Tuesday, October 31, 2000 Scribes: Chu-Kang production

Pharmacology 9am

Dr. Lombardini

Drug Therapy of Anemias(continued) & Fundamentals of Chemotherapy

  1. Vitamin B12 and folate in DNA synthesis
  1. Pathway (Diagram on top of P.9 in anemia notes)
  2. Additional explanations
  1. Serine acts as a methyl source for THFA
  2. Serine + THFA = Glycine
  3. Vit. B12 & folate deficiencies are called megaloblastic anemia

Cholin, betaine Myelin

S-Adenosyl Methionine (SAM)

HomocysteineMethionineProtein Synthesis

Vit B12 Deficiency (methyl-cobalamine(B12))

5-methyl tetrahydrofolic acid + Cobalamine (B12)Methyl-Cobalamine(B12) +

(5-methyl THFA)

Folic Acid DeficiencyGlycine

(Requires 5-methyl THFA)

DeoxyuridylateThymidylateDNA

(Uridine)(Thymidine)

  1. Folate Deficiency
  1. Uridine doesn’t go to thymidine, therefore, no DNA
  2. 5-methyl THFA is trapped in the liver
  3. Misdiagnosis:Instead of folate, give vit. B12 as treatment

a) Liver has stored 5-methyl THFA and form Methyl-cobalamine with the added vit. B12  form thymidine  form DNA  NO Anemia, but eventually, 5-methyl THFA will be depleted and folate deficiency symptoms will resurface. In other words, it’s a temporary improvement because the anemia will return

b)No nerve damage

  1. B12 Deficiency
  1. Misdiagnosis: Instead of vit. B12, give folate as treatment

a)With no vit. B12, can’t form methyl-cobalamine (B12) & in turn, uridine doesn’t go to thymidine, therefore, no DNA

b)With THFA & added folate, Uridine will be converted to thymidine, therefore, DNA synthesis. Hence, vit B12 deficiency is masked temporarily

c)However, other metabolic pathways that require vit. B12 suffer. For instance, homocystein requires methyl B12 for conversion to methionine which ultimately leads to myelin formation. If vit. B12 is lacking, you can’t make myelin, hence, nerve damage

d)Also, methyl malonyl CoA requires B12 & can’t convert to Succinyl CoA leading to abnormal fatty acids

e)Key point: Without B12, you have a faulty myelin production & nerve damage

  1. Vit. B12 therapy (Graph at bottom of P. 3 in supplement)
  1. White 54 yr. old 78 kg male with pernicious anemia. Initially, patient has low everything. Hematocrit @10-11, hemoglobin 4-5 (nl 15), etc. After given 1 unit of packed RBC, there is a slight increase in hematocrit to 18 (nl 45 for male) & hemoglobin. After cyanocobalamin (1g daily, i.m.), hematocrit & hemoglobin increase.
  2. Cyanocobalamin: Cyanide derivative of vit B12; not toxic (low cyanide concentration).
  3. Treatment of pernicious anemia (Chart on top of P.10 in anemia notes): Give daily i.m. dosage of vit. B12 for 1st week; 2nd week: every other day; 3rd-6th week: weekly; maintenance therapy: give monthly. Thus, lifetime treatment. Oral treatment with large quantity of vit. B12 does work (still require intrinsic factor for absorption), but is not the preferred way.
  1. Folate therapy
  1. Folic acid (Folvite) given orally or injection.
  2. Vit. C is an antioxidant & a reducing agent that can protect the folic acid. Hematocrit & hemoglobin levels return to normal with a burst of reticulocyte activity when given both folic acid & vit. C.
  1. History of patient is important in determining whether megaloblastic anemia is a vit B12 or folic acid deficiency
  1. There are tests which detect folate or B12 deficiency. Shilling test for B12: measures radioactive B12 absorption & vit. B12 excretion in urine, therefore, quantitate the amount of vit. B12 in blood.
  2. Conditions that result in either vit. B12 or folic acid deficiency

a)Malnutrition

b)Alcoholic

c)Increased requirements in pregnancy

  1. Conditions that result in a Vit. B12 deficiency

a)Vegetarians

b)Impaired absorption: lacking intrinsic factor, stomach problems (gastrectomy), gastric disease, small bowel resection, no ileum or damaged ileum

c)Tapeworm: Scandinavian & Japanese people because they eat lots of raw fish

d)Functional damage: Inflammatory bowel disease, etc.

  1. Conditions that result in a folic acid deficiency

a)No vegetables in diet

b)Folic acid antagonists: Methotrexate

c)Anticonvulsant drugs: barbiturates, nitrofurantom (prevent conversion of polyglutamate to monoglutamate)

d)Vitamin C deficiency (ascorbic acid): Required to keep folic acid in its reduced form which is the active form

e)Malignant tumors that require folic acid will deplete folic acid in normal body tissues

f)Hyperthyroidism

g)On dialysis

h)Chronic skin disease

  1. Different types of anemia (Two charts on P. 11 of anemia notes): Ex. Hemolytic: spherocytic, sickle cell (all hereditary); acquired, immune, non-immune anemia (take away the drug causing the problem). Don’t memorize. Just know that there are hemolytic anemias related to both immune & non-immune system types.
  1. (Chart on bottom of P.11 of anemia notes) Drugs that have oxidant properties can cause hemolytic anemias especially in glucose-6-phosphate dehydrogenase deficient individuals.

a)Glucose-6-phosphate dehydrogenase converts glucose-6-phosphate + NAD to 6-phosphate gulconate + NADH

b)Oxidized glutathione uses NADH to convert to the reduced form. If there are no NADH, there aren’t any reduced glutathione leading to hemolysis, therefore, anemia. Lots of people are borderline in glucose-6-phosphate dehydrogenase deficiency & are fine until one of the drugs with oxidant properties are given.

Fundamentals of Chemotherapy

  1. Introduction
  1. Drugs we have learned so far target the patient.
  1. Chemotherapeutic drugs target parasites defined as bacteria, fungus, virus, cancer, true parasites: nematodes, amoebas, cestodes, flukes, etc.
  1. Ideal chemotherapeutic drug has no effect on the patient and has maximal or all of the effect on the parasite.
  2. Physician needs to evaluate the toxicity to the host (patient): can have wide spectrum.

a)Amphotericin B has a high toxicity to patient (liver & renal toxicity)

b)Penicillin has little toxicity to patient

  1. Evaluate the toxicity to the parasite
  1. Overview of chemotherapeutic agents
  1. Anti-septic

a)70% alcohol is better than 100% alcohol as an anti-septic because water added enhances the action of the alcohol as an anti-septic.

  1. Inhibition to synthesis of folic acid (Note: Don’t memorize history)

a)Folic acid is necessary for life. If you make folic acid, then you can have antifolic’s that interfere with it or if you don’t make folic acid, then it needs to be taken in as a vitamin.

  1. Overview of antibiotics & their location of action

Site of action / Antibiotics
Cell wall synthesis / Cycloserine, vancomycin, bacitracin, penicillins, cephalosporins
DNA replication (DNA gyrase) / Nalidixic acid, quinolones
DNA dependent RNA polymerase / Rifampin
Folic acid metabolism / Trimethoprim, sulfonamides
Periplasmic space / -lactamase, aminoglycoside modifying enzyme
Cell membrane / Polymixins
Protein synthesis (30s inhibition) / Tetracycline, spectinomycin, streptomycin, gentamicin, tobramycin, amikacin
Protein synthesis (50s inhibition) / Erythromycin, chloramphenicol, clindamycin

II. Historical development of antimicrobial agents

  1. Paul Ehrlich (1854-1915): The “Father of Modern Chemotherapy”; came up with important concepts
  1. Standardized infection: Gave standardized doses. Hence, all the doses given were equal in concentration.
  2. Dosage schedules
  3. Therapeutic Index: TD50/ED50

Ex. 25/5 = 50/10 because the ratio are the same. 50/5 is a better drug.

  1. Chemical variants: Structure activity relationships
  2. Resistance: Need to give antibiotic in maximally tolerated dose to patient to prevent resistance

a)“-cidal” as in bactericidal, give in one large dose; ideal drug

b)“-static” as in bacteriostatic, give in little doses over length of time; stops organism from growing

  1. Hypersensitivity
  2. Prodrugs: Some drugs have to be metabolized in the liver usually by host (at times by the organism).
  3. Transport of drugs: Across membranes
  4. If resistant & hypersensitive to one drug, then the person is resistant & hypersensitive to the same family of drugs. Ex. If resistant or hypersensitive to tetracycline, then resistant & hypersensitive to chlortetracycline & oxytetracycline
  5. Early drugs were compounds that contained heavy metals such as arsenic

a)Ex. Atoxyl, p-aminophenylarsenoxide, mapharsen, salvarsan

b)Salvarsan was the 1st drug used to treat syphilis until the penicillin. Before salvarsan, malaria was used to treat syphilis, because syphilis can’t grow in 40C caused by malaria.

  1. Later drugs did not contain heavy metals & were less toxic to the patients

a)Suramin: Used for Trypanosomiasis

b)Mepacrine: Used for malaria

  1. Selective toxicity: Drugs have specific targets in body. Multiple toxic effects may occur & different toxic effects occur in different population of people. Natural body defenses kill the last remaining organism.
  1. Bactericidal & bacteriostatic drugs
  1. First, turbidity was used (cell lysis) to determine whether the drug was bacteriostatic or bactericidal (Refer to top of P.1 of supplement-Fundamentals of Chemotherapy)

a)Sulfonamide shown to be bacteriostatic

b)Penicillin shown to be bactericidal

c)Chloramphenicol & Streptomycin both shown to be bacteriostatic

  1. Bactericidal & bacteriostatic drug determination using viability (More accurate)

a)Penicillin still bactericidal

b)Streptomycin now shown to be bactericidal, but not seen when measuring turbidity because it does not lyse the organism

c)Chloramphenicol & sulfonamides still shown to be bacteriostatic

  1. Antibacterial drug combinations
  1. Additive effect (2+2=4) (Bottom left on P.1 of supplement)

a)No change in chemotherapeutic effect because drugs are working on the same target.

b)Like using twice as much drug A or B, but toxicity maybe a problem in this case.

c)Also called indifferent effect

d)Not gaining much

  1. Synergistic effect (2+2=6) (Bottom middle on P.1 of supplement)

a)Most desirable

b)Drugs act in two different places in the microbial pathway

ABCDF

c)Ex. Sulfa drug & anti-folate

  1. Antagonist effect (2+2=3) (Bottom right on P.1 of supplement)

a)Not desirable

b)Two drugs that are effective alone interfere with each other when given together

c)Ex. Clindamycin & Erythromycin: Drugs work close enough on the ribosome that they interfere with each other’s action

  1. Fixed dosage combinations
  1. In general, do not want to give two separate drugs in a same form as in tablet because that takes away the physician’s control to alter the doses. A & B is better than A+B
  2. However, some are effective such as trade names Bactrim & Septra (combination sulfa drugs & anti-folate used for UTI, prostatitis, ear infection, etc.)
  1. Reasons for administering more than one drug
  1. For synergism
  2. To delay resistance: Especially important in tuberculosis (Ex. Give 4 different drugs)
  3. Mixed infections: Ex. Bacterial & fungal diseases
  4. Life threatening situations: When the organism is unknown
  1. Advantages of combination drugs
  1. Synergism: Use less drug, decrease in cost (not likely), decreased toxicity

(Refer to top of P.2 on supplement: Dr. Lombardini read off values; read C antibacterial drug combination 1,2,3 above for definitions)

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