Pharm E3: Endocrine

which type of diabetes is characterized by extensive and selective loss of B-cells from the pancreas?

type 1 diabetes → autoimmune dz (type 1A) is MC

how is insulin cleared?

hepatic = 60%

renal = 40%

what does insulin do?

1. stimulates glucose uptake into target tissues (GLUT4)

2. initiates phosphorylation cascade within cells, translocated glucose transporters from inside cell to the cell surface

what are the effects of insulin in the liver?

stimulates: storage as glycogen, conversion to fatty acids, VLDL then adipose

inhibits: glycogenolysis, gluconeogenesis, conversion of fatty acids to ketones

what are the effects of insulin in skeletal muscle?

stimulates: storage as glycogen; storage of amino acids as protein (grow muscle)

inhibits: protein degradation into amino acids

what are the effects of insulin on adipose tissue?

stimulates: storage of fatty acids as TGs

inhibits: conversion of TGs to fatty acids

which insulins are ultra-short acting?

Lispro

Aspart

Glulisine

which insulins are short acting?

Regular (Humulin, Novolin)

which insulin is intermediate acting?

NPH (contains protamine)

which insulin is long-acting?

ultralente

which insulin is ultra-long acting?

glargine (lantus)

determir (levemir)

degludec (tresiba)

useful for basal insulin

which insulin is inhaled?

afrezza

what are the different insulin delivery methods?

injection (conventional)

portable pen injector (cartridges)

continuous subq infusion (pump)

inhaled Afrezza (dry powder)

which type of insulin should be used in continuous subcutaneous infusions?

short acting

when should you take rapid-acting insulin?

before meals (15-30 min onset)

what are the complications of insulin use?

hypoglycemia

immunopathology

lipodystrophy at injection site

weight gain

which drugs may decrease the hypoglycemic effect of insulin (making it less effective, requiring more insulin)?

1. oral contraceptives

2. corticosteroids

3. dobutamine

4. epi

5. niacin

6. smoking

7. thiazides

8. thyroid hormone

which drugs may INCREASE the hypoglycemic effects of insulin (making it more effective)?

1. alcohol

2. alpha blockers

3. anabolic steroids

4. beta blockers

5. MAO inhibitors

what are the indications for insulin?

1. all newly dx type 1 pts

2. pregnant women with type 2 DM or women who develop gestational DM

3. type II DM not controlled by diet, exercise, and oral meds

4. DKA

5. hyperglycemic hyperosmolar nonketoic syndrome (HHNS)

6. hyperkalemia

how does insulin treat hyperkalemia?

pushes K+ back into the cell

what are the pros and cons for more frequent insulin administrations?

pro = tighter glycemic control

con = increased complexity

what are the pros and cons for less frequent insulin administrations?

pro = less chance of hypoglycemia

con = looser glycemic control

how should insulin doses be changed according to diet?

change depending on carb intake and exercise

which type of insulin doses are taken in the morning and evening (basal)?

long acting ***

which type of insulin doses are taken around meals (bolus)?

regular or ultra rapid acting ***

why do type 2 DM require larger doses of insulin?

insulin resistance

how do you calculate the total insulin/day for T1 diabetics?

0.5 x weight (kg)

what is the rule of 15 for?

to correct hypoglycemia

15g of simple carbs (8 oz of OJ or 4 glucose tabs)

check glucose in 15 mins

if BG <70, repeat!

how should you treat hypoglycemia if a pt is unconscious?

glucagon

dextrose IV

what adverse rxn may occur after a glucagon injection?

n/v

what is another use for glucagon besides hypoglycemia?

pass FB in esophagus → bc of smooth muscle relaxation in GI tract

what may high concentrations of dextrose IV cause?

thrombophlebitis

what is the first line of treatment for DM2?

lifestyle changes

which drugs can stimulate the pancreas to make more insulin?

sulfonylureas/meglitinides

which drugs may sensitize the body to insulin and/or control hepatic glucose production?

thiazolidinediones

biguanides

which drugs may show the absroption of starches?

alpha-glucosidase inhibitors

which drugs suppress glucagon, decrease gastric emptying, and decrease food intake?

incretins (glucagon-like peptides)

which drugs may decrease reabsorption of glucose from renal tubules?

SLGT2 inhibitors

what are the first generation sulfonylureas?

chlorpropamide (diabinese)

what are the second generation sulfonylureas?

Glyburide

Glipizide

Glimepiride

how are sulfonylureas metabolized and excreted?

metabolized in liver

excreted in urine

use caution in liver/renal failure

do sulfonylureas cross the placenta?

YES! → may deplete insulin from fetal pancreas

which drug may cause disulfiram reaction with alcohol?

chlorpropamide → also avoid in elderly

which sulfonylureas are more likley to produce hypoglycemia?

chlorpropamide

glyburide

what are the adverse effects of sulfonylureas?

hypoglycemia

weight gain

constipation, n/d

rash, pruritis

leucopenia, ttp, aplastic anemia

resistance may develop

what are the contraindications for sulfonylureas?

DKA

T1D

pregnancy/breastfeeding

what interacttions may occur with sulfonylureas?

protein binding

hyperglycemic drugs decrease effectiveness

disulfiram- like rxn

which drugs are meglitinides?

Repaglinide (prandin)

Nateglinide (starlix)

what is the MOA of meglitinides?

block ATP-dependent K+ channels in beta cells → increase insulin secretion

what are the adverse effects of meglitinides?

hypoglycemia

weight gain

HA

Nausea

joint pain

use in caution w/ liver probs (hepatic metabolism)

which drugs are biguanides (oral antihyperglycemics)?

metformin (glucophage)

what is the MOA of Biguanides?

- decrease hepatic glucose production

- increase peripheral glucose uptake and utilization

- decrease glucose absorption from GI tract

what are the contraindications of metformin?***

- renal disease (GFR <30)

- metabolic acidosis or hypoxia

- hepatic disease

- cationic drugs compete for tubular excretion

- should be stopped before surgery d/t lactic acid

does metformin cause weight gain?

no → may be useful in obese pts with insulin resistance and HLD

how is metformin excreted?

unchanged in urine→don't use in renal impairment

what are the adverse effects of metformin?

- GI effects (anorexia, constipation, heartburn, diarrhea)

- lactic acidosis

- rash

- megaloblastic anemia (dec. B12)

which drugs are thiazolidinediones?

Pioglitazone

Rosiglitazone

Troglitazone (removed d/t liver tox)

metabolized in liver

what are the adverse effects of TZDs?

- expanded blood volume, edema, worsen HF

- HA, fatigue

- muscle pain

- weight gain

- increase HDL, LDL, variable TG

- monitor liver enzymes q2 months

which drugs may cause increased flatulence?

alpha-glucosidase inhibitors

which drugs are alpha-glucosidase inhibtors?

acarbose (precose)

miglitol (glyset)

what is the MOA of alpha-glucosidase inhibitors?

competitive inhibitors of a-amylase and a-glucosidase enzymes in intestinal brush border → decrease glucose absorption

how is acarbose metabolized?

intestinal bacteria?

how is miglitol excreted?

unchanged via kidneys

in which sx are use of alpha-glucosidase inhibitors contraindicated?

IBD

GI obstruction/ulceration

chronic intestinal disease

how do incretins work?

GLP-1 suppresses glucagon levels after meal, glucagon increases during fasting, increase glucose production → decreases gastric emptying and slows peak glucose absorption → increased satiety

what are the adverse effects of Exenatide?

- n/v

- hypoglycemia with sulfonylureas

- delay absorption of other oral meds

- weight loss

- pancreatitis

which drugs are incretins?

Exenatide

Liraglutide

Dulaglutide (Trulicity)

Albiglutide

which drugs are DPP-4 inhibitors?

Sitagliptin

Saxagliptin

Linagliptin

Alogliptin

what are the adverse effects of DPP-4i?

diarrhea, HA

angioedema

anaphylaxis

skin rash → SJS!!!

which drugs are SGLT2 inhibitors?

Canagliflozin (Invokana)

Dapagliflozin (Farxiga)

Empagliflozin (Jardiance)

what is the MOA of SGLT2 inhibitors?

inhibits SGLT2 in proximal renal tubules, inhibits reabsorption of filtered glucose →increased RENAL elimination of glucose → lowered blood sugar and body weight

what are the adverse effects of SGLT2 inhibitors?

- fungal UTIs

- hypotension

- raise serum K+/decreased kidney function

- bone resorption/bone fx risk (canagliflozin)

- risk for DKA (euglycemic)

what can be used to treat hyperprolactinemia?

dopamine agonists → bromocriptine, carbergoline

which drug can be used to for ovulation induction in hyperprolactinemia?

bromocriptine

what are the physiologic actions of testosterone and DHT?

T = internal genitalia, skeletal muscle, erythropoiesis

DHT = external genitalia, hair follicles

what are the physiologic actions of estrogen?

epiphyses, libido

what are the therapeutic uses of androgens?

- male infertility

- loss of gonadal function

- osteoporosis

- in HRT combined with estrogens

- inoperable breast Ca

- offset weight loss d/t burns, trauma, AIDs, COPD, other chronic dz

what are the therapeutic uses of anti-androgens?

metastatic prostate cancer

tx hirsutism in women

which drugs are AR antagonists?

flutamide (evlexin)

bicalutamide (casodex)

which drugs are mixed AR/MR antagonists?

spironolactone (aldactone)

what are the side effects of androgens?

- prostatic enlargement/prostate cancer

- testicular atrophy, azoospermia

- gynecomastia, acne

- erythrocytosis (not in most men)

- increased sodium/water retention (problem in CHF)

- masculinization in women

- hepatic effects (esp in oral admin)

what are the possible hepatic effects from oral administration of androgens?

first pass effect = liver actions

- cholestasis

- reduced HDLs

- maybe hepatitis

which drugs are DHT inhibitors?

finasteride (proscar, propecia)

dutasteride (avodart)

which drugs are GnRH analogues?

goserelin

leuprolide (lupron)

lowers testosterone production

what are pts with Addison's disease treated with?

20-30 mg hydrocortisone daily

increase amounts during stress

what drug must be given to pts with Addison's disease in addition to hydrocortisone?

fludrocortisone → salt-retaining hormone

what is the drug of choice for tx of hypothyroidism?

levothyroxine T4 (levothroid, synthroid)

which minerals interfere with absorption of levothyroxine?

iron, calcium, aluminum

which drugs enhance excretion of levothyroxine?

drugs that induce hepatic P450

which drug can be used for hypothyroidism if quick onset is desired?

liothyronine T3 (Cytomel, triostat)

which drugs are antithyroid drugs for hyperthyroidism?

- thioureylenes (thioamine family)

- propylthiouracil (PTU)

- methimazole (tapazole)

which hyperthyroidism drug has decreased metabolism in pts with severe liver disease?

methimazole (Tapazole)

10x more potent than PTU

what are the complications of hyperthyroidism drugs?

agranulocytosis

granulocytopenia

decreased lymphocytes/monocytes

what is the MOA of antithyroid drugs?

interferes with oxidation of iodide by inhibition of peroxidase enzyme,

interferes w organification of iodine

requires depletion of iodinated thyroglobulin stores in colloid before clinical effects become evident

which drugs are iodines, used to treat hyperthyroidism?

SSKI and lugol's solution

what are the side effects of iodides?

iodism → rash, swollen salivary glands, fever, mucous membrane ulcerations

which drug can be used prophylactically when at risk of radiation exposure?

iodides

use of which drugs may cause high incidence of delayed hypothyroidism?

radioactive iodine

what is used for emergency treatment of thyroid storm (thyrotoxic crisis)?

iodinated contrast media (Ipodate) → blocks conversion of T4 to T3