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Fluids and electrolytes 60% of body weight is provided by water. Two-thirds of this is in the intracellular (IC) compartment and the other one-third is in the extracellular (EC) compartment. The extra cellular fluid is divided into intravascular compartment (one-third) and the interstitial (tissue space) compartment (two-thirds). Average daily water consumption is
- 120-150mL/kg for infants,
- 120-130 mL/kg for children
- 30 mL/kg for adults. Loss of body fluids by as much as 20-30% leads to severe dehydration and death. Over hydration leads to edema. Major body electrolytes are sodium, potassium, calcium and magnesium. Sodium is the major ion of extra cellular fluid Potassium is the major ion of intra cellular fluid. Calcium is mostly found in skeletal tissue and plays a major role in intracellular enzyme reactions as a catalyst and co-factor. "Insensible" or unobserved loss of water occurs through:
- Skin -(evaporation, perspiration and sweat)
- Exhaled air - as water vapor
- Through feces "Observed" loss of water occurs through
- urination. Urine output accounts for 60% of total daily loss of water by the body. Constituents (contents) of fluid compartments in the body consist of: Electrolytes in the ionic form (expressed as mEq/L) Non-electrolytes such as glucose, urea, and creatinine Their concentrations in IC and EC compartments vary. (Ref. Table 61-1 p.779) Water freely travels from one compartment to another. Water crosses the cell membrane in both directions depending on the concentrations of solid particles ('solutes') on each side. Water moves from areas of lower solute concentrations to that of higher solute concentrations. This process is called "OSMOSIS" "OSMOLAITY" is a term used to define total solute concentration expressed as milliosmols per liter (mosm/L). Disturbance of electrolyte contents of IC or EC results in clinical signs and symptoms. This should be recognized and corrected promptly. Otherwise will result in altered homeostasis, and death. Measurements of serum electrolytes help us to decide which type of fluid should be administered in a dehydrated and clinically symptomatic patient (Refer Table 61-2 p.780).
Sodium ion is the major player in maintaining the dynamic equilibrium and helps to determine the type of body fluid status****. Body fluid status****. Fluid overload or overhydration(volume excess) results in low serum sodium ( hypo natremia ). Fluid loss or dehydration(volume depletion) is based on sodium levels as well. (Refer Table 61- p.781) Electrolyte Imbalances: Results from Excess or Loss of a particular ion. SODIUM (Na+) Normal plasma level- 136-145 mEq/L
HYPER- Natremia (High Na+) >150 HYPO- Natremia (Low Na+)<
- Edema
- Red flushed skin
- (^) Increased thirst
- Increased body temperature
- Oligurea Treatment: Reduce salt intake Infuse D5W
- Lethargy
- Hypotension
- (^) Stomach cramps
- Vomiting / Diarrhea
- Convulsions Treatment: Ringer's solution or Normal saline infusion
POTASSIUM (K+) Normal plasma level- 3.5-5 mEq/L
HYPER-Kalemia mild-<6.5/moderate 6.5-8/severe >
HYPO-Kalemia <3.
- Abdominal distension
- Diarrhea
- Weakness
- Paralysis
- Cardiac- ventricular fibrillation and cardiac arrest ECG- WIDE QRS complexes,
- Profound weakness and paralysis
- Paralytic ileus
- Enhances digoxin toxicity
- Cardiac: Heart block and cardiac arrest ECG- Flat T waves and low amplitude complexes Treatment:
3rd^ degree heart block and cardiac arrest ECG- PROLONGED P-R segment/ PROLONGED QRS Complex Treatment: Hemodialysis/ Calcium salts
Enhanced digitalis toxicity Treatment: IV fluids with Mg (3-5 mEQ/L) may prevent the condition or 10-40 mEQ/ day to correct and then 10 mEQ/day for maintenance
GI Tract Drugs: The GI tract starts at the oral cavity and ends at the anus. It has associated glands and organs that help the digestive process.
- salivary glands
- gastric glands
- liver
- gall bladder
- pancreas
- intestinal secretions Food is prepared (masticated) in the mouth, transported into the stomach by the esophagus.In the stomach it is broken into smaller particles, sieved and blended. The food is partially digested by stomach acid and is known as 'Chyme'. The chyme is released in small amounts into the duodenum. Here the bile from liver, and pancreatic juices facilitate absorption of the nutrients from the small intestine. Later undigested food and waste is passed on to large intestine by the peristaltic process. In the large intestine the water content from the still liquid chyme is slowly absorbed over the next several hours and this allows solid feces to be formed and expelled out of the anus. Gastric acid secretion depends on acetylcholine (M receptors), hormone gastrin , and histamine. Histamine acts on H2 receptors in the gastric parietal glands. A new class of drugs blocks the H2 receptors at the parietal cells and inhibit acid synthesis. (Ex.Ranitidine p.501) Another class of drugs blocks the enzyme, which exchanges hydrogen/potassium at the secretory side of the parietal gland. They are called H+/K+ ATPase (proton pump) inhibitors. (Ex. Omeprazole, p.500) A bacterium called Helicobacter pylori is found in peptic ulcer patients and eradication of this bug will cure peptic ulcer in majority of cases. The gut motility is controlled by serotonin (5 HT= hydroxy tryptamine). Major quantity of 5HT is found in the gut. The circular smooth muscle of the gut has opiate receptors as well. These two help to control the flow of chyme along the GI tract.
Drugs: Majority of the OTC drugs are used for oral cavity infections, gastric and colonic disorders. (Refer. Table 3-2 p.31, Table 3-3 p.32, Table 3-4 p.34m, Table 3-5 p.36, and figure 3-1 p.32.) They include anti fungal/ anti viral/ anti bacterial. There are antacids, H2 blockers, proton pump inhibitors for gastric acid related disorders. GI motility drugs like cisapride are used as antiemetics and motility facilitators. They work as serotonin agonists. Serotonin blockade at the vomiting center in the brain and in the gut with serotonin receptor antagonists (ondansetron) is a useful adjunct in cancer chemotherapy. (Refer Box: 35-3 p.493) Laxatives are used for increasing large intestine motility and help in constipation relief. Opiate receptor antagonists like immodium control diarrhea. In susceptible individuals use of antibiotics may result in oral candidiasis- 'Thrush'. In patients with H. Pylori infection and having peptic ulcer, a combination of antibiotics (clarithromycin) and proton pump blockade (omeprazole) Common medical problems of the GI tract are- oral infections, gastritis and acid reflux disease, peptic ulcers, gall bladder and liver disorders- cholecystitis, hepatitis, pancreatitis. The intestinal problems include diarrheas, constipation, irritable bowel syndrome, and colitis.
ENDOCRINE SYSTEM: Endocrine = Ductless glands secreting chemical substances "hormones" into the blood stream, and cause effect at a different site of the body. Endocrinal cells are activated in three different ways:
- Tropic - Steroid release controlled by ACTH
- Humoral - Hormones by cell membrane receptors on the cell surface - glucose and insulin
- (^) Neuronal - neuroregulation by hypothalamus / adrenal medulla - adrenaline/epinephrine Hypothalamus is the master controller of the entire endocrine secretion regulation. (Refer: Figure-38-3 page 534). It facilitates the homeostatic response of the body to external factors as perceived by the brain. It has direct neuro regulatory control over the pituitary gland. Pituitary is the major endocrine gland that controls the response by other endocrine glands. Pituitary is the master orchestrator. Hormone receptors are mediator protein molecules. Hormone receptors are of two varieties. Cell surface receptors are found on the outer cell surface plasma membranes and accommodate hormone molecules. They produce a rapid response. The other variety is intra cellular receptors. In contrast thyroxin and steroid group of hormones enter the cell readily and combine with intra cellular receptors to produce their effects. This intracellular activity requires DNA binding and changing the DNA transcription. This causes a slower mode of response by the target tissue. Pituitary:
Thyroid and Parathyroid glands: Note on vitamin D: The plant form is vitamin D2 (ergocalciferol) and needs to be activated in the skin by sun (UV) rays to the active form -D3 (cholecalciferol). This is metabolized in the liver to clacifediol, which is then transported to the kidney. Here it is further converted to calcitriol the most active form. Calcitriol is available and is the preferred dug for patients in renal failure related bone disease. Parathyroid Parathyroid glands activity is on the calcium metabolism. These are 2 pairs of glands situated at the back of the thyroid gland. The thyroid gland secretes calcitonin, which is an antagonist of Parathormone secreted by the parathyroid glands. Parathormone affects calcium metabolism: Inhibits bone resorption Increases calcium absorption and phosphate excretion by kidneys Increase calcium absorption from intestines (Vitamin D dependent) Calcitonin: an antagonist of parathormone secreted by the thyroid gland. Inhibits bone resorption Promotes calcium uptake by osteoblasts Increases urinary excretion of calcium and phosphates Treatment of Osteoporosis and hypocalcemia: (Refer table 40-1 p.547) for Calcium and vitamin D supplements Calcitonin is also useful for treating osteoporosis Biphosphonates (p.548) are also indicated in severe cases Hyperparathyroidism: Increased activity of parathormone leads to hypercalcemia due to:
- (^) Increased calcium reosrption from bone
- Increased absorption of calcium from kidneys and the GI tract
THYROID TSH from pituitary regulates thyroid activity by negative feed back mechanism. The hormone thyroxin is produced by utilization of iodine. Thyroid synthesizes the protein thyroglobulin. There are two active forms of the hormone: triiodothyronine (T3) and tetraiodothyronine (T4). Lack of iodine in the diet leads to 'goiter' (p.536) in adults and cretinism (p.537) in early childhood. Functions of thyroxin- controls growth, CNS metabolism, basal metabolic rate, fat/protein/ carbohydrate metabolism, and cardiovascular and GI tract activities. Disease is caused by over activity (Hyperthyroidism 'Thyrotoxicosis') or Under activity (Hypothyroidism 'Myxedema'/'Cretinism')
Refer Box 40-2 Page 551 Drugs for hyperthyroidism (antithyroid drugs) act by inhibiting iodine uptake by the gland. Propylthiouracil (p.553) Thyroid hormone replacement for hypothyroidism: (refer Table 40-3 p.550) These drugs need to be dose titrated for individual patients, May produce tacgycardia and angina, precipitate heart failure. Thyrotoxicosis: Antithyroid drugs
Class MOA Thioamides: Propylthiouracil Methimazole Iodine containing compounds: Lugol’s iodine (5% iodine/10% K iodide) Beta Blockers:Propranalol Radioactive iodine
Peroxidase inhibitor prevents peripheral conversion of T4 to T Similar as above Side effects: Pruritus / Dizziness/ Leukopenia/ Jaundice Dosage:15-60mg/day Inhibits release of T3 and T Reduces T3 activity on target organs Rapidly concentrates in the gland and destroys the thyroxin producing cells
ADRENAL GLANDS
STEROID hormones are synthesized from basic molecule- cholesterol Major types of steroid hormones are:
- Glucocorticoids - 'cortisone'
- Mineralocorticoids - 'aldosterone'
- Androgens Circadian (24 hour) rhythm of secretion is influenced by dark/light and sleep/wakefulness cycle of body activities. I n addition there are 4-8 periodic or intermittent bursts of CRH/ACTH release activity which is independent of the circadian rhythm known as Ultradian rhythm. Gluco - regulate blood glucose, CHO and Protein metabolism a. Cortisol (hydrocortisone) 10-25 mg /day secreted b. Cortisone 0.5-2.o mg secreted daily c. Corticosterone 30-150 mcg /24 hrs Functions:
- Increase liver glycogen stores
- Increase gluocneogenesis
- (^) Increase lipolysis
- CNS mood effects: Depression/Euphoria
Ocular inflammation Skin IBD (inflammatory bowel diseases - ulcerative colitis and Crohn's disease) Cerebral edema Inhaled in asthma, rhinitis SIDE EFFECTS
- PITUITARY SUPPRESSION
- Increased risk of infection
- Peptic ulceration
- Myopathy
- Steroid psychosis
- Cataracts- posterior subcapsular in children
- Osteoporosis inhibits osteoclast formation, intestinal Ca absorption
- Hyperglycemia
- (^) Arrests growth in children Mineralocorticoids -regulate renal electrolyte and water excretion
- Na+, phosphate, Ca+, bicarbonate retention
- Reduction of K+ absorption by renal tubules Aldostrone: Secreted by adrenal cortex Increased Na reabsorption and increased serum levels of Na Increased K and H ions excretion by kidneys Fludrocrotisone 'Florinef' Acts on distal tubule -Increased reabsorption of Na and K Side effects-Headaches/HTN Indication: Addison' s disease Anti adrenals: Used in Cushing's syndrome Aminoglutehemide MOA- prevents enzymatic action to convert cholesterol Inhibits peripheral tissue conversion of androgens to estrogens (useful in breast cancer treatment) Side effects: ataxia, dizziness, nausea, vomiting, rash, jaundice, bruising Trilostane another compound which blocks steroid synthesis "Metyrapone" Adrenal Medulla - Epinephrine - Neuronal release due to stress "short term response"
Adrenal medulla is under direct control of post synaptic sympathetic nervous system control
Pancreas and Diabetes 16 million Americans are affected and numbers are increasing (7 th^ leading cause of death) Commonest cause for Blindness/End Stage Renal Disease/Limb amputations in USA Terms to remember- Gluconeogenesis : Conversion of excess glucose to glycogen for storage in liver and skeletal muscle. Glycogenolysis : Breakdown of stored glycogen stores in the liver and muscle into glucose Glycogenesis : Conversion of excess blood glucose to glycogen for storage. Hypoglycemia "LOW Blood sugar" Hyperglycemia "HIGH Blood sugar" Islets of Langerhans have the secretory endocrinal cells situated inside the pancreas. There are Beta cells that secrete Insulin and lower the blood sugar Alpha cells that secrete glucagon and increase the blood sugar
Glucose metabolism: (Refer Page 565 Figure 42-1) Lack of insulin causes:
- (^) Reduced rate of glucose transport across cell membranes
- Reduced enzyme activity in converting glucose to glycogen
- Hyperlipemia, ketonemia, Acidosis due to increased lipase activity
- Leads to increased glucagon activity causing increased proteolysis and uremia Features of diabetes mellitus: Glycosurea - sugar in the urine and increased urination Polyphagea - increased eating Polydipsia- increased thirst Ketosis and acidosis- due to faulty glucose metabolism Patholgy: Over a period of time diabetes leads to thickening of the basement membrane (a thin layer of collagen filament which lines the base of the endothelial cells of blood vessels). This results in lack of oxygen to these cells and causes tissue injury and atherosclerosis. Major organs affected this way are: Eyes- leads to retinopathy Neuropathies in feet and legs Nephorpathy leading to renal failure
Treatment: Immediate oral glucose if patient is conscious Glucagon injection IV Glucose
Treatment: Correction of fluid and acid base balance Insulin as needed
Type II diabetics can be managed by dietary carbohydrate control assisted by oral anti diabetic agents. Sulfonylureas- act by stimulating pancreatic beta cells, and also improve insulin binding at insulin receptor sites on target cells. First generation example: Chlorpropamide. But they were associated with increased CVS disease risk. The newer second-generation sulfonylureas have the following benefits:
- Excreted by renal and biliary system. Therefore much safer for patients with renal failure.
- They are not highly protein bound like the first generation and cause less drug-drug interaction.
- They have longer duration of action and therefore can be administered once or twice daily and have better patient compliance with treatment. Examples of second generation: glipizide (Glucatrol) Side effect of sulfonylureas: Hypoglycemia, nausea, vomiting, sulfa allergy. Others: Biguanides- lowers glycogenolysis and increase uptake of glucose by the cells. Does not cause hypoglycemia. (p.573) Acarbose- blocks the enzyme alpha glucosidase in the intestine and prevents absorption of glucose. But has only a mild benefit. (p.572)
Reproductive system: Pituitary hormones FSH and LH (ICSH) regulate both ovaries and testes. In the males FSH controls spermatogenesis and LH causes secretion of testosterone. In the females FSH initiates ovulatory cycle, and proliferative phase of menstrual cycle, enhancing estrogen production. In mid cycle LH release resulting in ovulation and increased secretion of progesterone, and maintain estrogen levels. Elevated levels of estrogen and progesterone are necessary to maintain fertilized egg and it also suppresses further ovulation. Towards the end of the cycle if ovum is not fertilized, the hormone levels drop and menstruation occurs. The cycle repeats itself. Estrogen determines the female secondary sexual characteristics in the female. In the males the GnRH from hypothalamus causes release of FSH and LH resulting in testosterone production and spermatogenesis by the testes. Testosterone determines the secondary sexual characteristics in males.
Drugs affecting the female reproductive system: Basically the hormones estrogen, progesterone are used in various combinations to suppress ovulation and used as contraceptives. Estrogen plays a role in post menopausal hormone replacement therapy. Fertility enhancing drugs include GnRH agonists, clomiphene, menotropina and chorionic gonadotrophins. Other drugs include abortififacients, and labor-related drugs - tocolytics, and oxytocics. Oral contraceptives Estrogen and progesterone pills increase the circulating levels of these two hormones and suppress the release of FSH and LH. This causes suppression of ovulation, and causes contraception. Unwanted effects include: Headache, nervousness, nausea, swelling and weight gain. Cigarette smoking causes more side effects. Other drug-drug interaction may result in failure of contraception and result in pregnancy. (See Table 44-2 p.596 for correct choice of contraceptives) Fertility drugs: GnRH drugs (p.588) stimulate release of FSH and LH. Clomiphene acts by competitive binding at hypothalamic receptors and release GnRH (p.595) Oxytocis: Stimulate uterine contraction. Useful in postpartum hemorrhages. Syntocinon (p.599) Tocolytics: beta2 specific adrenergics, which help the uterine muscle to relax and prevent premature contractions. Ritodrine (p.601) Abortifacients: Useful in evacuating the uterus. Drugs act as endometrial progesterone receptor antagonists. Prostaglandin stimulators enhance uterine contractions and speed up the evacuation process. Testosterone is the prototype androgenic hormone. Used for development of primary and secondary sex characteristics in the male. They also have anabolic (body building) effect as well. Dihydotestosterone is the active molecule for prostatic growth and hypertrophy. Dihydrotestosterone is metabolized from testosterone by the enzyme alpha testosterone reductase. Finasteride is a drug, which blocks this enzyme activity. This MOA is useful in treating prostatic hyypertrophy. (p.605) Androgenic side effects: Acne, edema, hirsuitism, oily skin, weight gain, testicular atrophy. Hepatocellular cancer can also occur. Anabolic steroids: Controlled substances, but have been used illegally by athletes as performance enhancing drugs. Dangers include cardiomyopathy, liver cancer, personality changes, and sexual dysfunctions. Medical indications include: unresponsive anemias of renal failure, cachectic patients, aplastic anemia. Drugs for sexual dysfunction: Many drugs and alcohol interfere with sexual activity.
