Onset of action
+++ Rapid
++++ Rapid
+++ Rapid
++ Slow Only for uncomplicated, resistant P. falciparum +++ Allergy to sulpha
Use
Only for resistant P. falciparum
Only for Prototype drug, uncomplicated, first choice for all multi drug resistant cases P. falciparum
Toxicity Contra indications
++ +++ Almost none, only Epilepsy, Prior hypersensitive advanced liver psychosis, heart reactions disease block
+++
c. Gametocytocides: These drugs destroy the sexual forms of the parasite in the blood and thereby prevent transmission of the infection to the mosquito. Include: Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae, but not against P. falciparum. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum. d. Sporontocides: These drugs prevent the development of oocysts in the mosquito and thus ablate the transmission. Include: Primaquine.
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Thus in effect, treatment of malaria would include a blood schizonticide, a gametocytocide and a tissue schizonticide (in case of P. vivax and P. ovale). A combination of chloroquine and primaquine is thus needed in ALL cases of malaria.
SO Aims of Treatment
Causation Therapy Drugs Symptoms are To Chloroquine, quinine, caused by blood Blood schizonticidal alleviate pyrimethamine/sulphadoxine, forms of the drugs symptoms artemisinin parasite To Relapses are due Tissue prevent to hypnozoites of Primaquine schizonticidal drugs relapses P. vivax/ P. ovale To Spread is through Gametocytocidal Primaquine for P. falciparum, prevent the gametocytes drugs Chloroquine for all other spread Thus, in effect, a blood schizonticidal drug and Primaquine should be administered to ALL types of malaria. Aims
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Quinine
Mechanism of action:
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It is said to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme.
Food Vacuole Hemoglobin Degradation Toxic Heme ? Inhibited by Quinine Heme polymerase Non Toxic Hemazoin (Malarial Pigment)
Side effect (Mild to moderate cinchonism): Headache, dizziness, slight visual disturbances, mild tinnitus
Chloroquine
Chloroquine was until recently the most widely used anti-malarial. Mechanism of action These agents are probably acting in a manner similar to quinine (interfere with, or are active against, the life cycle of the plasmodium, primarily when it is present in the red blood cells). They may also increase the pH of the erythrocyte and decrease phospholipid metabolism of the protozoa, both of which could contribute to their efficacy.
Primaquine
Primaquine causes occasionally side effect includes:
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1. Anorexia, nausea, abdominal cramps, headache, dizziness and methemoglobinemia 2. Hemolytic anemia can occur especially in patients with genetic deficiency of glucose-6-phosphate dehydrogenase in red cells.
Proguanil
Mechanism of action This inhibits the malarial dihydrofolate reductase enzyme. Its most prominent effect is on the primary tissue stages of P. falciparum, P. vivax and P. ovale. It has no known effect against hypnozoites therefore is not used in the prevention of relapse. Proguanil is used as a prophylactic treatment in combination with another drug, most frequently chloroquine. 3mg/kg is the advised dosage per day, (hence approximate adult dosage is 200mg). Side effect There are very few side effects to Proguanil, with 1. Slight hair loss. 2. Mouth ulcers being occasionally reported following prophylactic use.
Treatment of amebiasis
What is Amebiasis? 10
Pharmacology III Amebiasis is:
Infection of the intestines with amebae, especially with the ameba Entamoeba histolytica, (a unicellular eukaryotic parasite). Characterized by frequent, loose stools flecked with blood and mucus., This parasite can live in humans commensally (without causing harm), or it can invade tissues causing intestinal or extra-intestinal disease. The disease can be obtained by people swallowing food or water that Contain cysts. There are two forms of E. histolytica: 1. Cysts (infective) can survive outside the human body. They are non-motile It ransform to trophozoite. 2. Trophozoites (noninfective) invasive: Exist inside the host and transform to cyst excreted in fresh feces. They are highly motile amoebas, Invade wall of large intestine, causing ulceration and may migrate to other tissues, especially the liver.
There are two forms of amoebiasis infections: 1. Intestinal amoebiasis
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This occurs when the parasite enters intestinal tissues, and is most common in young adults. Diarrhoea (runny tummy) is the main symptom and may be mild or severe. 2. Extra-intestinal amoebiasis This is caused by the trophozoites penetrating the intestinal wall and spreading by the bloodstream to other organs. In the liver the trophozoites can cause amoebic hepatitis (liver enlargement), as well as the formation of ulcers. Trophozoites can also create abscesses in the brain, lungs or heart.
Chemotherapy of aboebiasis
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Drugs Can be classified into either tissue or luminal amoebicides: 1. Tissue systemic amoebicides:
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Pharmacology III They include: Emetin dehydroemetine chloroquine(liver only)
Eliminate organisms primarily in the bowel wall, liver and They are not effective against organisms in the bowel lumen.
extraintestinal tissues. 2. Luminal amoebicides They include Halogenated 8-hydroxyquinolines ( Iodoquinol). Diloxanide furoate. Act in the bowel lumen. Used to treatment of asymptomatic amebiasis. They are not effective against organisms in the bowel wall.
3. mixed amebicides: Metronidazol and tinidazole. Effective against both luminal and systemic forms of the Less effective against parasites in the lumine disease
Metronidazole
Mixed amebicide Drug of choice for intestinal & extraintestinal amoebiasis Acts on trophozoite Has no effect on cysts
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Pharmacology III Mechanism of action:
It is activated by anaerobic organisms to a compound that damages parasites DNA, leading to parasite death. Nitro group of metronidazole is reduced by protozoal cell leading to cytotoxic reduced products that bind to DNA resulting into parasite death.
Clinical 1. Amoebiasis (with luminal amebicide) 2. Giardiasis (giardia intestinalis)
uses:
3. Broad spectrum of anaerobic bacteria e.g Helicobacter pylori infection (H. Pylori) 4. Pseudomembranous colitis (Closrtidium defficile). drug of choice Side Effects It may cause GIT disturbance as stomach pain, nausea, vomiting, dry mouth metallic taste. CNS symptoms as numbness, tingling, pain or weakness in hands or feet (neurological effect).
Tinidazole
Therapeutic uses Tinidazole may be a therapeutic alternative in the setting of metronidazole tolerance.
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Pharmacology III Mechanism of action
The same as metronidazole ,but it is eliminated more slowly ,having a half life of 12-14 hours Side effect The most common side effects reported with tinidazole are: Upset stomach, bitter taste, and itchiness.
Diloxanide furoate
It is an anti-protozoal drug used in the treatment of Entamoeba histolytica and some other protozoal infections. Side effect This drug had a low incidence of side effects and was successful in treatment of 86% of asymptomatic carriers of Entamoeba histolytica.
Trypanosomiasis
Trypanosomiasis refers to sleeping sickness caused by parasite trypanosome. There are two spices of trypanosome:
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Pharmacology III 1. Trypanosome brucei
which causes a chronic infection lasting years and affecting It is transmitted to humans through the bite of a tsetse fly.
countries of western and central Africa
2.
Trypanosoma cruzi which causes acute illness lasting several weeks in countries of It is transmitted to humans thought the blood-sucking When untreated, trypanosomiasis gives no respite from eastern and southern Africa assassin bugs. suffering and ultimately ends in death.
TrypanosomiasisTreatment; 1. Melarsoprol 2. pentamidine
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Melarsoprol
pentamidine
Mechanism of action
It reacts with sulfhydryl groups of enzymes in the organism. So it inhibits parasites enzymes
It binds to the parasite's DNA and interferes in the synthesis of RNA, DNA and protein of parasite.
Antimicrobial spectrum
Limited to the treatment of typanosomal infections
It is not effective against T. cruzi
Adverse effect
C.N.S toxicities the most serious effect.(it crosses blood brain barrier)
Serious renal dysfunction may occur.
Trichomoniasis
prostate. Trichomoniasis is caused by the trophozoite parasite Trichomonas vaginalis, and is usually confined to the vagina, urethra or
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Dr..Heba Abdelhammed Because of the site of infection, trichomoniasis is considered a Infections in the male are usually asymptomatic, but in women Tricomoniasis is generally treated with metronidazole or
sexually transmitted disease. symptoms include vaginitis and a foul-smelling discharge. tinidazole.
Giardiasis
A parasitic organism (Giardia lamblia) that causes an intestinal
infection marked by diarrhea and/or abdominal pain and weight loss (giardiasis); usually acquired from contaminated food or drinking water.
Giardiasis is generally treated with metronidazole or
tinidazole.
Leishmaniasis
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Leishmaniasis is a parasitic disease spread by the bite of the sandfly and can cause skin disease and systemic disease. The systemic form can be fatal, but treatment with antimony-containing compounds produces a high cure rate.
There are two common therapies; The first line compounds:

Antimony-containing compounds
1. sodium stibogluconate (Pentostam) 2. meglumine antimoniate (Glucantime). The second line compounds: 1. pentamidine (Lomidine).
2. amphotericine B (Fungizone) .
Antihelmintics
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Anthelmintics are drugs that are used to treat infections with (parasitic worms). This includes: 1. Round worms, i.e., nematodes. 2. Flat worms, e.g., flukes Parasitic Roundworm diseases Ascariasis is the most common roundworm infection, and affects as many as 1 billion people worldwide. Ascariasis Intestinal infection caused by the parasitic roundworm (Ascaris lumbricoides) Infection occurs through ingestion of food contaminated with feces containing Ascaris eggs. The larvae hatch, burrow through the intestine, reach the lungs, and finally migrate up the respiratory tract. They are then reswallowed and mature in the intestine, growing up to 30 cm (12 in.) in length and anchoring themselves to the intestinal wall. Infections are usually asymptomatic, especially if the number of worms is small. They may however be accompanied by inflammation, fever, and diarrhea, and serious problems if the worms migrate to other parts of body
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Pharmacology III Round worm treatment:
Pharmaceutical drugs that are used to kill roundworms are called ascaricides and include: pyrantel pamoate, piperazine, albendazole, and mebendazole. Mebendazole Albendazole
Mechanism of action Contraindication
Blocking glucose uptake in susceptible helminthes, thus depleting energy required for their survival. Cannot be given to: - Pregnant women because it may harm the fetus. - Children less than 2 years old. Hypersensitivity to benzimidazole derivatives.
Side effect
Gastrointestinal disturbance, headache, dizziness and drowsiness.
Flat worm
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Most of these worms are parasites, but all types fall into three categories: 1. Tapeworms (Cestoda) 2. flukes (Trematoda), 3. Planarians (Turbellaria).
Flukes (Trematoda)
Members of this class are primarily parasites (feed on a host species). The flukes can be classified into two groups: 1. Tissue flukes Infect the bile ducts, lungs, or other biological tissues. This group includes: a. The lung fluke, Paragonimus westermani, b. The liver flukes, Clonorchis sinensis and Fasciola hepatica. 2. Blood flukes Inhabit the blood in some stages of their life cycle. Blood flukes include: a. Species of the genus Schistosoma. BLOOD FLUKES A variety of diseases throughout t h e world are caused by three species of blood flukes: intestinal blood flukes, urinary blood flukes, a n d Oriental blood flukes.
1. Intestinal Blood Flukes.
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The intestinal blood fluke, Schistosoma mansoni, commonly attacks h u m a n s in China, Taiwan, Southeast Asia, India, Africa, a n d northern South America. 2. Urinary Blood Flukes. The urinary blood fluke, Schistosoma hematobium, is a parasite which occurs in Egypt, Africa, a n d in parts of t h e Middle East. 3. Oriental Blood Flukes. Schistosoma japonicum Schistosoma mansoni, hematobium or japonicum biology: adult flukes live in colon or bladder veins clinical: hepatic fibrosis, urethral obstruction, bladder cancer Treatment: Praziquantel and Oxamniquine Praziquantel Mechanism of Action Praziquantel works by causing severe spasms and paralysis of the worms' muscles. This paralysis is accompanied - and probably caused - by a rapid Ca 2+ influx inside the Schistosome. Morphological alterations are another early effect of praziquantel. The worms are then either completely destroyed in the intestine or passed in the stool. Uses: Praziquantel is used as a treatment for all varieties of Schistosome It is the most effective drug for the treatment of schistosomiasis. 25 (blood flukes)
transmission: human contact with stool/urine contaminated freshwater
Pharmacology III Drug Interactions: Praziquantel Chloroquine
Plasma-praziquantel concentration possibly reduced
Praziquantel
Dexamethasone Plasma-praziquantel concentration reduced Phenytoin Carbamazepine
Side effects: Common side effects include: Abdominal discomfort, nausea, vomiting, malaise, headache, dizziness, drowsiness, and rectal bleeding.
Chapter 2
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Chemotherapy of microbial disease

Antimicrobial
Antimicrobial is a general term given to substances including medicines that kill or slow the growth of microbes. Microbe is a collective name given to: 1. Bacteria (Staphylococcus aureus), 2. Viruses (influenza, which causes the "flu"), 3. Fungi (e.g., Candida albicans, which causes some yeast infections), 4. Parasites (e.g., Plasmodium falciparum, which causes malaria). Examples of antimicrobial agents:

Tetracycline (one antibiotic used to treat urinary tract infections) Oseltamivir or Tamiflu (antiviral that treats the flu) Terbinafine or Lamisil (antifungal that treats athletes foot)
Antibiotic
An antibiotic is a medicine derived from natural and synthetic source designed to kill or slow the growth of bacteria and some fungi.
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Pharmacology III They can be: bactericidal (killing the bacteria ) bacteriostatic ( inhibit the growth of the
bacteria) Antibiotics are commonly used to fight bacterial infections, but cannot fight against infections caused by viruses. Example of an antibiotic:
Azithromycin or Zithromax (Z-Pak) The mechanism of action of the antimicrobial agents is classified to:
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Types of antibiotic agents

Target Organisms & Infections Drugs that target cell wall synthesis Antibiotic Penicillins Cephalosporins Vancomycin Bacitracin Gram Positive organisms GN & GP GP GP & GN Allergies Beta lactamase more resistant to Beta lactamase Last line against MRSA only used topically Special Concerns
Drugs that target protein synthesis Aminoglycosides binds to ribosomes blocks translation Broad severe hearing and kidney damage spectrum but often used must draw blood levels synergistically with cephalosporins
Tetracyclines Only works on Sun sensitivity, bone and tooth damage in blocks tRNA stopping procaryotic children cells protein synthesis Macrolides Mycoplasma, Used for Penicillin allergic patients
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Pharmacology III prevent protein synthesis by binding GP, some GN to ribosomes Chloramphenicol Broad prevents peptide synthesis bonding by spectrum ribosomes
May inhibit bone marrow production (aplastic anemia)
Drugs that target nucleic acid synthesis Fluoroquinolones inhibit DNA gyrase interupting DNA replication Very Broad spectrum
increasing resistance noted
Rifampin GN and blocks RNA activity in Mycobacteria Quick resistance development ribosomes Drugs that inhibit Metabolic Processes Sulfonamides imitate PABA and GN, some GP allergic reactions, sun sensitivity disrupt folic acid metabolism Synergistic use of sulfa with trimethoprim Trimethoprim Broad sulfamethaoxazole/trimethoprim Drugs that target cell membrane integrity Polymyxin B GN Topical only Very harsh side effects
Amphotericin B Fungi Drugs that target AFB
Ethambutol - interrupt mycolic acid Mycobacteria used synergistically in multidrug therapy formation in call wall INH Isoniazid interrupt mycolic acid Mycobacteria used synergistically in multidrug therapy formation in call wall Clofazimine Mycobacteriu prevents replication m leprae and transcription
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Antimicrobial Drug Resistance

What is Drug Resistance? Antimicrobial resistance is the ability of microbes, such as bacteria, viruses, parasites, or fungi, to grow in the presence of a chemical (drug) that would normally kill it or limit its growth.
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Pharmacology III Genetic basis of resistance: 1. Intrinsic resistance:
The bacteria by their nature are resistant (no mutation are necessary) E.g. Mycoplasma do not have a cell wall and hence are resistant to beta lactamases Enterococci cannot make folic acid and are thus resistant to sulphonamides.
2. acquired resistance: Bacteria can change their genetic makeup via; a. Mutation Microbes reproduce by dividing every few hours, allowing
them to evolve rapidly and adapt quickly to new environmental conditions. With each replication, mutations arise, and some of these mutations may help an individual microbe survive exposure to an antimicrobial.
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Pharmacology III Diagram showing: How genetic mutation causes drug resistance. Bacteria multiply by the millions. A few of these bacteria will mutate.
Some mutations make the bacterium drug resistant. In the presence of drugs, only drug resistant bacteria survive. Drug resistant bacteria multiply and thrive.
Gene Transfer Microbes may also acquire genes from each other, including genes that make the microbe drug resistant.
Diagram showing: How gene transfer facilitates the spread of drug resistance.
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Pharmacology III Bacteria multiply by the billions.
Bacteria that have drug resistant DNA may transfer a copy of these genes to other bacteria. Non-resistant bacteria recieve the new DNA and become resistant to drugs. In the presence of drugs, only drug-resistant bacteria survive. The drug resistant bacteria multiply and survive.
Selection of antimicrobial agent

empiric therapy prior to organism identification: Ideally, the antimicrobial agent used to treat an infection is selected after the organism has been identified and its sensitivity established. However, in the critically ill patient, such a delay could prove fatal and immediate empiric therapy is indicated. identification and sensitivity of the organism: Characterization and sensitivity of the organism is central to the selection of the proper drug. A rapid assessment of the nature of the organism can sometimes be made on the basis of differential stains such as gram stain. Gram-negative Bacterial Membrane Structure
1.
2.
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Pharmacology III Gram-negative Cell Membrane Model Gram-negative bacteria are surrounded by two membranes. The outer membrane functions as an efficient permeability barrier containing lipopolysaccharides (LPS) and porins. The effect of the site of infection on therapy:
Cell Membrane
Peptidoglycan Cytoplasmic Membrane
3.
Gram-positive Bacterial Membrane Structure Gram-positive Membrane Peptidoglycan Layers The lipid bilayer cell membrane of most of the Gram-positive bacteria is covered by Cytoplasmic a porous Membrane peptidoglycan layer Adequate levels of an antibiotic must reach the site of infection in order for the invading microorganism to be effectively eradicated Natural barrier such as BBP may cause inadequate penetration of the drug into certain tissues such as the brain. Status of the patient: In selecting an antibiotic, attention must be paid to the condition of the patient for example, the status of the patient's immune system, kidneys and liver Safety of the agent
4.
5.
Selection of antimicrobial combination therapy
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Some clinical situations in which combination of antimicrobial drugs are indicated: 1. 2. When mixed infection are present When there is a risk of developing resistant organisms 3. 4. When the greatest anti-microbial coverage is desirable for An infection of unknown origin example meningitis or
Advantage of drug combinations: Certain combination of antibiotics, such as lactams and aminoglycosides, show synergism, that is, the combination is more effective than either of the drugs used separately Disadvantages of drug combinations: A number of antibiotics act only when organisms are growing. Thus, concomitant administration of a second agent that results in bacteriostasis may interfere with the action of the first drug that is bactericidal.
Misuse of antimicrobial dugs

Massive quantities of antibiotics are being prepared and used, which are followed by the widespread problems of drug as: 1. 2. Resistance in Misused antibiotic can microorganisms. interact with the human metabolism and in severe cases it can cause death of human being. 3. such as: Misuses of antibodies
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Pharmacology III 4. Penicillin can cause allergic reactions.
Streptomycin can affect auditory nerve thus causing deafness. Tetracycline and its related compounds cause permanent It is difficult for antibiotic to distinguish between a beneficial
discoloration of teeth in young children. and non-beneficial bacterium so the flora in the gut is affected with the use of antibiotics. 5. Stop taking antibiotics too soon, before illness is complete cured allows bacteria to resistant by not killing them completely.
Agents affecting cell wall synthesis(antibacterial)

Beta lactams are the commonest of these agents: Beta lactams include: 1. Penicillin 2. Cephalosporins Other agents which inhibit cell wall synthesis and are not beta lactams are: 1. Bacitracin 2. Vancomycin 3. Cyclosporine
Penicillins
Structure: A Thiazolidine ring connected to beta lactam ring The initial prototype benzyl penicillin (penicillin G) but it has several limitations;
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1. It is destroyed by gastric acid and so cannot be taken orally given parenrally. 2. It is easily destroyed by beta lactamases 3. Procaine penicillin G. is relatively water insoluble and hence slowly absorbed from the injection site. They are usually in suspension form, so they are given only I.M. and never I.V. 4. They are effective against gram-positive strains of streptococci, staphylococci, and some gram-negative bacteria such as meningococcus. 5. It has a short half life (rapidly excreted in urine) By modifying the side chain of penicillin: 1. Penicillin V is more stable to gastric acid and so can be taken orally. However, it is not resistant to b lactamases. 2. Methicillin and fluxacillin show beta lactamase resistance but cannot be taken orally. 3. Amoxicillin: The aminopenicillins were the first penicillins discovered to be active against gram-negative bacteria (such as E. coli and H. influenzae) and they are acid-resistant so administered orally. Mechanism of action: Penicillins are bactericidal and affect microorganisms during their growth, but not during resting state. 1. 2. 3. 4. 5. Penicillin kills bacteria by interfering with the ability to synthesize cell wall. Crosses the cell wall into bacterium Binds to the penicillin-binding protein Stops the PBP enzymes working The peptidoglycan is not made The cell losses its rigidity 38 their
Pharmacology III 6. 7. The fluid inside exerts outward pressure The bacterium bursts. Potential problems: 1. Getting across the outer lipid
membrane in gram negative bacteria This is why many antibiotics work well against gram .. Bacteria but not against gram bacteria 2. lactamases Interference by beta
These enzymes break down many of the commom penicillin-like drugs The susceptible drugs have a beta lactam group in their structure.
The effect of bacterial beta lactamases:
Mechanism of action of -lactamase enzymes
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If this happens: The drug will not work and the bacterium is resistant to the drug. lactamase inhibitor: Clavulinic acid is very powerful lactamase inhibitor. Administered alone, it has only weak antibacterial activity against most organisms, but given in combination with beta-lactam antibiotics (amoxicillin) prevents antibiotic inactivation by microbial lactamase. Mechanism of action of clavulanic acid
Pharmacokinetics of common penicillins: Uses: Penicillin G Pneumococci, Streptococci and Meninogococci Amoxicillin (good against G-ve bacteria) Respiratory and urinary tract infection
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Pharmacology III Haemophilus influenzae. Gram positive
Gram negative
Adverse effects: 1. 2. When the betalactam ring of penicillin is cleaved by beta This metabolite acts as an antigenic determinant, and is the reason why some people get hypersensitivity reaction to penicillin. The more common problems with penicillin use are the GI disorders: (Nausea, diarrhea). Note: Antacids and food interfere with the regular effect of penicillin by decreasing the bioavailability of penicillin while the certain drugs as probenecid and streptomycin increase the bioavailability and effectiveness of penicillin when used currently So: Penicillin should be adminidtered 1 hour before meals or 2 to 3 hours after meals in oreder to improve the bioavailability.
lactamases, penicilloic acid is produced.
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Cephalosporins
They are structurally and pharmacologically related penicillins. to the
Classification: Cephalosporins are classified into four "generations" according to their activity against gram-negative bacilli and their resistance to beta lactamases.
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Cephalosporin
1st generation
2nd generation
3rd generation
4th generation
Cefadroxil Cafazolin Cephalexin Cephradine
Cefaclor Cafprozil Cefuroxime Na Cefuroxime axetil Cefoxitin
Cefdinir Cefixime Cefotaxime Ceftazidine Ceftriaxone
Cefepime
More useful drugs shown in bold Drugs that can be used orally are shown in word Many of the cephalosporins must be administered IV or IM because of their poor oral absorption Exceptions are noted in this diagram
All cephalosporin are inactive against enterococci and methicillin resistant staphylococci. All cephalosporin are active against gram (+ve) cocci & bacilli First generation cephalosporin: These drugs are very active against gram positive bacteria and relatively modest activity against gram negative microorganisms. Clinical uses: Although the first generation cephalosporin have a broad spectrum of activity and are relatively non-toxic, they are rarely the drugs of choice for any infection Oral drugs may be used e.g: in urinary tract infection, for minor staph lesions and for minor polymicrobial infections such as cellulitis or soft tissue abscess Oral method should not be employed for serious systemic infections. 43
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I.V. drugs are those of choice for surgical prophylaxis. Second or third generations may have no more advantage for surgical prophylaxis and should not be used for that purpose. Second generation cephalosporin: They are active against organisms, by affected first generation but they have extended gram negative coverage Clinical uses: 1. Because of its activity against beta-lactamase producing H. influenza - - Cefaclor is used to treat sinusitis and otitis media in patients who are allergic or have not responded to ampicillin. Note: The drug is associated with serum thickness. 2. Cefuroxime is the only second generation that cross the blood brain barrier and CSF well enough to be used for treatment of meningitis especially H. influenza meningitis and sepsis. 3. Because of their activity against anaerobes including B. fragilis, cefoxitin can be used in such mixed anaerobic infections as in peritonitis.
Third generation cephalosporin: The major features of these drugs (except cefoperazone) are: 1. Their expanded gram negative coverage 2. Their ability to reach C.N.S Clinical uses: 1. Except cefoperazone, third generation can penetrate the CSF and can be used to treat meningitis. 2. Cefoperazone and ceftriaxone have been used effectively in typhoid fever.
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3. Used in sepsis of unknown etiology in the immunocompetent patients and susceptible infections. 4. The third generation ceftriaxone is now the therapy of choice for all forms of gonorrhea. Fourth generation cephalosporin: Extended spectrum of activity than IIIrd generation and have Cefepime must be administered parentally increased stability against hydrolysis by b lactamase
Mechanism of action and drug resistance: As penicillin. Adverse effects: 1. 2. Hypersensitivity reactions are more common. Nephrotoxicity has been reported especially with cafradine NOTE: - Elimination occurs through tubular secretion and or glomerular filtration therefore doses must be adjusted in cases of severe renal failure. - Cefriaxone is excreted through the bile into the feces and therefore, is frequently employed in patients with . RENAL INSUFFIENCY.
Drugs that target protein synthesis 1. Amionglycosides
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Pharmacology III
They are bactericidal drugs active against aerobic gram ve bacteria Their action against anaerobic and most gram +ve bacteria is limited. This group includes: o o o o Amikacin Gentamicin Tobramycin Streptomycin o o o Kanamycin Neomycin Netilmicin
They are highly charged, therefore not well aborsorbed from the Neomycin can be taken orally or topically. Neomycin sulphate is the only aminoglycoside can be taken orally.
intestine and almost all has to be injected.
Mechanism of action: They are rapidly bactericidal for susceptible organisms by Although most inhibitors of microbial protein synthesis are
producing irreversible inhibition of protein synthesis bacteriostatic, the aminoglycosides are bactericidal. Antibacterial spectrum: The aminoglycosides are effective against many aerobic gram They are most widely used against gram negative enteric Amikacin has the widest antimicrobial spectrum and, along with
negative and some gram positive organisms. organisms and in sepsis. netilmicin, can be effective in infections with organisms resistant to gentamycin and tobramycin. Uses:
46
Pharmacology III
Aminoglycosides can be used in respiratory tract infections, skin infections, urinary tract infections, and infections of the blood, abdomen or bones. Side effects: 1. 2. Ototoxicity: Netilmicin is less ototoxic than other aminoglycosides. nephrotoxicity: They are excreted mainly unchanged by the kidney, in persons with impaired renal function; there is a danger of drug accumulation and toxic effects. Gentamicin and tobramycin are the most nephrotoxic
Drug resistance: Inactivation by microbial enzymes. Resistance as a result of faliure of penetration can be overcome by the concomitant use of penicillin and/or vancomycin.
2. Tetracyclines
47
Pharmacology III They are broad spectrum antibiotics. They include: Demeclocycline Doxycycline. Minocycline Tetracycline Mechanism of action:
They inhibit bacterial protein synthesis and may be effective against a wide variety of microorganisms (bacteriostatic agents). Uses: These medications are used in the treatment of infections of the They are also used to treat Gonorrhoea. The most common current use is the treatment of moderately or Tetracyclines are the drug of choice for chlamydial infection,
respiratory tract, sinuses, middle ear, urinary tract and skin.
severe acne (as an alternative treatment) mychoplasma pneumonia, cholera and rocky mountain spotted fever.
Drug resistance: There are two types of tetracycline resistance: 1. Tetracycline efflux outside of cell. 2. Ribosomal protection. Tetracyclines side effects Common side effects associated with Tetracyclines include: 1. Cramps or burning of the stomach, diarrhea, sore mouth or tongue. 2. Tetracyclines can cause skin photosensitivity, which increases the risk of sunburn under exposure to UV light. 48
Pharmacology III 3. Effects on calcified tissues:
Because they chelate calcium, they are deposited in growing bones and teeth causing staining (teeth discoloration). These antibiotics should not be used in children under the age of 8, and specifically during periods of tooth development. 4. Tetracyclines are classed as pregnancy category D. Use during pregnancy may cause alterations in bone development. 5. Outdated (expired) tetracyclines may cause a form of the Fanconi syndrome (damage of proximal renal tubular cells). 6. Hepatotoxicity on high doses only. Tetracycline drug interaction: Antacids containing: aluminum, calcium, or magnesium, and ironcontaining preparations
Impaired the absorption of tetracyclines
Anticoagulant therapy
Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective.
Oral contraceptives
3. Macrolides
49
Pharmacology III
They are broad-spectrum antibiotics that are used to treat a wide Macrolides are valuable alternatives to penicillins and
range of bacterial infections. cephalosporins in allergic patients. They include: Erythromycin Clarithromycin & Azithromycin Erythromycin is very similar to penicillin: it is effective against gram
+ve bacteria but not against gram ve organisms, the exceptions being gonococci and to a lesser extent H.influenzae
ERYTHROMYCIN Erythromycin base is incompletely but adequately absorbed from the upper part of intestine, it is inactivated by gastric juice and so the drug is either administered as enteric-coated tablets (acid resistant coated tablet) or esterified as erythromycin estolate
CLARITHROMYCIN & AZITHROMYCIN Both are well absorbed from GIT.
50
Pharmacology III About 70% or more is bound to plasma proteins Oral administration especially of large doses is very frequently accompanied by epigastric distress with abdominal cramps, nausea, vomiting and diarrhea Erythromycin is the drug of choice in corynebacterial infections (diphtheria)
Dr..Heba Abdelhammed About 50% is bound to plasma proteins Both are well tolerated and cause little nausea or diarrhea.
- They are expensive alternatives to erythromycin and: - Clarithromycin: has also been used in the regimens for treatment of peptic ulcer related to H. pylori infection. Clarithromycin + amoxicillin + ampicillin and metronidazole - Azithromycin: is now the preferred therapy for urthritis caused by chlamydia trachomatis.
Erythromycin & Clarithromycin inhibit the hepatic metabolism of a number of drugs thus lead to toxic accumulation of these compounds No interaction has been reported with Azithromycin. Note: Erythromycin estolate may cause cholestatic hepatitis with jaundice if used for more than 14 days. Mechanism of action: Inhibit protein synthesis that is essential for them to grow The drug is bacteriostatic, but can be bactericidal in some
situations, that is in high concentrations against very susceptible organisms.
51
Pharmacology III Side effects:
1. Nausea, vomiting, abdominal pain & diarrhea( AAC) These side effects are more common and severe with erythromycin therapy. Azithromycin and clarithromycin have fewer gastrointestinal side effects than erythromycin. 2. Cholestatic jundice. (in Erythromycin estolate) 3. Ototoxicity: transient deafness associated with erythromycin in high doses.
LINCOSAMIDE Clindamycin
Similar mechanism of action to erythromycin
Clinical uses: Limited because of pseudomembranous colitis-fatal Used in: 1. Anaerobic infection caused by bacteroids (metronidazole is preferred) 2. Staphylococcal joint & bone infection such as osteomyelitis 3. Staph. conjunctivitis (eye drop) 4. Acne (1% topical gel & lotion).
Drugs acting by inhibiting DNA synthesis Quinolone

Quinolones
1st Generation
Fluoroquinolone
Nalidixic acid
2nd Generation
52
3rd Generation
4th Generation
Pharmacology III Ciprofloxacin Ofloxacin Norfloxacin
Dr..Heba Abdelhammed Levofloxacin Moxifloxacin
Nalidixic acid is a (1st generation) Quinolone. Is one of the older members of quinolone class of synthetic antimicrobial agents that were used for treatment of urinary tract infections. Note: Drugs of this class were of relatively minor significance because of their limited therapeutic ability and the rapid development of bacterial resistance. Fluoroquinolones (2nd, 3rd and 4th generation) The introduction of fluorinated quinolones such as represents a particularly an important therapeutic advance, since these agents have broad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious diseases Relatively few side effects appear and microbial resistance does not develop rapidly. Fluoroquinolones are well absorbed after oral administration and absorption is impaired when they are given with antacids containing aluminum or magnesium dietary supplement containing iron or zinc. The fluoroquinolones with the longest half-lives (levofloxacin & moxifloxacin) permit once-daily dosing. Adverse effects 0. 1. 2. GI intolerance. C.N.C problems: Headache, dizziness. Phototoxicity 3. Connective tissue problems:
In pregnancy, in nursing mother, and in children under 18 years of age: Fluroquinolones should be avoided,
53
Pharmacology III
Because: articular cartilage erosion occurs in immature experimental animals. In adults: Fluroquinolones can infrequently cause ruptured tendons. 4. Moxifloxacin may prolong QTc interval and thus, should not be
used in patients who are predisposed to arrhythmias or are taking antiarrhythmic medications. Note: - Ciprofloxacin and ofloxacin are potent P450 inhibitor and impairs theophylline and warfarin metabolism. - This not the case with the third and fourth-generation. Uses Nalidixic acid and norfloxacin is used for urinary tract infection Ciprofloxacin and ofloxacin are used for: 1. Urinary tract infection 2. Skin infection 3. Bone and joint infections 4. Gonorrhea , prostatitis, typhoid fever 5. Infectious diarrhea
Urinary antiseptic
Urinary antiseptic inhibit the growth of many species of bacteria They can not be used in the treatment of systemic infections because effective concentrations are not achieved in the plasma with safe doses However, because they are concentrated in renal tubules, they can be used in the treatment of urinary tract infection The most notable example is methenamine and nitrofurantoin
Drugs that inhibit Metabolic Processes Sulphonamides and Trimethoprim

54
Pharmacology III
Sulphonamides
Mechanism Folate is required for DNA and RNA synthesis in both bacteria and mammals Bacteria synthesize folic acid while mammalian cells require performed folic acid from the diet and can not synthesize it The sulphonamides act mainly by competing with PABA for the enzyme dihydropteroate synthetase, the action of sulphonamides is to inhibit the growth of bacteria. Classification of sulfonamides 1. Oral, absorbable; a. b. c. Short-acting (10 hours) Sulfisoxazole, (SIZ). Medium-acting (10-24 hours) Sulfamethoxazole, (SMZ). Sulfadiazine, (SD). Long-acting (>24 hours) Sulfadoxine, 2. Oral, nonabsorbable; Sulfasalazine, 3. Topical; 55
of action:
Pharmacology III Sodium sulfacetamide ophthalmic solution or ointment. Clinical uses of Sulfonamides: 1. SMZ+TMP (Co-Trimoxazole): Treatment of urinary tract infections 2. SD+Pyrimethamine::
First-line therapy for treatment of acute toxoplasmosis Used as a second-line agent in treatment for malaria. 4. Sulfasalazine Widely used in ulcerative colitis, enteritis, and other
inflammatory bowel disease. 5. Sodium sulfacetamide (SA-Na) Bacterial conjunctivitis and as adjunctive therapy for
trachoma.
Resistance to sulfonamides Over-production of PABA. Produce dihydropteroate synthetase with low sulfonamide affinity. Loss permeability to the sulfonamide. Use exogenous sources of folate. Adverse effects 1. Disturbances of the urinary tract: Crystalluria result from the precipitation of the acetylated metabolites in urine
56
Pharmacology III
Dr..Heba Abdelhammed The risk is very low with more soluble agents such as sulfisoxazole. Adequate hydration and alkalinization of urine also prevent this problem.
2.
Hypersensitivity reactions with dermatitis. conttaindication: Because sulphonamides condense with formaldhyde, they should not be given to patients receiving methenamine
Trimethoprim
Mechanism of action: It inhibits bacterial dihydrofolic acid reductase about 50000 Co-trimoxazole is a combination of Trimethoprim and
times more efficiently than the same enzyme of mammalian cells. Sulphamethoxazole in the ratio of 1:5.
Antiseptics and disinfectants.

Sterilization is the process of complete elimination of microThe chemicals used for sterilization are classified as: b) Disinfectants.
organisms.
a) Antiseptics
Antiseptic
It can be used to kill bacteria or prevent their multiplication.
57
Pharmacology III
They do not harm the living tissues. Therefore, they can be applied Some examples are gentian-violet, mercuro chrome, boric acid and
on cuts and wounds. potassium permanganate. Antiseptics are used for: 1. Handwashing chlorhexidine gluconate and povidone iodine solutions are often used in hand scrubs. 2. Pre-operative skin disinfection antiseptics applied to the operation site to reduce the resident skin flora. 3. Mucous membrane disinfection antiseptic irrigations may be instilled into the bladder, urethra or vagina to treat infections or cleanse the cavity prior to catheterization. 4. Preventing and treating infected wounds and burns antiseptic preparations are available over-the-counter from your pharmacist to treat minor cuts, abrasions and burns.
Disinfectant
It is used to kill bacteria. They are used to sterilize instruments, utensils, clothes, floors, They harm the living tissues and cannot be used on skin. Some examples are phenol, methyl phenol, hydrogen peroxide. Sometimes the same substance may be used as an When the concentration is less, it is an antiseptic and when For instance, 0.2% solution of phenol is an antiseptic and sanitary fittings, sputum and excreta.
antiseptic or disinfectant. the concentration is more, the substance acts as disinfectant. 1.0% solution of phenol is a disinfectant
58
Pharmacology III
Agents used for the treatment of Tuberculosis. T.B

Tuberculosis of the lungs
Tuberculosis is a contagious bacterial disease that primarily involves the lungs, but can occur in other tissues (lymph, CNS, pericardium, liver, etc.). Tuberculosis may develop after inhaling infected droplets sprayed into the air from a cough or sneeze of someone infected with Mycobacterium tuberculosis.
The modern treatment of tuberculosis:
Table of drugs used for the treatment of tuberculosis. First line drugs Essential Other Second line drugs Old New
59
Pharmacology III Isoniazid Rifampicin
Dr..Heba Abdelhammed Pyrazinamide Ethionamide Quinolones Ethambutol Ofloxacin Streptomycin Cycloserine Ciprofloxacin Amikacyn Kanamycin Macrolides Clarithromycin Clofazimine Amoxycillin & Clavulanic acid
New rifamycins Rifabutin Rifapentine
Isoniazid
Isoniazid is isonicotinic acid hydrazide (INH). It inhibits synthesis of mycolic acid and thus inhibits cell wall formation. A common complaint is hepatitis and development of peripheral neuritis. INH in a dose of 50 mg/day. This dose related complication because isoniazid increases the excretion of pyridoxine Isoniazid can reduce the metabolism of phenytoin increasing its blood level and toxicity. Isoniazid (INH) is considered to be: seful alone for prophylaxis of TB.
To avoid such a reaction, Pyridoxine is given prophylactically along with
Pharmacokinetics: It is metabolized in the liver by enzymatic acetylation
(acetylisoniazide) and enzymatic hydrolysis (isonicotinic acid).
60
Pharmacology III
The acetylation is under genetic control via the activity of The plasma concentration of the drug is affected by whether a
acetyltransferase given patient is a fast or slow acetylator of the drug.
Rifampicin (rifampin)
Rifampin is a semisynthetic derivative of rifamcin B which belong to a group of complex macrocyclic antibiotics It is a potent, orally active drug that inhibits mycobacterial RNA polymerase. It imparts a harmless orange red color to urine, saliva, sweat, tears and sputum and patients should be warned about this. It is used in the treatment of T.B and should never be used alone because of the rapidity with which resistance may develop It is usually combined with isoniazid or ethambutol it penetrate CSF unwanted effects are infrequent (but serious liver damage has occurred) It induces hepatic drug-metabolising enzymes.
Ethambutol
It is a bacteriostatic agent, it inhibit the incorporation of mycolic acid into mycobacterial cell wall Side effect: 1. Optic neuritis: It is dose related and manifested by decreased color perception, impaired visual field or reduced visual acuity This complication is reversible with early drug withdrawal 2. Hyperuricemia Due to decreased renal excretion of uric acid THERAPEUTIC PROTOCOLS OF T.B:
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Pharmacology III 1.
In uncomplicated T.B, short course therapy for 6 months can be One such regimen isoniazid + rifampin + pyrazinamide can be given for 2 months followed by 4 additional months of isoniazid + rifampin
satisfactory provided that both isoniazid and rifampin are administered
2.
In extensive pulmonary T.B, those with extrapulmonary disease
another drug is added to the above regimen which is usually ethambutol or streptomycin.
Agents used for the treatment of Leprosy
62
Pharmacology III
Leprosy bacterial
is a
chronic
disease of the skin and nerves in
the hands and feet and in some cases, the lining of the nose. Leprosy is caused by bacteria Mycobacterium leprae.
Leprosy treatment
For tuberculoid leprosy: Combination of Dapsone and Rifampin: Dapsone: It is sulfonamide-like and may inhibit folate synthesis. It induces hemolytic anemia in patients with G-6-PD deficiency Rifampin: see anti T.B drugs. For lepromatous leprosy: Combination of Dapsone, Rifampicin and Clofazimine Clofazimine is a dye that is given orally and can accumulate by sequestering in machrophages action is delayed for 6-7 weeks and half life is 8 weeks unwanted effects include red skin and urine, sometimes gastrointestinal disterbances
63
Pharmacology III
Antifungal drugs
Drugs for subcutaneous and systemic mycotic infections
1. Amphotercin
64
Pharmacology III
Amphotercin B is a polene macrolide antibiotic (polyene = containing many double bond, macrolide = containing a large lactone ring) Mechanism of action: The site of amphotercin action is the fungal cell membranes, where Amphotericin B induced pores resulted in fungal cell death. The drug is ineffective against bacteria because it binds to ergosterol -- changing cell permeability.
..? THEY LACK ERGOSTERIL REQUIRED FOR DRUG ACTION.
Pharmacokinetic aspects: orally Amphotercin is very poorly absorbed when given , and
this route is used only for treating fungal infection of the upper gastrointestinal tract. It can be used topically with success, but for systemic infection it is I.V generally administered by complexed with liposomes infusion or other lipid-containing preparations. Side effects: The common and most serious unwanted effect of amphotericin is renal toxicity.
65
Pharmacology III
Note: Nephritoxixity may be potentiated by sodium depletion, thus a bolus infusion of normal saline before and after amphotercin B infusion may reduce the incidence of drug-induced nephrotoxixity. Uses: It is the drug of choice for the treatment of life-threatening, systemic mycoses. Note: Amphotercin B is also used in the treatment of the ..? Protozoal infection, leshmaniasis 2. Flucytosine (5-FC) Flucytosine is a synthetic pyrimidine antimetabolite Animetabolite drug mean (They blocking pathways of DNA synthesis for formation of new cells). It inhibits DNA synthesis and cell division so it is fungistatic agent. 5CF enter fungal cells via a cytosine-specific permease It is often used in combination with amphotercin B Because: amphotercin B increases cell permeability, allowing more flucytosine to penetrate the cell, thus flucytosine and amphpotercin B are synergistic). Antifugal spectrum: 1. 5-fc is fungistatic agent. 2. It is effective in combination with amphotercin b for treatinh candidiasis or cryptococcosis Side effect: 1. GI disturbance (nausia, vomiting and diarrhea) 2. Dose related bone marrow depression 3. Hepatic dysfunction 4. Reversible neutropenia (an enzyme not found in mammalian cells)
66
Pharmacology III
3. Azoles The azole antifungal agents are predominantly fungistatic. They inhibit the synthesis of ergosterol by blocking the action of 14-alphademethylase, they include:
a. ketoconazole
Ketoconazole was the first orally active azole available for the treatment of systemic mycoses. Pharmacokinetics: It requires gastric acid for dissolution and is absorbed through the gastric mucosa. Oral absorption of ketoconazole varies among individuals because bioavailability is markedly depressed in patients taking H2 histamine receptor blocking agents as cimitidine or proton pump inhibitor.
67
Pharmacology III The drug does not enter CSF.
NOTE: The drug is active against many fungi but not aspergillus Drug interaction and contraindications: By inhibition of cytochrome p 450, ketoconazole can potentiate the
toxicities of drugs such as cyclosporine, phenytoin, tolbutamide and warfarin. Ketoconazole and amphotercin B should not be used together, because .? Because the decrease of in ergosterol in the fungal membrane, it reduces the fungicidal action of amphotercin B. Note: Although itraconazole has largely replaced ketoconazole in the treatment of most mycoses because of its broad spectrum, great potency, and fewer adverse effects, ketoconazole as a second line drug is a less expensive alternative for the treatment of mucocutaneous candidiasis Side effect: 1. Gastrointestinal disturbance 2. Pruritus. 3. Liver toxicity. 4. Endocrine effect with high doses: inhibition of adrenocortical steroid and testosterone synthesis: the latter resulting in gynaecomastia in some male patients. Ketoconazole is teratogenic and it should not be given during pregnancy.
68
Pharmacology III
b. Fluconazole It is clinically important because of: a. It lack of the endocrine side effect of ketoconazole b. Its excellent penetration into the CSF. So the drug of first choice for most types of fungal meningitis. Can be given orally or I.V Uses: 1. It is the drug of choice for cryptococcus neoformans and for candidemia. 2. Orally for the treatment of oro-pharyngeal and vaginal candidiasis. 3. Tinea pedis and Tinea versicolor. Side effect: 1. Nausea and Vomiting. 2. Rashes. 3. Impairment of hepatic functions. c. Itraconazole (Sporanox) It is an azole antifungal agent with a broad antifungal spectrum. Like fluconazole, it lacks the endocrinologic side effects of ketoconazole. Itraconazole is well absorbed orally, but requires acid for dissolution Therapeutic concentration is not attained the CSF. It is approved for single-dose treatment of vaginal yeast infections. Itraconazole should be avoided in pregnancy Itraconazole inhibit the metabolism of many drugs including oral anticoagulants, statins and quinidine Side effect: 1. Gastrointestinal disturbances, headache and dizziness
69
Pharmacology III
d. Voriconazole
It has the advantage of being a broad spectrum antifungal agent It is available for I.V. administration and also for oral administration. One unique problem is a transient visual disterbance that occurs within 30 minutes of dosing.
e. Posaconazole
Posaconazole is a new oral, broad spectrum antifungal agent with a It was approved in 2006 to: Prevent candida and aspergillus infection in severely immunocompromised patients and treatment of oropharyngeal candidiasis.
chemical structure similar to that of itraconazole
Drugs for cutaneous mycotic infections

Fungi that cause superficial skin infection are called dermatophytes Common dermatomycoses, such as tinea infection, are often referred to as ringworm 1. Terbinafine Terbinafine is the drug of choice for treating dermatophytoses and especially onychomycoses (fungal infection of nails)
2. Nystatin
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Pharmacology III Uses:
Nystatin is a polyene macrolide antibiotic similar in structure to
amhotercin and with the same mechanism of action. 1. Orally to control moniliasis (Candida albicans infection) of the mouth and of the gastrointestinal tract. 2. Candida infection of the skin and vulva, it is applied locally in the form of ointment. Side effect: Nystatin may cause side effects (TOPICAL USE).
Itching, irritation and burning.
Nystatin may cause side effects (SYSTEMIC USE).
Diarrhea, upset stomach and skin rash
3. azoles
Antifungal imidazoles for topical use include Clotrimazole and Meconazole, toxicity precludes their systemic use they are mainly used in: 1. Cutaneous lesions as tinea pedis 2. Vaginal candidiasis.
71
Pharmacology III
Antiviral drugs
Viruses present a more difficult problem of chemotherapy because: 1. virus replication depends primarily on metabolic processes of host cells and so drugs that inhibit viral replication also inhibit some host cell function and cause major toxicity 2. Substantial amount of viral multiplication often takes place before symptoms occur, so in order to be effective they have to be given before the onset of disease i.e. as chemoprophylaxis. 3. Viruses are capable of developing resistance to antiviral drugs.
Virus structure
72
Pharmacology III
Antiviral drugs
For respiratory virus infection
For hepatic viral infection
For herpes and cytomegalovi rus infections
For HIV infection
Amantadine Rimantadine Oseltamivir Zanamivir Ribavirin
Interferon Lamivudine
Acyclovir Valacyclovir Famciclovir
Zidovudine Didanosine
Treatment of respiratory virus infection

Neuraminidase inhibitor: Oseltamivir, Zanamivir
73
Pharmacology III
Orthomyxovirus that cause infleunza contain the enzyme Viral neuraminidase can be selectively inhibited by the sialic acid
neuraminidase which is essential to the life cycle of the virus analogs (Oseltamivir, zanamivir). Pharmacokinetics: Oseltamivir ia an orally active prodrug that is rapidly hydrolysed by Zanamivir, on the other hand, is not active orally and either inhaled the liver to its active form or administered intranasally. Side effects: 1. 2. 3. The most common side effect of oseltamivir are GI discomfort and Zanamivir is not associated with gastrointestinal disturbance, Irritation of the respiratory tract does occur, however zanamivir nausea, which can be alleviated by taking the drug with food because it is administered directly to the airways should be avoided in individuals with severe reactive asthma or chronic obstructive respiratory disease, because bronchospasm. May occur with the risk of fatality.
Inhibitors of viral uncoating a. Drugs for influenza A virus infection Amantadine & rimantadine(PK-Merz)
Amantadine acts by interfering with the uncoating and release of viral genetic material into host cell. Side effect: 1. 2. They are dose related and are associated with CNS toxicity in Rimantadine cause fewer CNS reactions, because it does not the form of insomnia, difficulty in concentration, nervousness efficiently cross the BBB.
74
Pharmacology III
Note: Amantadine is used in Parkinsonism and this has been discussed before.
Drugs for respiratory syncytial virus (RSV) infection Ribavirin

Mechanism of action: Ribavirin is a synthetic quanosine analog. The phosphorylated form, ribavirin triphosphate, is the one that is
active in inhibiting viral RNA polymerase. Uses: 1. It is used in treating infants and young children with severe RSV infection (It is not indicated for use in adults). 2. It is also effective in chronic hepatitis C infection when used in combination with interferon 2b. Note: Ribavirin is given in aerosol form using a specific nebulizer. Ribavirin is contraindicated in pregnancy
Treatment of hepatic viral infection

1. Interferon Note: Interferon is not active orally, but it may be administrated intralesionally, S.C, or I.V. Mechanism of action: Interferon is a family of naturally occurring, inducible glycoproteins They are synthesized by recombinant DNA technology At least three types of interferon exist .
that interfere with the ability of viruses to infect cell.
75
Pharmacology III
It appears to involve the induction of host cell enzymes that inhibit
viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA. Uses:
Some approved indications for interferons

Interferon Chronic hepatitis B abd C Hairy-cell leukemia Interferon - Relapsing remitting multiple sclerosis Interferon - Chronic granulomatous disease
Side effect: 1. 2. 3. suppression. Drug interaction: 1. 2. Interferon interfere with hepatic drug metabolism, and toxic Interferon may also potentiate the myelosuppression caused accumulation of theophyllin have been reported by other bone marrow depressing agent such as zidovudine. Adverse effects include flu-like symptoms on injection, such Fatigue and mental depression are common. These symptoms subside with subsequent administration. The principle dose limiting toxicities are bone marrow as fever, chills, and GI disturbance.
2. Lamivudine
This cytosine analog is an inhibitor of both: 1. 2. Hepatitis B virus (HBV) DNA polymerase Human immunodeficiency virus (HIV) reverse transcriptase. It is approved for treatment of HIV in combination with AZT.
76
Pharmacology III
Treatment of herpes and cytomegalovirus infections

Acyclovir
Antiviral spectrum: Acyclovir has a great specificity against herpesviruses. Herpes simplex virus-1 (HSV-1), (HSV-2) and vericella zoster virus. Pharmacokinetics: Administration can be by an I.V, oral, or topical route. Fairly poor oral absorption (15-30%) Improved by design of suitable prodrugs as valacyclovir (50% oral absorption) and famciclovir. Adverse effect: Side effect depends on the route of adminstration: For topical application: local irritation may occur. For oral administration: diarrhea, naysea, and vomitting For I.V administration :local phlebitis and nephrotoxicity
Treatment of HIV infection

Zidovudine(AZT)
77
Pharmacology III
Zidovud ne
Thymidine Inhibition of virus DNA synthesis Antiviral spectrum: Presently the only clinical use of AZT is in the treatment of patients infected with HIV (human immunodeficiency virus).
Adverse effect: AZT is toxic to bone marrow for example, severe anemia and leucopenia occurs in patient receiving high doses. Uses: It is effective in decreasing the symptoms and prolonging the life of patients with AIDS in oral daily dose of 500 mg divided every 4 hours.
Zalcitabine
Zacitabine was the first cytosine analog developed however, due to sever toxicity; it was removed from the market.
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Pharmacology III
Cancer
Cancer is a disease of cells in which there is uncontrollable cell proliferation and differentiation with ability to invade surrounding tissue and to spread to distant sites. Cell life cycle:
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Pharmacology III
Both normal and malignant cells that are proliferating pass through four discrete phases.
Phase Gap 0
Abbreviation G0
Description A resting phase where the cell has left the cycle and has stopped dividing. Initial phase associated with synthesis of enzymes required for DNA synthesis. DNA replication occurs during this phase. Associated with specialized protein and RNA synthesis. Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells.
Gap 1
G1
Synthesis Gap 2
S G2
Mitosis
Classification of anticancer drugs: Cell cycle specific (CCS): Cytotoxic drugs that exert their action on cells traversing the cell cycle Antimetabolites Vinca alkaloid
80
Pharmacology III
They are more effective in hematologic malignancies and tumors in which large proportion of cells are proliferating. Cell cycle non specific (CCNS): They act on tumor cells whether they are cycling or resting in the G0 phase, although cycling or proliferating cells are more sensitive. Alkylating agents Cisplatin Antibiotics They are useful in both high proliferating as well as low proliferating (solid tumor) Alkylating agents These drugs are activated to highly reactive intermediates with subsequent binding of the alkyl groups irreversibly (through covalent bond) to the nitrogen atom in the position no 7 of the quanine residue of DNA, thus preventing replication or causing miscoding i.e. they alkylate DNA.
1.
Cyclophosphamide is the most commonly used Alkylating agent. 2. Mechlorethamine

Its ability to cause lymphocytopenia led to its use in lymphatic cancers
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Pharmacology III
Mechlorethamine is very unstable, and solutions must be hade up prior to administraton. It causes severe nausea and vomiting (diminished by pretreatment with ondansetron) Severe bone marrow depression limits extensive use
3. Nitrosoureas
(Carmustine and lomustine) Because of their ability to penetrate into the C.N.S, the nitrosoureas are primarily employed in the treatment of brain tumors. Antimetabolites (structral analogs) These drugs bear a structural similarity to a natuoccuring substrate with which they compete and are incorporated into DNA or RNA and thus disrupt cellular function. Most of them act during DNA synthesis i.e. S-phase specific.
82
Antimetabolites
Folate antagonist Methotrexate Dr..Heba Abdelhammed mechanism Methotrexate is structurally related to folic Fluorouracil is acid and act as an antagonist of the vitamin analogue of uracil of action: by inhibiting dihydrofolate reductase, the Uracil is enzyme that converts folic acid to its active essential for synthesis .coenzyme, tetrahydrofolic acid of DNA, thus block the Folate plays a central role in a variety of ultimate formation of .metabolic reactions .DNA Pyrimidie analogues 5-Fluorouracil
purine analogue 6-Mercaptopurine
Purines are involved in ribonucleotide synthesis. Mercaptopurine interferes at one or more metabolic sites involved in this process and thus blocks nucleic acid synthesis and stop cell multiplication.
Note: Note: Potential drug interaction Because of its severe toxicity between allopurinol and 6to the GI tract, 5-FU is given mercaptopurine IV. .
Side effect
Pharmacology III
1. Nausia, vomiting and diarrhea 2. Stomatitis, rash, alopecia and myelosuppression - These can be prevented or reversed by administration leucovorin. 3. Renal damage with high doses 4. Cirrhosis with long term use 1. In acute lymphoytic leukaemia in children. 2. In treatment of breast cancer and head, neck carcinomas 3. In severe psoriasis and rheumatoid arthritis.
1. Bone marrow depression: 2. Anorexia and nausa, stomatitis and diarrhea. 3. Alopecia and dermatitis. 5-flurouracil has little selectivity of action and is mainly used as palliative agent in cases of carcinoma of the colon, rectum, breast and ovaries.
1. Bone marrow depression. 2. Anorexia, nausea, vomiting and diarrhea.
Uses
1. In acute leukaemia, particularly lymphocytic leukaemia. 2. It is analogo Azathioprine used as an immunosuppressant
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Pharmacology III Natural products 1. Plant derivatives Vinca alkaloid Vincristine and vinblastine: They are cell specific agents
They block mitosis and poduce arrest of cells in metaphase (M phase). 2. Antibiotics The antitumor antibiotic owe their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA function. 1. Dactinomycin (actinomycin-D): is the first antibiotic to find therapeutic application in tumor chemotherapy. 2. Bleomycins: Tthis a name given to a group of glycopeptides with antitumor activity. its primarily employed in the treatment of testicular cancers in combination with vinblastine. pulmonary toxicity is the most serious adverse effect. 3. Enzymes L- Asparaginase Lymphoblastic leukemic cells have lost the gene for the synthesis of essential amino acid asparagines (essential for protein synthesis) and so die when the supply from extracellular fluid is reduced by L-asparaginase L-asparaginase catalyzes the hydrolysis of asparagines to aspartic acid and ammonia. Hormones and related drugs 1. Adrenal corticosteroids: 2. Estrogen and progestins: a. Estrogens as diethylstilbesterol may be used as palliative therapy in metastatic cancer prostate which is androgen dependent
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Pharmacology III
b. Progestins as hydroxyprogesterone is useful in the management of endometrial carcinoma previously treated by surgery and radiotherapy This because endometrial carcinoma results from prolonged unopposed overstimulation by estrogens. c. Tamoxifen (nolvadex): is an antiestrogen that acts as a competitive inhibitor of cytoplasmic estrogen receptors Tumors that contain estrogen receptors are more likely to respond to the drug than those without; it is thus useful in the palliative management of post menopausal cancer breast. Miscellaneous agent
Cisplatin
It has a mechanism of action analogous to Alkylating agents It is used to treat testicular, ovarian and bladder cancer.
The main toxic effects: 1. Nausea. 2. Vomiting. 3. Nephrotoxicity. 4. Myelosuppression. 5. Ototoxicity.
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Pharmacology III 6. Peripheral neuropathy. The immune system
The immune system protects the body from potentially harmful Antigens are molecules (usually proteins) on the surface of cells, Nonliving substances such as toxins, chemicals, drugs, and The immune system recognizes and destroys substances that
substances by recognizing and responding to antigens. viruses, fungi, or bacteria. foreign particles (such as a splinter) can be antigens. contain these antigens. Innate immunity born with. It protects you against all antigens. Innate immunity involves barriers that keep harmful materials from These barriers form the first line of defense in the immune Innate, or nonspecific, immunity is a defense system that you are
entering your body. response. Examples of anatomical innate immunity include:

Cough reflex Enzymes in tears and skin oils Mucus, which traps bacteria and small particles Skin Stomach acid
Acquired immunity
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Pharmacology III
Acquired immunity is immunity that develops with exposure to Your immune system builds a defense that is specific to that
various antigens. antigen.
Passive immunity Passive immunity involves antibodies that are produced in a body Infants have passive immunity because they are born with These antibodies disappear between 6 and 12 months of age. Passive immunization involves injection of antiserum, which It provides immediate protection against an antigen, but does not Gamma globulin (given for hepatitis exposure) and tetanus
other than your own. antibodies that are transferred through the placenta from the mother.
contains antibodies that are formed by another person or animal. provide long-lasting protection. antitoxin are examples of passive immunization Blood components The immune system includes certain types of white blood cells. It also includes chemicals and proteins in the blood, such as Some of these directly attack foreign substances in the body, and
antibodies, complement proteins, and interferon. others work together to help the immune system cells. Lymphocytes are white blood cells, which includes B cells and T cells.
B cells produce antibodies. Antibodies attach to a specific antigen and make it easier for the immune cells to destroy the antigen. 87
Pharmacology III
T cells attack antigens directly and help control of the immune response. They also release chemicals, known as interleukins, which control the entire immune response.
As lymphocytes develop, they normally learn to tell the difference between your own body tissues and substances that are not normally found in your body. Once B cells and T cells are formed, a few of those cells will multiply and provide "memory" for the immune system. This allows the immune system to respond faster and more efficiently the next time you are exposed to the same antigen, and in many cases will prevent you from getting sick. For example, an individual who has had chickenpox or has been immunized against chickenpox is immune from getting chickenpox again.
Vaccines and Toxoids

There are four main ways to develop vaccines:
Live attenuated vaccines: contain bacteria or viruses that have been altered (reducing virulence) so they can't cause disease. Example: MMR vaccine Killed vaccines: contain killed bacteria or inactivated viruses. Example: Inactivated influenza vaccine Toxoid vaccines: contain toxins (or poisons) produced by the germ that have been made harmless. Example: Diphtheria toxoid vaccine Component vaccines: contain parts of the whole bacteria or viruses. Example: Hepatitis B (Hep B) vaccine
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Pharmacology III
Immunosuppressant agent Immunosuppressant medications are a group of drugs that suppress or slow down the immune system. Immunosuppressant drugs are used to prevent the body from rejecting transplanted organs or tissues and to slow down the immune response in people with certain autoimmune disorders. They include: Cyclosporins: These drugs act by inhibiting T-cell activation, thus preventing Tcells from attacking the transplanted organ. Azathioprines (Imuran): These drugs disrupt the synthesis of DNA and RNA as well as the process of cell division. Corticosteroids as prednisolone: These drugs suppress the inflammation associated with transplant rejection. Cyclosporins Mechanism of action:
Act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ.
Uses 89
Pharmacology III
Prophylaxis and treatment of organ rejection in allogenic transplant of kidney, liver and heart.
Adverse effect:
Nephrotoxicity is the most and common and important adverse effect. Azathioprines
Mechanism of action: These drugs disrupt the synthesis of DNA and RNA as well as the process of cell division. It is the prodrug that is converted first to 6-mercaptopurine (6-MP) then to the corresponding nucleotide, thioinosinic acid The immunosuppressive effects of azathioprine are due to this nucleotide analog. Side effect: Bone marrow depression.
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Pharmacology III
VITAMIN
VITAMIN means vital for life Two main categories: Water soluble Vitamin Vitamin B Vitamin C Fat Soluble Vitamin Vitamin A Vitamin D Vitamin E Cannot be stored in body - regular supply needed Excess is excreted in urine - no danger of toxic levels Unstable to heat and light, leach into cooking liquids Vitamin K Can be stored in body - regular supply not needed Can accumulate to toxic levels if large amounts ingested Fairly stable at normal cooking temperatures
Water soluble vitamins
Vitamin B complex:
Are eight water-soluble vitamins that play important roles in cell metabolism. List of vitamin B complex:

Vitamin B1 (thiamine) Vitamin B2 (riboflavin)
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Pharmacology III

Vitamin B3 (niacin, includes nicotinic acid and nicotinamide) Vitamin B5 (pantothenic acid) Vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) Vitamin B7 (biotin). Vitamin B9 (folic acid). Vitamin B12 (various cobalamins. Vitamin B1 (Thiamine)
Functions Essential for release of energy from carbohydrates Necessary for appetite and good health Needed for normal functioning of nervous system
Deficiency: Beriberi disease (thiamine deficiency) Characterized by : Early symptoms of beriberi are
nonspecific and include fatigue, irritability, restlessness, loss of appetite, and vague abdominal discomfort. As the disease progresses, patients
develop burning sensations, tingling in the extremities, and changes in sensation such as numbness.
Therapeutic uses: It is used in cases of vitamin B1 deficiency and in peripheral neuritis due to chronic alcoholism or pregnancy. Vitamin B2 (Riboflavin)
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Pharmacology III Functions Metabolism of carbohydrates, proteins and fats
Growth, repair, development of body tissues - healthy skin, eyes and tongue The principal growth promoting factor in the vitamin B complex
Deficiency Ariboflavinosis: characterized by angular stomatitis, cheilosis, corneal vascularisation, anaemia and seborrhoeic dermatitis. Therapeutic uses: In cases of ariboflavinosis
Vitamin B3 Niacin (Nicotinic acid) Functions Metabolism of carbohydrates, proteins and fats Needed for normal functioning of nervous system
Deficiency Deficiency leads to pellagra which is characterized by dermatitis, diarrhea and dementia. Therapeutic uses: It is used in treatment of pellagra. It is used in treatment of some hyperlipidaemias. (Nicotinic acid lowers circulating concentrations of low-density-lipoprotein, cholesterol and triglycerides, plasma fibrinogen, and lipoprotein (a). Vitamin B6 (Pyridoxine) Functions
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Pharmacology III Protein metabolism
Involved in formation of haemoglobin, hormones and structural proteins Healthy development of nervous system
Deficiency Tiredness and Fatigue, irritability Premenstrual tension Infants may suffer convulsions if there is deficiency
Therapeutic uses: Pyridoxine is used in cases of dietary deficiency of the vitamin. It is used as an anti-emetic in treating vomiting of pregnancy. It is also used in premenstrual tension. It is used to prevent peripheral neuritis in patient treated with isoniazid.
Vitamin B9 (Folic Acid) Functions Red blood cell formation Essential for synthesis of DNA and RNA Development of brain, spinal cord and skeleton in foetus Reduces risk of neural tube defects e.g. spina bifida May play role preventing heart attacks, strokes and cancer Important to take folic acid prior to conception and vital during first 3 months pregnancy
Deficiency Fatigue in mild cases Anaemia in severe cases Neural tube defects
Therapeutic uses: Treatment of folic acid deficiency states which may be due to 1. Inadequate dietary intake (nutritional megaloblastic anaemia).
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Pharmacology III
2. Conditions requiring increased intake e.g. in cases of pregnancy "megaloblastic anaemia of pregnancy". 3. Defective absorption in malabsorption syndrome. 4. As an adjuvant to anticonvulsant therapy. 5. Treatment of Pernicious anemia together with vit.B12.
Vitamin B12 (Cyano) Cobalamin Functions Red blood cell formation Nervous system - maintains myelin sheath around nerves
Deficiency Pernicious anaemia Nerve degeneration No B12 in plant foods Vegans so vegetarians risk of deficiency
Therapeutic uses: Pernicious anaemia
Vitamin C -Ascorbic Acid Functions Vitamin C is required for the synthesis of collagen, an important structural component of blood vessels, tendons, ligaments, and bone SO Promotes healing of wounds and healthy blood vessels Critical to immune system (vitamin C has been shown to stimulate both the production and function of leukocytes (white blood cells)). Helps absorption of iron Prevents scurvy Acts as antioxidant, protects HDL cholesterol
Deficiency
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Pharmacology III
Vitamin C deficiency leads to scurvy, a condition characterized by the following symptoms: Bleeding and bruising easily, hair and tooth loss, and joint pain and swelling.
Bleeding under the nails Therapeutic uses: 1. Prophylaxis and treatment of scurvy. 2. Methaemogloinaemia, as a reducing agent. 3. Urinary acidification. 4. Large doses of vitamin C have been claimed to be effective in preventing common cold, hypercholesterolemia, and cataract (decreased vitamin C levels in the lens of the eye have been associated with increased severity of cataracts in humans).
Major food sources of water-soluble vitamins Grain Fruit Vegetable s s s Thiamin Riboflavin Niacin Pyridoxine Folate Vitamin B12 Vitamin C Meats, Eggs Legumes, Nuts, Seeds Milk, Dairy
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Pharmacology III
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Fat soluble Vitamin facts Pharmacology III Vitamin Sources A (retinol) Vitamin A: liver, vitamin \ (pro A fortified milk and vitamin A, dairy products, butter, such as beta carotene) whole milk, cheese, egg yolk. Pro-vitamin A: carrots, leafy green vegetables, sweet potatoes, pumpkins, winter squash, apricots, cantaloupe. Note: Vitamin A daily dose for: Correction of deficiency is 30,000 50,000 IU Therapy from 100,000 - 200,000 IU / daily D Vitamin D-fortified dairy margarine, fish oils, egg yolk. Synthesized by sunlight action on skin. Physiological Functions 1. Helps to form skin and mucous membranes and keep them healthy, thus increasing resistance to infections. 2. Essential for night vision. 3. Beta carotene is an antioxidant and may protect against cancer. Dr..Heba Abdelhammed Deficiency 1. Hyperkeratosis. 2. Night blindness. 3. Xerophthalmia. 4. Bitot spots. 5. Keratomalacia. 6. The incidence of respiratory infections may be increased. So can be used in: 1. Vitamin A Dermatological deficiency disease. 2. disease: Vitamin A may be helpful in certain disease of the skin such as acne and psoriasis. 3. Conditions of impaired vitamin A absorption e.g. steatorrhoea 1. Increases the absorption of calcium. 2. Promotes hardening of bones and teeth. Vitamin D is also known as the "sunshine vitamin," since it is manufactured by the body after being exposed to sunshine. E Wheat germ oil, green and leafy 2. vegetables, egg and meat. Antioxidant Protects vitamins A and C and fatty acids; prevents damage to cell membranes. 98 Vitamin E may affect the followings: 1. Reproductive system: early evidence indicated that vitamin E is essential for normal reproduction in several mammalian species. Severe: Rickets in children. Osteomalacia in adults (Calcitriol) products, fortified
Pharmacology III
Psoriasis
Psoriasis is a chronic, non-contagious autoimmune disease which affects the skin and joints It commonly causes red skin with silvery scales
Topical agents:
Medications applied directly to the skin are the first course of treatment options. The main topical agents are: 1. Corticosteroids 2. Calcipotriene (vitamin D-3 derivatives) 3. Coal tar
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Pharmacology III 4. Anthralin 5. Tazarotene (topical retinoid)
There isn't one topical drug that is best for all people with psoriasis. Because each drug has specific adverse effects or loses potency over time, it is common to rotate them. Sometimes topical preparations are combined together. For example, keratolytics (substances used to break down scales or excess skin cells) are often added to these preparations. Some preparations should never be mixed together because they interfere with each other. For example, salicylic acid inactivates calcipotriene cream or ointment (a form of vitamin D-3).
On the other hand, drugs such as anthralin (tree bark extract) may require addition of salicylic acid to work effectively.
Systemic agents: Cytotoxic agents include: 1. 2. 3. Methotrexate Acitretin Cyclosporin
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Pharmacology III L

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The Saudi German Institute for Nursing& Allied Health Sciences Division of Academic Affairs Department of Pharmacy

Ruptured blood cells release free parasites (gametocytes) into the

Comparison between blood schizonticidal drugs

Efficacy Onset of action

++ Slow Only for uncomplicated, resistant P. falciparum +++ Allergy to sulpha

Only for resistant P. falciparum

Toxicity Contra indications

Pharmacology III Amebiasis is:

There are two forms of amoebiasis infections: 1. Intestinal amoebiasis

Pharmacology III They include: Emetin dehydroemetine chloroquine(liver only)

Pharmacology III Mechanism of action:

Clinical 1. Amoebiasis (with luminal amebicide) 2. Giardiasis (giardia intestinalis)

Pharmacology III Mechanism of action

Pharmacology III 1. Trypanosome brucei

countries of western and central Africa

TrypanosomiasisTreatment; 1. Melarsoprol 2. pentamidine

Limited to the treatment of typanosomal infections

It is not effective against T. cruzi

Serious renal dysfunction may occur.

Giardiasis is generally treated with metronidazole or

There are two common therapies; The first line compounds:

Pharmacology III Round worm treatment:

Mechanism of action Contraindication

Gastrointestinal disturbance, headache, dizziness and drowsiness.

1. Intestinal Blood Flukes.

transmission: human contact with stool/urine contaminated freshwater

Pharmacology III Drug Interactions: Praziquantel Chloroquine

Plasma-praziquantel concentration possibly reduced

Dexamethasone Plasma-praziquantel concentration reduced Phenytoin Carbamazepine

Chemotherapy of microbial disease

Types of antibiotic agents

May inhibit bone marrow production (aplastic anemia)

increasing resistance noted

Amphotericin B Fungi Drugs that target AFB

Antimicrobial Drug Resistance

Pharmacology III Genetic basis of resistance: 1. Intrinsic resistance:

Pharmacology III Bacteria multiply by the billions.

Selection of antimicrobial agent

Peptidoglycan Cytoplasmic Membrane

Selection of antimicrobial combination therapy

Misuse of antimicrobial dugs

Pharmacology III 4. Penicillin can cause allergic reactions.

Agents affecting cell wall synthesis(antibacterial)

The effect of bacterial beta lactamases:

Mechanism of action of -lactamase enzymes

Pharmacology III Haemophilus influenzae. Gram positive

lactamases, penicilloic acid is produced.

Cefadroxil Cafazolin Cephalexin Cephradine

Cefaclor Cafprozil Cefuroxime Na Cefuroxime axetil Cefoxitin

Cefdinir Cefixime Cefotaxime Ceftazidine Ceftriaxone

Drugs that target protein synthesis 1. Amionglycosides

intestine and almost all has to be injected.

respiratory tract, sinuses, middle ear, urinary tract and skin.

Pharmacology III 3. Effects on calcified tissues:

Impaired the absorption of tetracyclines

CLARITHROMYCIN & AZITHROMYCIN Both are well absorbed from GIT.

situations, that is in high concentrations against very susceptible organisms.

Pharmacology III Side effects:

Drugs acting by inhibiting DNA synthesis Quinolone

Pharmacology III Ciprofloxacin Ofloxacin Norfloxacin

Dr..Heba Abdelhammed Levofloxacin Moxifloxacin

Drugs that inhibit Metabolic Processes Sulphonamides and Trimethoprim