Pharm Test 3- Endocrine

Catecholamines (EPI, NE)

Corticosteroids:
1)Glucocorticoids- Cortisone, prednisone (influences carbs and glucose metab) 2)mineralocorticoids- aldosterone (moderate salt and water balance)
3) Androgens- expression of sexual characteristics

Androgens, progesterone and estrogens

Excess of adrenal hormone

Adrenal Hormone deficiency

Stress factors cause the hypothalamus to release corticotropin-releasing hormone (CRH) which activates the anterior pituitary to release adrenocorticotropic hormone (ACTH).

ACTH causes the adrenal cortex to release glucocorticoids, estrogens, androgens and cortisol

Circulating cortisol then feeds back to the hypothalamus to stop producing CRH & ACTH which inhibits cortisol's own synthesis and release therefore maintaining a safe level of glucocorticoids.

They suppress the release of CRH from the hypothalamus & ACTH front he anterior pituitary, thereby inhibiting the release of endogenous glucocorticoids by the adrenals.

the pituitary loses its ability to manufacture ACTH & thus the adrenals stop synthesizing cortisol & other glucocorticoids.
So when a pt. abruptly stop taking exogenous glucocorticoids it takes time for the adrenals to get back to normal (5 days to 1 year)

Hypotension
hypoglycemia
myalgia (pain in muscle)
arthralgia (pain in joint)
fatigue

Increase the availability of glucose (Cortisol) cause hyperglycemia

Physiologic effect – occur at low levels produced from the adrenal cortex and drugs are used to tx adrenocortical insufficiency. No toxic effects when used at physiologic doses. At Pharmacologic high doses (exogenous doses) more intense effects will be seen.

1) Stimulation of gluconeogenesis & glucose secretion by the liver
2) Increasing the hepatic sensitivity to the gluconeogenic actions of glucagon and catecholamines
3) Decreasing glucose uptake and utilization by peripheral tissue (adipose and muscle)
4) Promotion of glucose storage
5) Increasing proteolysis and decreasing protein synthesis in muscles to support the gluconeogenesis activities

Main pharmacologic effect of glucocorticoids is to suppress immune system and inflammation (swelling, redness, warmth & pain) by inhibiting chemical mediators

Glucocorticoids act differently than NSAIDs

Glucocorticoids bind to DNA and does RNA coding for protein synthesis

NSAIDs act by inhibiting prostaglandin synthesis
**Glucocorticoids have much greater anti-inflammatory actions than do NSAIDs***

Take in the morning and with food.

Rheumatoid Arthritis – reduce inflammation & pain but does not alter dz.
Local injections are effective and less toxic than systemic tx

Systemic Lupus
Erythematosus (SLE)
Inflammatory Bowel dz

Misc. Inflammatory Disorders (Ulcerative Colitis & Crohn’s dz (PO & IV) & Allergic rxn’s (bee stings, drug rxn’s, poison ivy etc…)

-Usually seen at high doses, & are usually brief with tapered doses
-Adrenal insufficiency
-Osteoporosis – (check bone mineral density with long term tx b/4 tx starts) give Ca++ with vit D. Dec Na+ intake & give thiazide diuretic with bisphosphonates or calcitonin. Long term tx have bone mineral density because high dose/long term tx can inhibit Ca++ absorption, dec bone formation of osteoblast & accelerate the bone resorption of osteoclasts. More likely with systemic tx.
-Infection – (Pneumocystis carinii pneumonia (PCP) possible prophylaxis tx necessary
-Glucose intolerance – can inc plasma glucose levels (hyperglycemia)
-Myopathy – muscle weakness (arms & legs)

Pregnancy - Crosses placenta (cleft palate, spontaneous abortion & low birth weight)

Lactation – enter breast milk (doses > 5 mg/day prednisone) cause growth retardation

Digoxin, thiazide & loop diuretics- because of K+ loss watch for cardiotoxicity. Glucocorticoids with high mineralocorticoid activity (cortisone & hydrocortisone) can cause retention of Na+ and H2O and K+ depletion (caution in pts with HTN, CHF & if taking digoxin)
-NSAID’s
-Insulin & oral hypoglycemics (may need insulin & hypoglycemic agents.
-Vaccines – can dec antibody rxn to vaccines esp. if live vaccine can develop viral inf.(do not give vaccines if taking glucocorticoids)

Contraindications:
Do not give with systemic fungal infections or if giving live vaccines

Precautions-
Pediatric patients, pregnant women, breast feeding, HTN, heart failure, renal impairment, esophagitis, gastritis, PUD, myasthenia gravis , diabetes, osteoporosis, diuretics, digoxin, insulin, hypoglycemics (or hyper!) & NSAIDs

If you have high mineralocorticoids DO NOT administer systemically for long periods of time

PO, IV, IM, SQ, topically, local injection or inhalation

Prolonged tx with high doses only done if: life threatening, threat of permanent disability (may need to increase dose in times of stress)

1) A mobilization of fatty acids, converting cell metabolism from using glucose for energy to using fatty acids for energy
2) Antagonistic effect on antidiuretic hormones to maintain water balance
3) Reduction in the amount of new bone synthesis
4) Allows the body to deal with stress by allowing epi and glucagon to activate gluconeogenesis and glycogenolysis

1) Extracellular Na+ & K+ levels – when serum Na+ levels are low or K+ levels are high, aldosterone levels rise
2) Renal renin release – a reduction in renal blood flow inc aldosterone levels by the renin-angiotensin-aldosterone system (RAS)
3) Pituitary ACTH – the glucocorticoid hormones produced in the adrenal cortex have mineralocorticoid effects

Has both high minealocorticoid and glucocotricoid activity
Used for adrenocortical insufficiency (Addison dz)
and for tx of salt-losing adrenogenital syndrome

Readily absorbed from the GI tract with peak conc. in 1.7 h
Metabolized by the liver and excreted by the kidney
Crosses the placenta and is excreted into the breast milk (use cautiously)
Use cautiously in pts. with cardiovascular dz due to Na+ & fluid levels

Acts on the distal renal tubule to enhance the reabsorption of Na+ and to inc the urinary excretion of both K+ & H+ ions
Low doses – mineralocorticoid effect K+ excretion and Na+ retention which inc blood pressure
High dose – glucocorticoid activity

systemic fungal infection

conditions not requiring mineralocorticoid activity

Small dose- Na+ retention and K+ excretion causing inc BP

Large dose-
1) Inhibits endogenous adrenal cortical secretions & pituitary corticotropin excretion
2) Promotes the deposition of liver glycogen

Macrovascular damage –
heart dz,
HTN & stroke usually due to artherosclerosis (hyperglycemia & lipid metabolism)

test on 2 separate days & both must be positive

Diet – caloric intake should be spread throughout the day
Exercise – inc response to insulin & inc glucose tolerance
Insulin replacement – Since pancreas is basically dead it produces no insulin so daily doses of insulin are needed.
ACE inh or ARB – helps prevent diabetic neuropathy & diabetic HTN (goal 130/80 mm/Hg)

“Statins” – reduce high levels of LDL (prevents CV events) possibly should be given to all diabetic pts.

Glycemic control (diet & exercise) – In type 2 most pts are obese and diet & exercise can normalize insulin release & dec insulin resistance

Glycemic control with drug tx – PO, insulin & injectable
Initiate diet exercise
Initiate drug tx with one drug
Add second drug
Add third drug
Add insulin
Tx with insulin alone

Hemoglobin A1c (HbA1c) –accesses long term progress over 3 months. Binds to Hbg in RBCs & HbA1c inc during hyperglycemia. So it reflects the average glucose level.

Goal is to keep HbA1c < 7% (measure 2 to 4 x’s/yr)

Insulin is ANABOLIC

*Insulin synthesized in the pancreas by beta cells within the islets of Langerhans and is secreted by sympathetic activation of beta receptors in the pancreas.


Activation of alpha cells in the pancreas inhibit release of insulin*

Deficiency puts body in catabolic State

-Glycogen will break down into glucose, proteins into AA and fats into glycol
THIS IS WHAT CONTRIBUTES TO THE S/SX of DIABETES

Insulin deficiency promotes hyperglycemia in 3 ways:
1) inc glycogenolysis (breakdown of glycogen to glucose)
2) inc gluconeogenesis (breakdown of protein & fats to form AA & fatty acids.
3) reduced glucose utilization (dec cellular uptake & dec conversion from glucose to glycogen)

Rapid acting/Short duration: lispro (Humalog), aspart (NovoLog), glulisine (Apidra)

Slower acting/Short duration: Regular (Humulin R)

Intermediate duration: NPH insulin (Humulin N, Novolin N & Exubera)

Long duration: Glargine (Lantus)

Give with meals to control postprandial rise in glucose to control glucose between meals & HS.
-Clear solutions
All 3 require prescriptions (Insulin Lispro, Aspart & Glulisine)
Do NOT give IV

Effects begin within 15-30 min of SQ inj. and last 3-6 h
Acts faster than R but shorter DOA
Can give before or after eating (insulin R is given 30-60 min b/4 meals)

Short Duration/Rapid Acting


Rapid onset 10-20 min & short DOA 3-5 h
Give 5-10 min AC

Short duration/Rapid Acting


Rapid onset 10-15 min & short DOA 3-5 h
Do not give 15 min AC & no later than 20 min PC
Administered SQ inj or continuous SQ infusion but NOT IV

Regular insulin (Humulin R, Novolin R & Exubera):

-SQ inj, SQ infusion, IM inj, oral inhalation & off label IV
-Only insulin given by IV *****
-Can be inhaled or injected AC to control postprandial hyperglycemia
-Infused SQ to provide basal glycemic control
-Humulin & Novolin R are available without prescription. Exubera needs prescription

Cloudy suspension should be gently shaken b/4 administration

Available without prescription

The protamine component slows absorption & delays DOA

Do not administer at mealtime but use bid between meals & at bedtime

Is the only long acting insulin that can be mixed with a short acting insulin

Clear colorless solution, dosed qd-bid SQ injection. Do NOT give IV nor mixed with other insulins
Available by prescription only
Slow onset & dose dependant DOA. At low doses(0.2 units/kg) persist about 12 h. At higher doses (0.4 units/kg) persist 20-24 h.
Because of slow onset it is used for basal glycemic control
It is not given before meals for postprandial hyperglycemia

Insulin Glargine (Lantus):
Clear colorless solution, do NOT mix with other insulins and do NOT give IV
Long DOA 24 h, qd dosing SQ injection*****
Because of long DOA and a stable steady state there is less risk of hypo or hyperglycemia.

-All insulins made in the U.S.A. are clear and colorless except NPH. Except for NPH discard insulin that has any precipitate.
-If have to give a short acting & long acting insulin mix the preparations rather than inject them separately.
-ONLY NPH is appropriate for mixing with short acting insulins (R, lispro, aspart & glulisine)
-Draw short acting insulin into syringe first to avoid contamination of NPH vial.

Beta Blockers
-It will also cause further hypoglycemia by blocking glycogenolysis

Thiazides
Glucocorticoids
sympathomimetics

BG <50 mg/dl

Much worse than hyperglycemia!

S/Sx:
-SNS activation *tachycardia, palpitations, sweating, nervousness)
-HA, confusion, drowsiness, fatigue

-take fast acting sugar

produced by alpha cells in the pancreas. Increases plasma levels of glucose and relaxes smooth muscle in the Gi tract

Stimulates the release of insulin from pancreas depending on how much glucose there is (insulin sensitivity)

Only works in type 2 diabetes
Can be used alone or in combo
Avoid during pregnancy/nursing mothers

Hypoglycemia (fatigue, excessive hunger, profuse sweating, palpitations)
Weight gain

Alcohol (disulfuram rxn)
Drugs that intensify hypoglycemia: NSAIS’s, sufonamide antibiotics, ranitidine & cimetidine
Beta blockers – beta rec promote insulin release & mask S/Sx of hypoglycemia

Repaglinide
Nateglinide

MOA-

Stimulates the release of insulin from pancreas depending on how much glucose there is. It is glucose dependant (if no glucose no insulin is produced) pt MUST eat no longer than 30 min after drug intake
Only approved for type 2
If no response with sulfonylureas there will be no response with metglitinides
Approved for monotx or combo with metformin or a glitazone

Metformin


Dec glucose production in the liver & enhances glucose uptake & utilization by muscle. Does NOT promote insulin release
Because of MOA could possibly use it in pts with type 1 also
Can be used alone or with sulfonylureas or Exenatide
Absorbed slowly from small intestine and excreted unchanged in the kidneys (Check renal fxn, creatine cl)

Contraindicated:


Males with creatine clearance > 1.5
Females with creatine clearance > 1.4
Liver dz, severe infection, alcohol excess or pt. with shock (cause hypoxemia), alcohol use

Dec insulin resistance by inc insulin sensitivity of skeletal muscle, liver & adipose tissue (cellular response to insulin inc). Insulin must be present for drug to work.
Only approve for type 2
Approved for monotx & for combo with metformin, sulfonylurea or insulin (carefully b/c insulin & glitizones cz edema)

Fluid retention (edema & wt gain), inc HDL, LDL and triglycerides
Contraindicated in Class III or IV heart failure or hepatoxicity

Acarbose (Precose) & Miglitol (Glyset)

MOA
Dec absorption of carbohydrates, by preventing their breakdown into monosaccharides, in the small intestine. It dec the rise in glucose after a meal.
Can be used in monotherapy or with insulin, sulfonylurea or metformin (try to avoid metformin & alpha-gluc together b/c of GI affects)

Pramlintides

Delays gastric emptying and suppresses glucagon secretion. Also acts to inc sense of satiety, and can thereby lower caloric intake.
Can be used in type 1 or 2
Used as an adjunct to insulin in type 1 & 2 in pts that have not glucose control even with insulin.
In type 2 in combo with metformin &/or a sulfonlyurea
Peaks in 20 min after SQ injection

Exenatide


MOA
Slows gastric emptying, stimulates glucose-dependent release of insulin, inhibits postprandial release of glucagon & suppresses appetite
Give oral drugs at least 1h before Exenatide
Used to improve glycemic control of type 2 taking metformin a sulfonylurea or both
Should not be used in pts with end-stage renal dz.

Thyroid produces 2 hormones triiodothyronine (T3) & thyroxine (T4, tetraiodothyronine). T3 is the more potent. MOST of the effects of thyroid hormones are mediated by T3 not T4. So T4 serves only as a source for T3.

Usually dosed as in AM.

Metabolized in liver & excreted in the urine

Overdose: irritability, insomnia, tachycardia, arrhythmias, inc. blood pressure anxiety, wt. loss

Thyroid contraindicated in pts. with recent MI. If have to use start low dose & titrate slowly over 3 wks.

Potentiates effects of other adrenergic agonist drugs being used

May produce inhibitory effects if pt. using adrenergic antagonist

All thyroid preparations are metabolized in the liver & excreted in the urine

1) stimulation of energy use, which elevates basal metabolic rate resulting in inc O2 & inc heart rate production. Speeds metabolism of fats, carbs & proteins
2) stimulation of the heart, which stimulates both rate & force of contraction resulting in inc cardiac output and an inc in O2 demand.
3) promotion of growth & development during fetal stages, maturation of skeletal muscle, reproductive system, development of the brain & CNS.
4) increases the production & release of other hormones, estrogen, testosterone, insulin catecholamines (epi, NE) & glucocorticoids (esp. cortisol)
5) stimulates appetite

Natural Thyroid Extract T3 &T4: desiccated thyroid (Armour Thyroid)

Synthetic name for T3: liothyronine (Cytomel)

Synthetic name for T4: levothyroxine, L-Thyroxine (Synthroid, Levoxyl, Levothroid)

A mixture of T4 & T3, 4:1 mixture: liotrix (Thyrolar)
Liothyronine is better absorbed then levothyroxine
Levothyroxine is available IV

T3 & T4
Animal extract, desiccated thyroid (identical to natural hormone)
Dispensed in mg and grains (15, 30, 60 90 & 120 grains)
Levothyroxine, L-thyroxine: (Synthroid, Levoxyl, Levothroid)
T4 rapidly converted to T3, No real advantage of combing T3 & T4. (PO, injection)
Low cost, synthetic (minimal allergic rxn), Long DOA
Half-life approx 7 days, PO onset 3-5 days , IV 6-8 h. Take 4-8 wks b/4 full effects of dosage adjustments can be seen.

Available T3 & does NOT require conversion of T4 so has faster onset of axn.
Synthetic (minimal allergic rxn), PO & injection
Better absorbed & more potent than levothyroxine
Long DOA 3 days shorter DOA than levothyroxine
Can see effects of dosage adjustments in 1 to 2 wks.
Serum T3 fluctuates so serum level high after admin & low at end of day, because of fluctuation not recommended for maintenance.
More cardiotoxic than levothyroxine
Liotrix: (Thyrolar)
T4 & T3 (4:1 ratio by weight)
Synthetic (minimal allergic rxn)

Severe deficiency of thyroid hormone

Hypothyroidism in infancy

pale face, puffy, expressionless, skin cold & dry, hair is brittle, hair loss, heart rate & temp is lowered, lethargy, fatigue, intolerance to cold, mentally may be impaired, goiter if low T3 & T4 promotes excessive TSH release.

T4 identical to the naturally occurring hormone. T4 will be converted to T3
Narrow therapeutic range, test TSH 6-8 wk after initiation of tx
Take on empty stomach in the morning 30 min ac.
Pharmacokinetics:
Variable absorption; metabolized liver; elimination bile/feces; slow onset with long DOA; half-life 6-7 days b/c protein bound; full effects in 2-3 wk. qd dosing

Variable absorption; metabolized liver; elimination bile/feces; slow onset with long DOA; half-life 6-7 days b/c protein bound; full effects in 2-3 wk. qd dosing

Pharmacodynamics:
Binds to rec throughout body to inc metabolic rate; stimulates protein synthesis; promotes cell growth

Wt loss, palpitations, tachycardia, angina, CHF, tremors, nervousness, HA, insomnia, menstrual irregularities, impotence, > bowel motility, hyperthermia, heat intolerance & sweating

Cholestyramine (Questran), Colestipol (Colestid)
Ca++ supplements (Tums, Os-Cal), Sucralfate (Carafate), Aluminum-containing antacids (Maalox, Mylanta)
Iron supplements (Ferrous sulfate)

Phenytoin (Dilantin), Carbamazepine (Tegretol, Carbatrol)
Rifampin, Sertraline (Zoloft), Phenobarbital

Warfarin (levothyroxine acceleration of Vit K) dose of warfarin may need to be reduced if pt taking levothyroxine & warfarin

Thyroid hormones inc cardiac responsiveness to catecholemines (epi, dopamine, dobutamine)

Hyperthyroidism

Autoimmune disorder

Exophthalmos (protrusion of the eyeballs), enlarged thyroid gland

Thyrotoxicosis - Elevated thyroid hormone, rapid heartbeat, dysrhythmias & angina, wt loss even though appetite is inc b/c metabolism is inc

Treatment – PTU, beta blocker, exophthalmos use glucocorticoids

hyperthyroid

Clinical manifestations are same as Graves disease without exophthalmos

Hyperthyroid

No laboratory test to confirm
S/Sx – hyperthermia (>105° C), hypotension, CHF

Treatment – potassium iodide or iodine soln, beta blocker, PTU

antithyroid drugs (propylthiouracil (PTU), Methimazole)
Radiation or Surgery

Quick onset of action 30 min to 1 h; half life 75 min so dosing throughout day; crosses placenta & can enter breast milk; PTU is used during pregnancy. Use for nursing mothers is controversial but is preferred over methimazole

Take with food
If dose missed, take ASAP
Store in light resistant container
Report wt gain, cold intolerance, depression, bruising, bleeding, fever & sore throat
Usually TID dosing & usually reduced to qd dosing later with high rate of recurrence once tx dc’ed (50-70% recurrence) & may produce hypothyroidism w/ long term tx (20% incidence)
Takes 6 -12 wks to become euthyroid
May cause: rashes, urticaria, N/V, agranulocytosis, Thrombocytopenia, hepatotoxicity & hepatic necrosis

Methimazole (Tapazole)
NOT protein bound
More potent & less toxic than PTU
Long DOA (several wks) & provides better control of hyperthyroidism
The only specific CI is women that are lactating

Usually Propranolol (Inderal or Inderal LA):(PO, IV) for emergency use

Qd – qid dosing, Rapid onset of axn 1 h

Does NOT correct hyperthyroidism ONLY controls the adrenergic effects of excessive thyroid hormone until slower-acting anti-thyroid medications can take effect