Archive for the ‘Pharmacology’ Category

Toxicology

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)

[...]

Nonsteroidal Antiinflammatory Drugs (NSAIDS)

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 [...]

Immunosuppressive Agents

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 [...]

Introduction to Pharmacology

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

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, [...]

Introduction to Chemotherapy

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 [...]

Chemotherapeutic Antibiotics

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 [...]

Chemoantimetabolite Agents

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 [...]

Chemotherapy Alkylating Agents

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 [...]

Vitamins

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 [...]

Thyroid Pharmacology

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 [...]

Sex Steroids

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 [...]

Parasites Chart

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.      [...]

Oral Contraceptives

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 [...]

Insulin and Hypoglycemics

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 [...]

Insulin and Hypoglycemic Agents

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 [...]

Hypothalamic and Pituitary Agents

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 [...]

Glucocorticoids

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 [...]

Gastrointestinal Pharmacology

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 [...]

Other Beta-Lactam Antibiotics Cephalosporins, Carbapenems, Monobactams, and Glycopeptides

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 [...]

Pharmacology of Calcium Metabolism

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  [...]

Antiviral Agents

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 [...]

Antiparasitic Agents

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
[...]

Antimycobacterial Agents

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 [...]

Antimicrobial Therapy

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
[...]

Antifungal Agents

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 [...]

Antibiotics that Inhibit Bacterial Protein Synthesis

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 [...]

Antibiotics that Inhibit Intermediary and Nucleic Acid Metabolism

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 [...]

Anorexiants and Antiemetics

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 [...]

Introduction to Pharmacology

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. [...]