Endo, Repro, Teratogens pharm Flashcards
Insulin and its effects
Preproinsulin (synthesized in RER) > cleavage
of “presignal” > proinsulin (stored in secretory
granules) > cleavage of proinsulin > exocytosis
of insulin and C-peptide equally. Insulin and
C-peptide are increased in insulinoma and sulfonylurea
use, whereas exogenous insulin lacks C-peptide.
Glucose is the major regulator of insulin release. INcreased insulin response with oral vs IV glucose because of incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are released after meals and increase β cell sensitivity to glucose. Release decreased by α2, increased by β2 (2 = regulates insulin)
RELEASE:
Glucose enters β cells > increasing ATP generated from glucose metabolism closes K+ channels (target
of sulfonylureas) and depolarizes β cell membrane . Voltage-gated Ca2+ channels open
>leading to Ca2+ influx and stimulation of insulin exocytosis
Binds insulin receptors (tyrosine kinase
activity ), inducing glucose uptake (carrier mediated
transport) into insulin-dependent
tissue and gene transcription.
Anabolic effects of insulin:
increase glucose transport in skeletal muscle and
adipose tissue
increase glycogen synthesis and storage, inhibit lysis
increase triglyceride synthesis
increase Na+ retention (kidneys)
increase protein synthesis (muscles)
increase cellular uptake of K+ and amino acids
decrease glucagon release
decrease lipolysis in adipose tissue
Unlike glucose, insulin does not cross placenta.
Brain utilizes glucose for metabolism normally
and ketone bodies during starvation. RBCs
utilize glucose because they lack mitochondria
for aerobic metabolism.
Nateglinide
Repaglinide
Meglitinides
Used as monotherapy in
type 2 DM or combined with
metformin.
Stimulate postprandial insulin release by binding to K+ channels on β cell membranes (site differs from sulfonylureas).
Hypoglycemia (increase risk with renal failure), weight gain (same as sulfonylureas - increase TG storage).
-no sulfa group so no allergy
INcrease C PEPTIDE
Metformin - biguanides
Oral. First-line therapy in type 2 DM, causes modest weight loss. Can be used in patients WITH NO islet function. [MECH] -Inhibit hepatic gluconeogenesis (inhibits GDPC, increase AMPK - think ENZYMES) and the action of glucagon. decrease gluconeogenesis, increase peripheral glucose uptake ( insulin sensitivity). GI upset; most serious adverse effect is lactic acidosis (thus contraindicated in renal insufficiency). -lactate can't be used for gluconeogensis, also metformin is excreted all renaly with no metabolism.
*increase glycolysis which makes no sense because insulin reduces lysis while glucagon induces lysis.
Pioglitazone
A glitazone/thiazolidinediones
Used as monotherapy in type 2 DM or combined with above agents. Safe to use in --renal impairment.
INcreases insulin sensitivity in peripheral tissue. Binds to
PPAR-γ intracellular nuclear transcription
regulator which is found in muscle, liver, and fat
1. increase glucose utilization
2. decrease glucose production
3. Increases expression of Glut4
4. Produces adiponectin - increasing insulin sensitivity and fatty acid oxidation
-since effects are via gene expression takes days to weeks to lower glucose
Weight gain - differentiation of adipocytes, lowering blood TGs, uptake into cells, increased fat mass
Edema - water retention in the collecting ducts
HF - exacerbation via increased volume
Increase risk of fractures - thought to be because of inhibition of osteoblasts
Genes activated by PPAR-γ regulate fatty acid storage and glucose metabolism. Activation of PPAR-γ INcrease insulin sensitivity and levels of adiponectin.
Acarbose,
Miglitol
"wigglers" no carbs sugar free Inhibit intestinal brush-border α-glucosidases which dissociates polysaccharides into monomers that can be absorbed. . Delayed carbohydrate hydrolysis and glucose absorption > decreasedpostprandial hyperglycemia. SEVERE GI disturbances - really gassy, diarrhea
Exenatide,
liraglutide
GLP-1 analogs
Exenatide,
liraglutide (sc injection)
Type 2 DM. increases glucose-dependent insulin
release, ironically decreases glucagon release,
decreases gastric emptying (slows glucose reabsorption), decreases satiety.
-its glucose dependent so hypoglycemia is NOT a concern.
-HAS C PEPTIDE
Nausea, vomiting, **pancreatitis;
modest weight loss.
-agliptins-
Linagliptin,
Saxagliptin,
Sitagliptin
.DPP-4 inhibitors
Type 2 DM. Inhibit DPP-4 enzyme that deactivates GLP-1, thereby
increasing glucose-dependent insulin
release, decrease glucagon release,
decrease gastric emptying, increase satiety.
Mild urinary or ***respiratory
infections; *weight neutral.
Pramlintide
.Amylin agonist (sc injection)
- **Type 1 DM, type 2 DM. delays gastric emptying, decreases glucagon.
- **amyloid peptide that is usually secreted with insulin and can be used for postprandial glucose spike)
Hypoglycemia (in setting of
mistimed prandial insulin),
nausea.
Canagliflozin,
Dapagliflozin,
Empagliflozin
-agliflozins
.Type 2 DM. Block reabsorption of glucose
in PCT.
Glucosuria leads to: UTIs, vaginal yeast infections, hyperkalemia, dehydration (orthostatic hypotension), weight loss.
The GLUTS
Insulin-dependent glucose transporters:
GLUT4: adipose tissue, striated muscle
(exercise can also increase GLUT4
expression)
Insulin-independent transporters:
GLUT1: RBCs, brain, cornea, placenta
GLUT2 (bidirectional): β islet cells, liver,
kidney, small intestine
GLUT3: brain, placenta
GLUT5 (fructose): spermatocytes, GI tract
BRICK L (insulin-independent glucose uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver.
Glulisine, Aspart, Lispro
gals and lads
Rapid acting Type 1 DM, type 2 DM, GDM (postprandial glucose control). Binds insulin receptor (tyrosine kinase activity).
-Liver: increased glucose stored as
glycogen.
-Muscle: increased glycogen, protein synthesis; increased K+ uptake.
-Fat: increased TG storage.
[ADVERSE]
Hypoglycemia, lipodystrophy,
rare hypersensitivity reactions.
-do not polymerize into hexamers, their onset is 15 min, they can mimic nrmal insulin spike which makes them useful for postprandial
Regular Insulin
NPH
Insulin, short acting
Regular: Type 1 DM, type 2 DM, GDM, DKA (IV), hyperkalemia (+ glucose),
stress hyperglycemia.
-regular insulin is the only one that can be administer IV and so you see its blood implications (hyperkalemia + DKA)
-for IV dilutions it dissociates immediately for fast onset
[Insulin, intermediate acting
NPH]
Type 1 DM, type 2 DM,
GDM.
For both the concerns are expected, hypoglycemia
Detemir, Glargine
Type 1 DM, type 2 DM, GDM
(basal glucose control).
These are long acting with glargine lasting the longest with 24 hrs. Most people with diabetes need a mix of short acting for post meals and long acting.
Chlorpropamide,
Tolbutamide
First gen sulfonyl urea Stimulate release of endogenous insulin in type 2 DM. Require some islet function, so useless in type 1 DM.
BINDS AND CLOSES K+ channel in β cell membrane > cell depolarizes > insulin release via > Ca2+ influx. Risk of hypoglycemia in renal failure, weight gain.
First generation: disulfiram-like effects. Especially alcohol ingestion with chlorpropamide
These are barely used
-INCREASED C PEPTIDE
glimepiride,
glipizide,
glyburide
2nd gen sulfonyl urea Stimulate release of endogenous insulin in type 2 DM. Require some islet function, so useless in type 1 DM.
BINDS AND CLOSES K+ channel in β cell membrane > cell depolarizes > insulin release via > Ca2+ influx. Risk of hypoglycemia in renal failure, weight gain Only hypoglycemia is the concern
-INCREASED C PEPTIDE
Rosiglitazone
A glitazone/thiazolidinediones
Used as monotherapy in type 2 DM or combined with above agents. Safe to use in --renal impairment.
INcreases insulin sensitivity in peripheral tissue. Binds to
PPAR-γ intracellular nuclear transcription
regulator which is found in muscle, liver, and fat
1. increase glucose utilization
2. decrease glucose production
3. Increases expression of Glut4
4. Produces adiponectin - increasing insulin sensitivity and fatty acid oxidation
-since effects are via gene expression takes days to weeks to lower glucose
Weight gain - differentiation of adipocytes, lowering blood TGs, uptake into cells, increased fat mass
Edema - water retention in the collecting ducts
HF - exacerbation via increased volume
Increase risk of fractures - thought to be because of inhibition of osteoblasts
Genes activated by PPAR-γ regulate fatty acid storage and glucose metabolism. Activation of PPAR-γ INcrease insulin sensitivity and levels of adiponectin.
Somatropin used for?
Recombinant GH
These conditions include genetic disorders like Prader-Willi, Turner, and Noonan
Syndromes, as well as Idiopathic Short Stature
Children generally tolerate GH treatment well.
• Adverse events are rare and include pseudotumor cerebri (intracranial
pressure), progression of scoliosis, edema, and hyperglycemia (due to induction
of peripheral insulin resistance)
Toxicities in Adults:
• Adults tend to have more adverse effects from GH therapy.
• Peripheral edema, myalgias, and arthralgias (especially in the hands and wrists)
occur commonly, but remit with dosage reduction.
• Carpal tunnel syndrome can also occur.`
Mecasermin
severe IGF-1 deficiency that
is not responsive to exogenous GH.
• A recombinant form of human IGF-1 termed Mecasermin (Increlex®) has been approved for treatment of severe IGF-1 deficiency
• The most important adverse effect with mecasermin is hypoglycemia, which is
thought to be related to potentiation of the actions of insulin (activates insulin
receptor).
• As a result, the prescribing instructions require consumption of a carbohydratecontaining
meal or snack 20 minutes before or after drug administration.`
Octreotide (Generic) & Lanreotide
Long acting somatostatin analog
Uses: Acromegaly,
carcinoid syndrome (secreting serotonins), gastrinoma,
glucagonoma,
insulinoma
esophageal varices - reduces portal pressure by reducing portal flow.
Nausea, cramps, steatorrhea. increase risk of cholelithiasis due to CCK inhibition.
Pegvisomant
Pegvisomant is a GH receptor antagonist used to treat acromegaly.
• It is a pegylated derivative of a mutant GH that targets the GH receptor, but does
not result in signal transduction.
Can lead to increased GH levels
Urofollitropin, Follitropin a and Follitropin b
Urofollitropin (a.k.a., uFSH) is a purified preparation of human FSH extracted
from the urine of postmenopausal women.
Follitropin a and Follitropin b are recombinant forms of FSH (rFSH) with
shorter half-lives than urofollitropin. They are also much more expensive.
The gonadotropins are used in states of infertility to stimulate spermatogenesis in men and to induce ovulation in women.
• They are generally reserved for anovulatory women who fail to respond to other
less complicated and less expensive forms of treatment (e.g., clomiphene).
Most commonly used for controlled
ovarian hyperstimulation (COH) in
assisted reproductive procedures,
such as in vitro fertilization (IVF).
two most serious
complications are:
1. Ovarian Hyperstimulation Syndrome (OHSS) – 0.5 to 4% of patients
(It is characterized by ovarian enlargement,
ascites, hydrothorax, and hypovolemia,
sometimes resulting in shock.)
2. Multiple Pregnancies – 15 to 20% of patients
Lutropin a
a recombinant form of LH (rLH) available in the US.
• It is approved only for use in combination with follitropin a for stimulation of
follicular development in infertile women with profound LH deficiency.
The gonadotropins are used in states of infertility to stimulate spermatogenesis in
men and to induce ovulation in women.
• They are generally reserved for anovulatory women who fail to respond to other
less complicated and less expensive forms of treatment (e.g., clomiphene)
Most commonly used for controlled
ovarian hyperstimulation (COH) in
assisted reproductive procedures,
such as in vitro fertilization (IVF).
.
two most serious
complications are:
1. Ovarian Hyperstimulation Syndrome (OHSS) – 0.5 to 4% of patients
(It is characterized by ovarian enlargement,
ascites, hydrothorax, and hypovolemia,
sometimes resulting in shock.)
2. Multiple Pregnancies – 15 to 20% of patients
Leuprolide
others (Goserelin, Histrelin, Leuprolide, Nafarelin, and Triptorelin)
Leuprolide
MECHANISM GnRH analog with agonist properties
when used in pulsatile fashion; antagonist
properties when used in continuous fashion
(downregulates GnRH receptor in pituitary
> decreased FSH/LH).
Leuprolide can be used in lieu of GnRH.
CLINICAL USE
Uterine fibroids, endometriosis, precocious
puberty, prostate cancer, infertility.
Adverse effects:
women - causes the typical symptoms of
menopause, which include hot flashes, sweats, and headaches.
Depression, diminished libido, generalized pain, vaginal dryness, and breast
atrophy may also occur.
• Reduced bone density and osteoporosis may occur with prolonged use, so bone
density should be monitored before repeated treatment courses.
In Men
• Adverse effects of continuous treatment include hot flashes, edema,
gynecomastia, decreased libido, decreased hematocrit, reduced bone density,
and asthenia.
Endometriosis
• A syndrome of cyclical abdominal pain in premenopausal women caused by the
presence of estrogen-sensitive endometrium-like tissue outside the uterus.
• The pain of endometriosis is often reduced by abolishing exposure to the cyclical changes in estrogen and progesterone that occur during the menstrual cycle.
• Continuous treatment with a GnRH agonist
greatly reduces estrogen and progesterone
levels and prevents cyclical changes.
Uterine Leiomyomata (Uterine Fibroids)
• Uterine fibroids are benign, estrogen-sensitive, fibrous growths in the uterus that
can cause menorrhagia, with associated anemia and pelvic pain.
• Treatment for 3 to 6 months with a GnRH agonist reduces fibroid size and, when combined with supplemental iron, improves anemia
Anti-androgen therapy is the 1st-line pharmacological therapy for prostate cancer.
• Combined therapy with a continuous GnRH agonist and an androgen receptor
antagonist (such as flutamide or bicalutamide) is effective in reducing serum
testosterone levels and effects
CPP is the onset of secondary sex characteristics before 7 to 8 years of age in
girls or 9 years of age in boys.
• Continuous administration of a GnRH agonist is indicated for treatment of GnRH dependent
- A child whose final height would be otherwise significantly compromised (as evidenced by a significantly advanced bone age).
- A child in whom the development of pubertal secondary sexual
characteristics or menses causes significant emotional distress.
• Treatment most commonly entails a monthly IM depot injection of leuprolide or a
once-yearly implant of histrelin.
• Treatment is generally continued to age 11 in females and to age 12 in males.
Ganirelix, Cetrorelix, and Degarelix
Ganirelix, Cetrorelix, and Degarelix
inhibit the secretion of FSH and LH in a
dose-dependent and more complete manner than do GnRH agonists.
controlled ovarian
hyperstimulation procedures, with a lower risk of OHSS than with GnRH agonists.
approved for the treatment of symptomatic advanced prostate
cancer.
• Like continuous treatment with GnRH agonists, degarelix leads to the signs and
symptoms of androgen deprivation (e.g., hot flashes and edema).
