General Principles of Toxicology
Scope of Medical Toxicology: Occupational (Chemicals), Environmental (agricultural/air), Clinical (drug toxicity, accidental, intentional)
Oral > Eye > Skin > Bites/Stings > Inhalation > Aspiration
90% poisonings occur in the household (children- most common): cosmetics, cleaning products,
plants, pharmaceuticals, etc)
[...]
NSAIDS
Aspirin
Salicylic Acid
Indomethacin
Diclofenac
Sulindac
Tolmetin
Ibuprofen
Naproxen
Ketoprofen
Pranoprofen
Miroprofen
Phenylbutazone
Apazone
Piroxicam
Celecoxib
Acetaminophen
Chloroquine
Gold salts
Colchicine
Probenecid
Sulfinpyrazone
Allopurinol
Common Feature of All NSAIDS
1) anti-inflammatory
2) analgesic - effective against pain of low to moderate intensity
3) anti-pyretic
4) GI/intestinal ulceration: local irritation and inhibition of PGs
5) Prolonged bleeding due to inhibition of thromboxane synthetase - TXA2
6) Intolerance crosses over all NSAIDS
7) Can be used in pregnancy but discontinue prior to partuition
Salicylates - Aspirin [...]
Azathioprine
Corticosteroids
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil
Polyclonal antithymocyte globulin
Anti-CD3 monoclonal antibodies
Azathioprine (AZA)
imidazole derivative of 6-mercaptopurine
blocks DNA synthesis
decreases the migration of leukocytes into grafts and inhibits the proliferation of premyelocytes within the bone marrow
useful for blocking the 1o response
NOT USEFUL [...]
Drug Information and Nomenclature
A. Drug Classification
OTC drugs: Adequate directions can be written for the layman and they’re safe for the not-so-careful customer.
B. Prescription Drugs
Adequate directions can not be written for the layman. Directions are intended for the physician, and the proper and successful use of these drugs is the responsibility of the physician.
C. [...]
Eicosanoids
Arachidonic Acid
Prostaglandins: PGE1, PGE2, PGF2a, PGI2
Thromboxane A2
Drugs
NSAIDS - Aspirin, Indomethacin, Ibuprofen, Celecoxib
Prostin - PGE1
Alprostadil - PGE1
Misoprostol - PGE1 derivative
Dinoprostone - PGE2
Epoprostenol - PGI2 (prostacyclin)
Iloprost - PGI2a
Latanoprost - PGF2a
Carboprost tromethamine - PGF2a derivative
Leukotriene Modifiers
Zafirkulast
Zilueton
General
specific cell stimulation, or shear-stress of blood flow, causes release of free arachidonic acid from membrane phospholipids
COX-1 - GI tract, [...]
cancer affects 1 in every 3 individuals
Cancer incidence and mortality
Ø Males - lung #1, prostate #2
Ø Females - lung #1, breast #2
Causes of cancer
Ø most are non-inherited genetic diseases of somatic cells
Ø mutations can occur spontaneously or can be induced or increased by exposure to mutagenic substances in the environment
Ø Tobacco [...]
Agents that intercalate DNA
Doxorubicin (Adriamycin)
Daunorubicin (Daunomycin)
Dactinomycin
Plicamycin (Mithramycin)
Agents that fragment DNA
Bleomycins
Agents that inhibit Topoisomerase II
Etoposide (VP-16)
Teniposide
Amsacrine
Agents that inhibit Microtubules
Vincristine
Vinblastine
Paclitaxel (Taxol)
Hormones and related agents
Prednisone
Tamoxifen
Leuprolide
Androgens
Progestins
Estrogens
Miscellaneous
L-Asparaginase
Agents that intercalate DNA - Doxorubicin, Daunorubicin, Dactinomycin, Plicamycin
Doxorubicin and Daunorubicin
*Doxorubicin is the most powerful and widely used drug in cancer chemotherapy
Inhibit both DNA replication and RNA synthesis
*Intercalate into [...]
1. Antifolates
2. Methotrexate (MTX)
3. Pyrimidine Analogs
4. Cytosine Arabinoside - (araC, cytarabine)
5. Fluorouracil (5-FU)
6. Purine Analogs
7. Mercaptopurine (MP)
8. Thioguanine (6-TG)
9. Misc
10. Hydroxyurea
11. Rescue Drug (Not for CHEMO)
12. Leucovorin
ALL OF THESE DRUGS ARE S-PHASE SPECIFIC and interfere with DNA synthesis
Antifolates - Methotrexate (MTX)
Methotrexate
inhibits dihydrofolate reducatse (enzyme necessary for conversion of FH2 to FH4
Ø depletes [...]
Nitrogen Mustards
Mechlorethamine
Cyclophosphamide
Melphalan
Chlorambucil
Nitrosureas
Carmustine (BCNU)
Lomustine (CCNU)
Semustine
Streptozocin
Alkyl Sulfonates
Busulfan
MISC
Cisplatin
Procarbazine
Dacarbazine
Mitomycin
Nitrogen Mustards - Mechlorethamine, Cyclophosphamide, Melphalan, Chlorambucil
General
Crosslinking of the DNA strands is the main source of toxicity
ALL ARE CELL CYCLE PHASE NON-SPECIFIC
Dose limiting toxicity: bone marrow suppression
These alkylating agents are mutagenic and can cause secondary cancer, sterility later in life
Mechlorethamine
*very unstable
*has to be given by [...]
B & C are H2O soluble; excreted rapidly in kidney; overdoses are rare
A,D,E, & K are fat soluble; stored; hypervitaminosis syndromes result
usually multiple deficiencies of Vit B exist (not single) so supplementation is in multiple combos
Thiamine (Vit B-1) - precursor for TPP which is required for decarboxylation of a-keto acids and [...]
Levothyroxine (T4)
Propylthiouracil - PTU
Methimazole - MMI
Potassium iodide - KI
Radioactive iodide 131I
Thyroid Hormone Synthesis:
Thionamides: Propylthiouracil (PTU) and Methimazole (Tapezol)
PTU and Methimazole inhibit the peroxidase enzyme throughout the pathway.
PTU has the additional effect of blocking the peripheral conversion of T4 to T3 by inhibiting the 5′-iodinase.
Actions reversible when drug is stopped
Some [...]
Estrogens & Progestins
Introduction to the players:
Estrogens: estradiol, conjugated estrogens (Premarin), ethinyl estradiol, mestranol
SERMS: clomiphene, tamoxifen, raloxifene
Functional Anastrozole, exemestane (inhibit production from androgens). Block
estrogens: enzyme.
Progestins: progesterone, medroxyprogesterone acetate, norethindrone, norgestrel
progest.: mifeprostone or mifeprix (ru 486)
Sex Steroids:
1. widely used
2. efficacious
3. several potenetial [...]
Class
BUG
Infective Stage
Local of Path Stage
Drug
MECH
Protizoans
Amebiasis: invasive
Cyst
Extraintestinal
Iodoquinol
Unknown
Amebiasis: luminal
Cyst
Large intestine
Flagyl + iodoquinol
Flagyl –inhibits DNA replication
Amebiasis: luminal
Cyst
Large intestine
Emitine + iodoquinol
Emitine –inhibits protein synthesis
Amebiasis: luminal
Cyst
Large intestine
Chloroquine + iodoquinol
Chloroquine –unknown for amebae
Balantidiasis
Cyst
Large intestine
Iodoquinol + tetracycline
Tetracycline –eliminates bacterial symbiots on which B. coli is dependent
Giardiasis
Cyst
Small intestine
1. Flagyl
2. [...]
Serious side effects esp older women (older than 35) who smoke/predisposed to thromboembolic disease or cv disease. Start with lowest possible doses. (ie low dose tri-phasic preparation).
Combination OC: ethinyl estradiol (most common) or — estrogen component. 19-nor steroid — progestin. Higher doses of estrogen used for OC than for ERT. Monophasic, biphasic, and triphasic [...]
INSULINS
DRUGS
INFO
Insulin (general)
Pre-pro insulin is cleaved (-NH3) in the ER — pro-insulin is cleaved in the golgi (C-peptide) — insulin (A & B chains).
Glucose is primary physiological stimuli for insulin secretion.
ANS — islets are innervated by vagus — cholinergic stimulation will increase insulin secretion.
Phase I [...]
Treatment Approaches
1) limit carb intake
2) weight loss and exercise
3) insulin for type I; for type II when fasting glucose > 250 mg/dl
Insulin Preparations
administered subQ, IM, and IV
Onset/duration
Ø Regular insulin - 0.5hr/5-7hrs
Ø Isophane insulin & Lente Insulin - 1-2hrs/24-30hrs
Ø Protamine Zinc Insulin, Ultralente insulin - 4-8 hrs/24-36 hrs
Complications of Insulin Therapy
1) resistance [...]
1. Growth Hormone
Somatropin
Octreotide - somatostatin analogue
hMG/Menotropins (LH/FSH)
hCG/Chorionic Gonadotropin (LH)
Oxytocin
Desmopressin
Bromocryptine -Dopamine agonist used paradoxically in Acromegaly treatment; Prolactinemia
Growth Hormone
Secretion
Ø stimulated by GHRH
Ø inhibited by somatostatin
Effects
Ø Direct: plasma membrane receptors triggers kinase cascade (the [...]
Remember that the11-OH is required for activity
All glucocorticoids are excreted completely in the urine (no biliary or fecal)
Anti-inflammatory Effects of Glucocorticoids
effective against ALL FORMS of inflammation
Requires HIGH DOSES
Mechanisms
1) induce synthesis of lipocortin which in turn inhibits phospholipase A2
- this inhibits the release of arachidonic acid from the plasma membrane
- inhibition [...]
Most Peptic Ulcer Disease Results from:
1) infection with H. pylori
2) use of aspirin, NSAIDS
3) gastrin-secreting tumors
Antacids - Sodium Bicarbonate, Calcium Carbonate, Magnesium Hydroxide, Aluminum Hydroxide
Sodium Bicarbonate
systemic
do not use long term
can change pH of blood and urine (alkalosis)
Contraindications - HTN
Calcium Carbonate
partially systemic
do not use long term
prolonged neutralizing [...]
I. Cephalosporins-
A. Structure- 2 rings.
B. Mechanism- inactivate transpeptidases just like PNC, but less susceptible to lactamases.
C. Spectrum-
1. lactamase producers: Klebsiella, N. gonorrhoeae
2. potent inducers of -lactamases in other species: Enterobacter and Pseudomonas.
3. Staph. aureus and streptococci.
4. Activity against G(-) pathogens increases from 1st to 4th generations.
5. Activity against G(+) pathogens decreases from 1st to 4th [...]
Drugs used to treat Hypocalcemia
Calcium Salts -
Calcium Carbonate
Calcium Citrate
Calcium Lactate
Calcium gluconate
Ø use with caution in patients on Digitalis
Vitamin D preparations
drugs of choice for treatment of Chronic hypocalcemia
several preps
DHT - dihydrotachysterol
Ø duration of action - 2 weeks
Ø requires liver and kidney for metabolism
Ø $20/week
25-(OH)-D3 - calcifediol
Ø [...]
Introduction: All Antiviral Drugs are virustatic
Antiviral Drugs for - Herpes viruses
remember that these are DNA viruses
Includes HSV 1&2, VZV, CMV, EBV, HHV-6, HHV-7, HHV-8
Specific Drugs
Acyclovir - guanosine analogue
requires phosphorylation to triphosphate form for activity
the viral thymidine kinase performs the initial phosphorylation
Mechanism
Ø irreversibly binds to viral DNA polymerase
Ø acts as [...]
Protozoa
Amebiasis - Entamoeba histolytica
Treatment directed against the trophozoites
Luminal - Diiodohydroxyquinoline (Iodoquinol)
Invasive - 1) Metronidazole + Iodoquinol
2) Emetine + Iodoquinol
3) Chloroquine + Iodoquinol (not understood for ameba)
Balandidiasis - Balantidium coli
Iodoquinol + tetracycline
Tetracycline acts on bacteria that the parasite is dependent upon
Giardiasis - Giardia lamblia
DRUG OF CHOICE - Metronidazole
[...]
Mycobacterium Tuberculosis
In patients < 35, with suspected exposure to TB with positive PPD and no clinical symptoms
Ø Isoniazid - 6-9 months
In patients with a positive X-Ray, &/or positive smear of TB give 1st line agents
Ø Isoniazid - 6 months - inhibits cell wall synthesis
Ø Rifampin - 6 months - inhibits RNA [...]
General
Selective Toxicity - destroy the microorganisms w/o harming the host
Bactericidal -antibiotic causes cell death (Ex. Ags, penicillin, cephalosporins, vancomycin)
Bacteriostatic - antibiotic inhibits bacterial growth ( Ex. Chloramphenicol, erythromycin, clinda, tetra
-cidal vs. -static not hard and fast rule - Ex. Ampicillin -cidal against S. pneumonia and -static against Enterococcus
Antagonism
[...]
Polyenes - Amphotericin B, Nystatin
Amphothericin B
Mechanism
Ø Binds to ergosterol in fungal membranes better than to cholesterol in mamallian cells - selective toxicity
Ø Alters fungal cell permeability and transport properties
Ø No activity in bacteria, some in mycoplasma
Structure
Ø polyene antibiotic
Ø insoluble in H2O
Ø restricted activity between pH 6 and 7
Absorption
Ø poor from the [...]
I. Review of the principle reactions in protein synthesis- basic mechanism is the same for bacterial and mammalian cells. The main difference is in ribosome structure.
A. Initiation- requires an initiation complex made up of ribosomes, mRNA, various initiation factors, and GTP for hydrolysis. The mRNA must have an initiation codon (AUG) that corresponds [...]
I. Sulfonamides- Inhibitors of Folic Acid Metabolism
A. Structures- all single or double ring structures.
B. Mechanism- Bacteriostatic. Inhibits folic acid metabolism, depleting Tetrahydrofolate which is necessary for biosynthesis of purines (A & G), thymidine, and methionine. Mammals can get the folate they need from their diet; microbes can’t.
C. Pharmacology- Variable intestinal absorption among compounds. Many [...]
Emetics
Apomorphine
Ipecac
Anorexogenics
Amphetamine
Diethylpropion
Phentermine
Mazindol
Sibutramin
Orexogenic
Dronabinol
Antiemetics
Anticholinergics
Scopolamine
H1 antagonists
Dimenhydrinate
Dopaminergic antagonists
Chlorpromazine
Metaclopramide (Reglan)
Anxiolytics
Diazepam
Corticosteroids
Dexamethasone
Others
Dronabinol
5HT Antagonists
Ondansetron
General
Emesis
Ø both autonomic and somatic nervous reflex elements are involved
Ø Vagal afferent fiber in the GI tract® nucleus and tractus solitarius in the brain stem® vomiting center, Chemoreceptor trigger zone, and dorsal motor [...]
Drug Information and Nomenclature
A. Drug Classification
OTC drugs: Adequate directions can be written for the layman and they’re safe for the not-so-careful customer.
B. Prescription Drugs
Adequate directions can not be written for the layman. Directions are intended for the physician, and the proper and successful use of these drugs is the responsibility of the physician.
C. [...]
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