Anti Infective Agents / Cancer Chemotherapy

I. Chemotherapy- treatment of disease by chemical agents that produce a toxic effect on the disease causing organism without harm to host

Chemotherapy- exists for many human parasites ranging from the 20 nm polio virus to the 10 m tapeworm taenia saginata

Parasite Greek- one who dines at the table of the rich and tries to earn welcome by flattery

Most parasites are microbes- microscopic in size

- rely on differences between invading and host cells

- the greater the difference the greater the success

- the difference can be biochemical or physiological - selective toxicity.

Invading Pathologic organisms

Anti-microbial agents - agents that kill these microorganisms or inhibit growth: viruses, bacteria, fungi, protozoa, etc.

Special names:

antiviral, antibacterial, antifungal - ringworm, athletes foot, antiprotozoal- maleria, amoebas, anthelmintic- worms

also Cancer Chemotherapy

A. History-

1. Prior to 1900s bacterial infections could not be treated systemically only topically using antiseptics and disinfectants (First Antiseptic - Lister-surgeon - in hospitals gangrene killed 40% of patients in 1865 - sprayed area with carbolic acid to kill germs - confirmed Pasteur's germ theory of microbes)

2. Paul Ehrlich (1900) coined term receptor -- for antigen-antibody- high degree of specificity found antiparasitic effect of some agents- but not closely related agents. Ehrlich received Nobel Prize in 1908 -- he started chemotherapy - made 605 useless synthetic drugs - than Salvarsan -- magic bullet against syphilis (bacteria)

3. In 1935- German (Domayk-Nobel Prize 1939) found that red azo dye Prontosil protected and cured mice infected with streptococcal infection

In test tube the drug was ineffective

Found that body metabolizes Prontosil to sulfanilamide (from family sulfonamides)

These works and other work on Penicillin (see below) revived interest in anti-microbial agents and antibiotics (which are compounds produced by some micoorganisms that inhibit other microorganisms).

A. Anti-microbial Agents

1) Interactions between Drug and Parasite - Initially discussing Bacteria - ie. antibacterial

A) Spectrum of activity

1. narrow- agents that affect a limited number of microorganisms- isoniazid, erythromycin, penicillin (sort of)

2. broad- inhibit a wide variety of organisms - tetracyclin, streptomycin, chorlamphenicol, fluoroquinolones

3. extended-some Penicillins -ampicillin-kills gram negative and positive bacteria

B) Types of activity

Bacteriostatic - inhibit multiplication and growth of microorganism, therefore, body's defense destroys the disease

ie. WBC's, antibodies - from B-cells -- some examples

1. Sulfonamides- (family) specific example - sulfanilamide (150 others)

2. Tetracyclines

3. Chloramphenicol (first synthetic antibiotic)

       

Bactericidal- drug inhibits growth and kills parasite

 

4. Penicillin

5. Streptomysin and gentamicin (family of aminoglycosides)

6. Cephalosporins

7. Isoniazid (specific for tuberculosis)

8. Macrolides - at high concentations - also bacteriostatic (erythromycin is the prototype - also Azithromycin)

9. fluoroquinolones (new group - used for lower respiratory diseases and sexually transmitted diseases)

also need host defense to eradicate disease

B. Mechanisms of action

3 Major mechanisms of action

1. Inhibition of bacterial cell wall synthesis - b Lactam Drugs (the structure of these drugs contains a b Lactam 

- remember- cell wall is different from cell membrane (only in prokaryotes - no nucleus)

They contain mucopeptides (mucous secretions) and peptidoglycans (peptides + sugars) not present in mammalian cells

----Penicillins (oral, IV IM) and cephalosporins (IV) - bind with specific receptors and inhibit cell wall synthesis--kills cell by inhibiting transpeptidation enzymes (for example - inhibits cross-linking of proteins)

2. Inhibition of protein synthesis

----aminoglycosides like streptomycin (parenteral) - blocks initiation complex of synthesis by binding to 30s ribosomal subunit

----tetracycline (oral) - blocks attachment of tRNA to 30s subunit

(prokaryotes 50s-30s subunits 70s rib.)

(eukaryote 40s -60s subunit 80s rib.)

----chloramphenicol (IV, oral) and macrolides (erythromycin - oral) - block 50s subunit (prevents binding of new amino acids by inhibiting peptidyl transferase)

3. Inhibition of nucleic acid synthesis

----sulfonamides (enteral) - bacteria uses PABA to make folic acid (can not get from diet) human get folic acid only from diet - drug competes with PABA for the enzyme dihydropteroate synthetase which produces folic acid - therefore no folic acid, no purines, no DNA)

----isoniazid (oral) -inhibits myolic acid production-this inhibits the myobacterial cell wall - TB

---fluoroquinolones - block DNA replication - selective for bacterial enzymes

----rifampin (oral) - blocks RNA polymerase- used to prevent TB, tuberculosis

2) Penicillin-many different types -  (can't discuss all drugs but a bit about penicillin)

1929 Fleming by mistake found that colonies of staphylococci contaminated with Penicillin mold (Penicillium notatum - Camembert and Roquefort cheese)

mold- kills bacteria

Flory in 1940 isolated penicillin (Fleming, Florey and Chain - Nobel Prize - 1945)

and in 1949 mass produced penicillin G. 

Limitations:

-susceptible to b-lactamase (bacteria can produce this) (penicillinase)

use Nafcillin - one of many semi-synthetic penicillins

-and inactive against gram-negative bacteria.

use Ampicillin or Amoxicillin

A. Pharmacokinetics

-parenteral- absorption is quick and complete

-enteral (oral) absorption differs for different penicillin - must minimize binding to food, thus, no food for 1 hour

even then not all absorbed - gastric acid inactivates Pen. G

therefore take Pen. V (this is the letter V) or Ampicillin (orally)

-absorbed penicillin is rapidly excreted by kidneys

10% -glomerular filtration

90% -tubular secretion- in proximal tubule

t _(1/2) penicillin G - 1/2 -1 hour

if renal failure - 10 hours

Clinical uses - most widely effective and used antibiotics - see textbook

3) Tetracyclines - includes doxycycline and tetracycline

a. good GI absorption

b. prolonged blood levels

c. prototype broad spectrum drug - see text for clinical uses

cholera - gram neg bacteria

chlamydia

rickettsiae

bronchitis

skin infection, ie. acne

d. forms complexes with Ca⁺⁺ ie.teeth and bones - discoloraton of teeth, should not take with food, also sensitive to sunlight or ultraviolet light

Summary of  major categories

Sulfonamides

Tetracyclines

Chloramphenecol

Penicillins

Aminoglycans-streptomycin

Cephalosporins

Macrolides - erythromycin and azithromyocin

Fluoroquinolones

Immunoglobulins (IgA) - bind to bacteria - trigger immune response - increased by "having sex once or twice a week" - but too much causes levels to decrease

C. Antifungal agents

most fungi are resistant to the action of anti-bacterial drugs

-need new and better drugs- especially since spread of fungal infections in immunosuppressed patients - AIDS -

(secondary infections 5-Fungi diseases i.e. candidiaris, 3-Bacterial, 4-Viral, 4-Protozoal, 4- Cancers i.e. Kaposes Sarcoma)

1. Superficial infections

tinea (ringworm) infections of skin, hair

a. Undecylenic acid (Desenex)- athletes' foot - tinea pedis - topical

b. Tolnaftate (Tinactin) - (Aftate) topical -(similar drug is Naftin-contains naftifine)

c. Azoles

clotrimazole (lotrimin) -a lot of TV advertisement - topical

miconazole (monostat)

d. Griseofulvin- oral - drug has affinity for diseased skin and is deposited - bound to keratin, therefore, keratin resistant to fungus - good for treating toe nails - some kidney problems

e. Itraconazole (sporanox) - 3 months or oral treatment to remove toenail fungus -little kidney problems

The above drugs all block biosynthesis of fungal lipids

2. Deep infections - infections of the mucous membrane - GI tract - visceral organs

-drugs are fungistatic and fungicidal

-bind to sterols which are plentiful in membranes of fungi and yeast (class of steroid - ie. cholesterol).

-drug forms channels in membranes, therefore, small molecules leak out

a. Amphotercin B - antibiotic

-Poorly absorbed, therefore, IV

oral -if fungus in oral tract

-little makes it into CSF, therefore, need intrathecal administration if fungal meningitis

b. Ketoconazole and fluconazole - imadazole (oral)

c. many others - usch as Nystatin

• -antibiotic similar to amphotercin B in mechanism of action - not absorbed but has local effect in bowl lumen

D. Antiviral

viruses are intracellular parasites - require active participation of host to survive

1. Amantadine (oral)

prevents viral uncoating - the drugs acts as a base which prevents formation of acid needed to release virus from endosome

- prohibits release of virus into host, therefore, no replication this is due to prevention of endosomes containing the virus from being released into the cytoplasm -- the endosomes that carry virus get into cell but virus can not get out of endosome because virus envelope does not fuse with endosome

- inhibits replication of influenza A (not B) rubella and some tumor viruses

- orally administered - not metabolized - excreted via kidney

2. Acyclovir  (oral, IV, topical) also Valacyclovir (converted to Acyclovir)

blocks DNA polymerase - inhibits nucleic acid synthesis in viral infected cells, uninfected cells do not have enzymes to activate acyclovir

- used to treat herpes virus

3. Vidarabine (IV) - similar to Acyclovir

similar to acyclovir, inhibits viral DNA polymerase much more effectively than mammalian DNA polymerase, therefore prevents replication of the virus

-used for herpes - IV or ointment.

4. Ribavirin (oral, IV, aerosol)

inhibits viral coded RNA polymerase - inhibits replication of both RNA and DNA viruses, blocks nucleic acid synthesis and synthesis of viral mRNA (blocks guanosine monophosphate formation)

- broad spectrum - used for influenza A and B, respiratory infections - Aerosol, hemorrhagic fever (Ebola) etc

5. Zidovudine or Azidothymidine (AZT) - Product name Retrovir (oral)

inhibits retrovirus HIV by inhibiting HIV reverse transcriptase - can not make viral DNA -- HIV reverse transcriptase is 20-30 times more susceptible than mammalian DNA polymerase

- orally, t_1/2 = 1 hour, treatment for AIDS, ARC and asymptomatic patients (slows progress ???) - increases the number T4 lymphocytes-virus mutates

new drugs combined with AZT - Didanosine (Vidix - ddI) - Zalcitabine (Hivid - ddC)

also new Lamivudine (Epivir) (another inhibitor of retrovirus) - for Hepatitis B

6. Protease Inhibitors - Ritonavir, Indinavir, Saquinavir - HIV proteases produce viral enzymes and core proteins needed for HIV to make copies - these inhibitors block production of viral enzymes and core proteins - thus stop spread of virus

7. Oseltamivir (Tamiflu) - influenza virus - oral - recover 1.3 days faster - neuriminidase inhibitor

8. Plconaril (new January 2000) - may work on 169 different viruses - rhinovirus, enteroviruses, etc - binds to virus and alters ability of virus to enter cells

9. Interferons (IM) - naturally occurring glycoproteins produced by:

leukocytes - IFN-a

fibroblasts - IFN-b

lymphocytes - IFN-g

stimulated during inflammatory process

They induce antiviral state - the first infected cells produce IFN which signal other cells to produce antiviral agents

- IFN binds to specific receptors on surface of cells (near and far to infected cell)

- block viral replication by causing host to produce enzymes that are inactive until invaded

-protein kinase- inhibits peptide elongation; RNase-degrades viral mRNA; phosphodiesterase-degrades viral tRNA

- IFN increase effect of macrophages against intracellular pathogens

Produce drugs - milligrams in fibroblast cultures and pooled leukocytes

also recombinant DNA technology with bacteria acting as producing cells - get grams

Used to treat hepatitis, maybe cancer (Hairy Cell Leukemia) and AIDS related Kaposi’s sarcoma - several excellent papers on this

The combination of Interferon and certain antiviral drugs (Ribavirin) is very beneficial in the treatment of Hepatitis C - called Rebetron

E. Antiseptics and Disinfectants

1. Antiseptic- substances that when applied to living tissue kills microorganisms

2. Disinfectant - kills microorganisms in inanimate environment - air, rugs

3. Germicides- cover both antiseptics and disinfectants

This was the only way to kill microorganisms before chemotherapeutic drugs

ie. alcohol (also take a shot of alcohol -sedative)

- most do not aid wound healing but impair it

- better to clean using soap and water (rub off microorganisms)

4. Mechanism of action

a. coagulation of proteins

b. destruction of normal cell membrane permeability

c. poisoning of enzyme systems

because nonselective -may also kill host cells

5. Agents -- mechanisms are not clear for all of these

a. alcohol - denatures proteins --lyses organism

b. phenols denatures proteins

first antiseptic - used by Lister in 1867 -- spray of phenol or carbolic acid

3% solutions are used by doctors for cleaning

(hexachlorophene - Phisohex)

in 1850 die from infections, when began washing hands - much healthier

c. cresol (lysol) - alkylating compounds (add CH₃) - works similar to phenols

d. acids (boric acid)

e. oxidizing agents - hydrogen peroxide -- attacks membrane lipids

f. iodine- mechanism A and C

g. chlorine - forms acid - HOCL kill organisms (hypochlorus acid)

mechanism is not known - maybe oxygen oxidizes components in protoplasm or it interfers with metabolism

(deodorants, foot powders) aluminum chlorohydrates

- some produces hydroxide

(antiper- decrease perspiration while deodorants decrease bacteria)

F. Antiprotozoal agents

1 billion suffer from malaria and amoebiasis - neglected area

1. Antimalarial - one of the most important of all infectious diseases

malarial parasite is a protozoan- plasmodium (4 different species)

- female mosquito (doesn't make a noise) is carrier

protozoa invades liver and RBC's

Drugs:

Only antifols prevent disease (pyrimethamine) - prevents maturation of plasmodium

Drugs that suppress the symptoms and hopefully provide a cure (fever, chills, shaking, convulsive delerium - death results from intravascular hemolysis)

- for some plasmodiums 4 weeks of treatment provides cure

-Quinine- oral (bark of chinchona tree) similar to quinidine- antiarrhythmic

-Chloroquine - IV, oral

-Primaquine - oral

- etc.

They alter microbial and host DNA - preventing strand separation

therefore, no replication, no protein synthesis

Usually effective on microbial DNA at lower concentrations than mammalian DNA

2. Amoebicides- amoebae- one celled protozoan organism

produce severe intestinal infection - i.e. dysentery (blood in stool) this may also be due to bacteria or worms

Drug of choice:

metronidazole (Flagyl) (oral) - usually combined with with diloxanide furoate- a luminal drug (mechanism is not known).

Very small molecular size, therefore, enters all tissues of the body

- action - nitro group on drug is reduced in protozoa or amoebae (by ferredoxin a reducing agent containing iron) and the reduction product combines the macromolecules in the cell to kill it

G. Anthelmintic Drugs

Used to rid the body of parasitic worms

worms are most common parasitic disease in world - about 40% of world's population - 2 billion

If in intestine - easy to treat - if in tissue very difficult.

1. Mechanism of action

a. Paralysis of musculature of worms-they are then expelled

- some work on microtubules - ie. Mebendazole (oral - not absorbed), thiabendazole (oral - absorbed - thus get side effects)

- praziquantel (oral) increases permeability to calcium - get paralysis

b. Inhibition of metabolism - ie. niclosamide (oral)

All drugs are taken orally

exact drug depends on worm

H. Cancer Chemotherapy

Next to heart disease cancer kills more people in US 500,000/year = 1400/day

Present treatment cures 50% of patients

33% by surgery and radiation: destroys cells that rapidly turn over

17% by chemotherapy

(new techniques include photodynamic therapy - using photo sensitive agents free radicals alter cells, abnormal tissues tumor)

1) Cancer - group of neoplastic (newly formed) abnormal tissue - tumor

Cancer can be caused by carcinogens - smoking (***--men and women), benzenes, viruses, aberrant nucleic acid sequence , free radicals produced by the body can alter the nucleic sequence, etc

there are oncogenes (code for growth factors) and tumor suppressor genes (such as p53 which can mutate into an oncogene - in several human cancers)

(tumor stem cells may involve production of a protein coded for p53 gene on chromosome 17 that normally checks cell division)

whatever the cause- cells no longer control cell proliferation - tumor stem cells

get repeated cycles of proliferation:

cell cycle - G1 (synthesis for DNA synthesis), S (DNA synthesis), G2 (synthesis for mitosis), M (mitosis)

Cancer cells also can migrate to other tissues - metastasis

2) Cancer drugs

ideal drugs would kill cancer cells but not normal tissue - no currently available drugs

new area with possibilities - attack blood flow to tumor - angiostatin and endostatin

Problems:

No qualitative differences between cancer and normal cells - only quantitative differences (metabolism and reproduction)

for microbial cells many qualitative differences (cell wall, ribosomes etc.)

must take advantage of rapid division - but many cells in body have normal rapid division, therefore, toxic effects

-ulceration of GI tract (mucosal lining)

-skin rashes, hair loss (epidermis)

-decreases in RBC's (blood)

-microbial infections -because suppress immune response (WBC's)

Host mechanism for eliminating moderate numbers of cells is ineffective, must destroy all cancer cells - for example with leukemia -10¹² = 1 trillion tumor cells - if kill 99.9% - still have 1 billion cells.

A. Classes of Drugs

Cell cycle- specific (CCS) act specifically on cells undergoing cycling

Cell cycle nonspecific (CCNS) - kill cells if cycling or resting- for lower growth rate tumors

1. Groups of Drugs

a. Alkylating Agents - CCNS agents 

Action- cross links base pairs of DNA, therefore, inhibits cell division

transfer alkyl group (ie. CnH2n+1 - CH3Cl -methyl chloride, note that CH4 is an alkane-methane)

1) nitrogen mustard - first cancer treatment - WW II - cancers were due to exposure to mustard gas (specific example - mechlorethamine) - IV

2) chlorambucil - orally

3) nitrosoureas - ie. carmustine (BCNU) and lomustine - oral

-very lipid soluble, therefore, good for brain tumors

4) cisplatin - inorganic metal complex (neutral platinum) - IV

5) cyclophosphamide - oral

6) melphalan - oral

b. Antimetabolites - CCS

Interact with enzymes preventing metabolism

1) folic acid antagonists - methotrexate (IM, IV, oral) - cells need folic acid to synthesize nucleic acids

2) purine antagonists (adenine and guanine - double ring) - 6- Mercaptopurine (oral but irregular)

3) pyrimidine antagonists (cytosine and thymine - single ring) - fluorouracil (IV)

Side effects- bone marrow depression, GI irritation, irritation of skin

c. Plant alkaloids- CCS in M phase

Interact with tubulin to block mitotic spindle formation

1) vinblastine and vincristine (IV but must be careful - rapid cell destruction)

2) paclitaxol (Taxol) (IV) - recently approved - used to treat breast and ovarian cancer - comes from Western Yew - $1,000.00/treatment - fungus on tree produces drug - also made synthetically

d. Antibiotics- come from soil fungus (Streptomyces)

1) Actinomycin D (also called Dactinomycin) (IV) - CCNS-too toxic to be used as antibacterial agent

forms complex with DNA and blocks production of RNA

2) Bleomycin - CCS (IV, SC, IM)

binds to DNA - generates free radicals - causes strand breaks and inhibits DNA synthesis

3) Antracyclins (IV) (doxorubicin and daunorubicin) - CCNS - binds to DNA - alters free radicals and alters membrane fluidity - stops DNA synthesis

etc. Tamoxifen - antiestrogen (oral) - used to treat breast cancer

FINAL EXAM 

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