Basic Pharmacology

GONADOTROPINS

• GnRH: Stimulates release of FSH and LH.
  • EFFECTS:
    • Pulsatile release of GnRH ------> pulsatile release of LH ------> stimulates follicular growth, the luteal surge (via positive feedback effect of estrogen at mid-cycle), and ovulation.
    • Continuous release of GnRH can actually supress the gonadotropins.
  • STRUCTURE: GnRH is a decapeptide. Two analogues have replaced one amino acid (Lys-6) in order to give the structure a longer half-life.
    • Leuprolide: Replace Lys-6 with d-Leucine
    • Nafarelin: Replace Lys-6 by a naphthalene-derived Alanine.
  • SECOND MESSENGER: GnRH-Receptors are coupled to the IP₃/DAG/Ca⁺² second messenger system.
  • FSH + LH: They are large molecules and there is no synthetic analogue. They can only be obtained from natural products.
    
     
  
  

  ESTROGEN:

  • PHARMACOKINETICS: Estrogen is lipophilic, metabolized in the liver, and is recycled through the enterohepatic circulation.
    • It has a high concentration of effects on the liver compared to the periphery.
    • Antibiotics can destroy normal GI flora ------> interfere with enterohepatic recycling of estrogen ------> reduce estrogen levels. This is why oral contraceptives can fail when taken with antibiotics.
  • Natural Estrogens: The natural estrogen are not used in oral contraceptives, because they are metabolized
    • Estradiol: Most potent. Formed primarily in ovary.
    • Estriol: Less potent. Formed in the liver from estrogen, or in peripheral fat from androstenedione.
    • Estrone: Less potent. Formed in the liver from estrogen, or in peripheral fat from androstenedione.
  • POST-MENOPAUSAL THERAPY: Equine natural estrogens are used for post-menopausal therapy.
    • BENEFICIAL EFFECTS:
      • Antagonizes the effect of PTH on bone ------> prevent bone loss after menopause.
        • Estrogen does not appreciably add bone mass, but it can prevent bone loss.
      • Increases plasma levels of HDL, and decreases LDL, thus it is effective in preventing heart disease.
      • Even in low doses, it prevents hot flashes associated with Menopause.
    • ADVERSE EFFECTS:
      • Post-menopausal bleeding.
      • Nausea
      • Breast tenderness
      • Migraine headaches.
      • Can promote estrogen-dependent cancers, particularly uterine cancer but also breast cancer.
        • If you use progestins along with estrogen, then this risk is completely eliminated.
        • Give estrogen during first 25 days of month, and add progestin during last 10-15 days. Bleeding will result.
  • ORAL CONTRACEPTION:
    • ESTROGEN ADVERSE EFFECTS: The adverse effects of estrogen are dose-related. They were a bigger deal in the past, because estrogen doses used to be much higher. Today's doses are much lower, and the adverse effects are not as pronounced.
      • Increased synthesis of clotting factors ------> Thromboembolism, stroke, especially in women who smoke.
      • Increased production of liver hormone-binding proteins (CBG, TBG, SHBG) ------> increased circulating levels of Thyroxine, Cortisol, sex hormones.
      • Cholelithiasis
      • Depression
      • Minor effects: weight gain, breast tenderness, nausea
  • POST-COITAL CONTRACEPTION: Take extremely high doses of estrogens alone after intercourse. Any of the estrogen would work.
    • Mechanism unclear, but they think it disturbs the environment in the uterus, making it unfavorable for implantation.
      
       

  PROGESTINS: They generally modulate the effects of estrogens (and lessen their side-effects) when used in oral contraceptives.

  • EFFECTS:
    • Makes cervical mucous thicker. This is an important effect in contraception, as the thick mucous inhibits movement of sperm and can even be spermicidal.
    • Decreases the endometrial proliferation caused by Estrogen.
  • PHARMACOKINETICS: Natural Progesterone is rapidly degraded in liver, thus it cannot be given PO. Synthetic (oral contraceptive) progestins can be given PO.
  • ORAL CONTRACEPTIVES:
    • Combined Oral Contraceptives: The main reason progestins are added to oral contraceptives is to ensure prompt withdrawal bleeding.
    • Progestins used alone are not as effective (96.5-97%) as combined oral contraceptives (99%).
    • There is no menstruation at all when using progestins alone.
    • Depo-Provera and Norplant are both pure-progestin mixtures.
      
       

  DIABETES:

  	Diabetes Type I (IDDM)	Diabetes Type II (NIDDM)
  Mechanism	Insulin is defective or is never formed. Antibodies against pancreatic beta-cells.	Insulin resistance; down-regulation of insulin receptors; failure of pancreas to release insulin even though it being formed.
  Survival	Insulin is absolutely required for survival.	Patient will survive without insulin
  Synonyms	Ketosis-Prone Diabetes Juvenile-Onset Diabetes	Ketosis-Resistant Diabetes Adult-Onset Diabetes
  Onset	Sudden, often discovered by ketoacidosis. Childhood polydipsia, polyphagia, polyuria.	Gradual, insidious. Often discovered incidentally, or when chronic complications arise.
  Nutrition	Often thin. Failure of action of insulin.	Usually obese.
  Ketoacidosis	Frequent	Seldom or never
  Treatment (order of importance)	Insulin always required Diet Never oral hypoglycemics	Diet and exercise Oral hypoglycemics Insulin

   
  • KETOACIDOSIS: Lack of insulin (i.e. high Glucagon:Insulin ratio) promotes lipolysis, breakdown of proteins, and glycogenolysis.
    • Coma: In hyperglycemia, high sorbitol in plasma ------> dehydration ------> coma.
      • Coma is more often seen with hypoglycemia than with hyperglycemia.
    • TREATMENT:
      • Crystalline Zinc Insulin is the most immediate-acting insulin, which is the treatment of choice for acute ketoacidosis.
      • Ketoacidosis is treated with both HCO₃^- (to relieve the acidosis) and K⁺ (to replace lost K⁺ in cells).
        • In Ketoacidosis, there is plenty of K⁺ in the blood, but the cells are starving for K⁺ because the patient is dehydrated.
        • When you give the IV insulin, glucose goes into cells, and K⁺ follows it. We therefore must replace this K⁺ to avoid hypokalemia.
    • BIOCHEMICAL CAUSE:
      • Glucagon promotes Lipolysis ------> lots of Acetyl-CoA in the blood.
        • Acetyl-CoA builds up in liver.
      • Glucagon promotes Gluconeogenesis ------> Oxaloacetate is diverted to work on making glucose and is therefore unavailable for the TCA cycle.
      • Excess Acetyl-CoA cannot be used in TCA cycle and is hence diverted to Ketone Body production.
  • HYPOGLYCEMIA:
    • SYMPTOMS: Palpitations, sweating, tachycardia, fainting, coma.
    • TREATMENT: IV-Glucose.
    • COMA: Hypoglycemic coma is more common in Diabetic than ketoacidosis coma, due to over treatment with insulin.
      • Give a comatose diabetic IV glucose, until their blood sugar is known for sure. If you give insulin to a hypoglycemic patient, you'll probably kill them!
    • ALCOHOL inhibits gluconeogenesis and thus can lead to hypoglycemia in Diabetics. Alcohol combined with insulin can lead to hypoglycemia.
  • EXERCISE: The cornerstone of treatment of Type-II Diabetes.
    • It leads to lower blood-sugar and the up-regulation of insulin receptors.
    • It allows for greater penetrance of insulin into muscle tissue, improving the utilization of insulin.
  • INSULIN:
    • SYNTHESIS: Proinsulin is hydrolyzed to Insulin + C-Peptide
    • SECRETION: Stimulated by Glucose, Vagal stimulation, and some amino acids. Mechanism involves a K⁺ channel and Ca⁺² channel on the pancreatic beta-cell.
      • Fasting State: No glucose is around.
        • ATP is depleted.
        • K⁺ channels are open.
        • The cell is in the resting, hyperpolarized state.
      • Resting State: Plenty of glucose is around (or vagal stimulation).
        • ATP is plentiful.
        • The K⁺ channel closes.
        • The cell depolarizes.
        • Ca⁺²-channels open, Ca⁺² flows in, and insulin is secreted.
      • Sulfonylureas: They promote insulin release by blocking the K⁺-channel, such that it is always closed. Hence the cell is depolarized and insulin is released.
    • INSULIN RECEPTOR: It's a Tyrosine Kinase.
      • Down-Regulation: Binding of insulin causes aggregation of receptor-subunits, and repeated binding can cause internalization and destruction o-f the receptor. This is one way in which continual insulin stimulation can lead to Type-II Diabetes.
    • ACTION:
      • GLUCOSE-TRANSPORTERS: Insulin up-regulates the transport of GLUT4 transporters into the membranes of target cells.
      • LIVER:
        • Insulin promotes glycogenesis
        • Insulin antagonizes glucagonic effects of glycogenolysis, ketogenesis, and gluconeogenesis.
      • MUSCLE: Insulin promotes protein synthesis and glycogenesis.
      • FAT: Insulin promotes fat uptake and storage in adipocytes.
        • It stimulates lipoprotein lipase ------> free fatty acids from circulating lipoproteins.
        • Glucose transport and glycolysis generate glycerophosphate, which is needed as the glycerol backbone in triglyceride synthesis.
        • It inhibits intracellular lipase, preventing lipolysis in adipose tissue.
    • TYPES of Therapeutic Insulin:
      • Porcine Insulin: Has a better allergy profile than the bovine insulin.
      • Bovine Insulin: Insulin antibodies are formed, but they usually don't hurt anything. They can decrease the effectiveness of the insulin, at which point a different insulin prep can be used.
        • Allergic reaction is possible, usually due to impurities in preparation.
      • Human Insulin: Created by DNA recombination technology. More expensive, and more pure. Use with folks who are allergic to other types.
    • Lipodystrophy: Adverse reaction of hypertrophy or atrophy in the adipose site where injection was given. To prevent lipodystrophy, switch injection sites.
  • SULFONYLUREAS: Oral hypoglycemics used to treat Type II Diabetes.
    • MECHANISMS:
      • They promote insulin secretion in beta-cells. They block K⁺ channels on pancreatic beta-cells ------> K⁺ remain closed ------> beta-cells remain depolarized ------> promote insulin secretion.
      • They antagonize the effects of glucagon.
      • They potentiate the action of insulin in target tissues.
    • CONTRAINDICATIONS:
      • Do not use in pregnancy. They cross the placental border. Never use with gestational diabetes.
    • DRUG INTERACTIONS:
      • Drugs that neutralize the action of Sulfonylureas:
        • Diazoxide: Inhibits release of insulin.
        • Phenytoin
        • Propanolol
        • Corticosteroids: Leads to "adrenal Diabetes."
      • Drugs that potentiate the action of Sulfonylureas, and thus must be used with care to avoid hypoglycemia:
        • Sulfonamides: They displace sulfonylureas from plasma proteins
        • Salicylates: Interferes with urinary secretion.
        • Phenylbutazone: Competition for liver enzymes, plus interfere with urinary excretion
        • Chloramphenicol: Competes for liver enzymes
        • Probenecid: Interferes with urinary secretion.
  • COMPLICATIONS of DIABETES:
    • MECHANISMS:
      • GLYCOSYLATION of blood proteins
        • Examples of glycosylated proteins: hemoglobin, components of the lens, collagens, myelin.
        • Advanced glycosylation products are formed through time. The initial glycosylations are usually reversible.
      • POLYOL PATHWAY: The way to get rid of excess glucose in non-insulin-dependent tissues, such as the brain.
        • Glucose + NADH + N⁺ ------> Sorbitol + NAD⁺ (Aldolase Reductase).
        • Accumulation of Sorbitol is believed to play a role in Diabetic retinopathy, nephropathy, neuropathy, and microangiopathy.
    • Major Complications:
      • Atherosclerosis
      • Neuropathy
        • Loss of sensation can lead to foot ulcers.
      • Retinopathy
      • Nephropathy
      • Microangiopathy

      PARATHYROID HORMONE (PTH): It increases serum Ca⁺² and promotes resorption of Ca⁺² in bone.

      • EFFECTS: It increases serum Ca⁺² and decreases serum phosphate.
        • BONE: It increases resorption of Ca⁺² from bone. It increases osteoclastic activity by promoting the action of osteoblasts.
        • KIDNEY:
          • It increase resorption of Ca⁺², Na⁺, Cl^-, and some amino acids.
          • It promotes synthesis of 1,25-(OH)₂-Vit-D
          • It increases excretion of PO₄^-3.
      • REGULATION:
        • Increased serum Ca⁺² inhibits PTH secretion.
        • Increased serum PO₄^-3 ------> decreased free serum Ca⁺² ------> increased PTH secretion.
          
           

      VITAMIN-D:

      • EFFECTS:
        • GUT: Increased Ca⁺² and PO₄^-3 absorption in gut.
        • BONE:
          • 1,25-(OH)₂-Vit-D increases resorption of Ca⁺² ------> increase plasma Ca⁺².
          • 24,25-(OH)₂-Bit-D may increase deposition of Ca⁺² into bones (i.e. osteoblastic activity)
        • KIDNEY:
          • Increases reabsorption of Ca⁺² ------> higher blood Ca⁺²
          • Increases reabsorption of PO₄^-3 ------> higher blood PO₄^-3.
      • SYNTHESIS: It is promoted by PTH.
        • SKIN: Cholesterol ------> Cholecalciferol is a non-enzymatic cleavage catalyzed by UV-Light.
        • LIVER: Form Calcifediol. 25-Hydroxylase puts a hydroxyl group on the side chain.
        • KIDNEY: Form Calcitriol. 1alpha-Hydroxylase puts a hydroxyl at the 1alpha position.
      • ADVERSE EFFECTS:
        • Hypervitaminosis D = Vitamin D toxicity, characterized by hypercalcemia and nephrocalcinosis.