Post on 07-Aug-2020
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Pituitary (GH) and Thyroid Pharmacology
JACOBS Wednesday, Jan 20
2:00 – 3:50 PM
PHPP 516 (IT-II) Spring 2016
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Pituitary (GH) Pharmacology
HYPOTHALAMUS • Releasing Hormones (GHRH, TRH, CRH, GnRH) • Dopamine (DA, PIF) • Somatostatin (SST)
ANTERIOR • GH* • TSH • ACTH • LH, FSH • PRL
POSTERIOR • AVP • OT
*5-10 mg stored – most abundant hormone in pituitary
1. GH Axis 2. Regulation of GH release 3. GH signaling, physiological effects 4. IGF-1 signaling, physiological effects
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LECTURE OVERVIEW
Pituitary (GH) Pharmacology
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Hormones that regulate GROWTH Growth Hormone (indirect: via IGF-1)
OTHERS: Insulin-like Growth Factors (IGF-1, IGF-2) Fibroblast Growth Factors (FGF-1, FGF-2) Thyroid hormone (T3) Insulin Sex Steroids
Pituitary (GH) Pharmacology
Pituitary GH
GHRH Hypothalamus SST
Bone, Muscle, Soft Tissues GROWTH
PRO-INSULIN Effects
NORMAL GH Axis
Somatomedins (IGF-1)
Liver
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Muscle, Adipose ANTI-INSULIN Effects
Pituitary (GH) Pharmacology
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GHRH: Growth Hormone Releasing Hormone Released from Hypothalamus Travels through portal blood
GH: Growth Hormone
Released from Anterior Pituitary (also from placenta during pregnancy) • Highly similar to prolactin (PRL)
causes release of:
Pituitary (GH) Pharmacology
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GHRH Receptor
ATP cAMP
SOMATOTROPH (Anterior Pituitary)
GHRH
GH Gene Expression
Ca2+
P
Gas AC
GH GH
GH
GH
Pituitary (GH) Pharmacology
STIMULATE release
HYPOGLYCEMIA SLEEP ADRENERGIC (EPI/NE) ACTIVITY
INHIBIT release
EATING (GLUCOSE + FATTY ACIDS) GLUCOCORTICOIDS (CORTISOL) IGF-1 (Negative feedback)
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Control of GHRH/GH Release
Pituitary (GH) Pharmacology
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Control of GHRH/GH Release GHRH
ANABOLIC
PRO-INSULIN “GROWTH”
SST
ANTI-INSULIN
Somatomedins (IGF-1)
liver
pituitary GH
hypothalamus
GH t1/2 = 20-25 min
IGF-1 t1/2 = 6 hr
Pituitary (GH) Pharmacology
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LOW Blood Sugar
GH release Gluconeogenesis, Lipolysis HIGH Blood
Sugar, FAs IGF-1
Growth Hormone Effects
Glucose, Fat Uptake and Storage
ANTI-INSULIN
Daily levels vary considerably High during sleep Low after meals
= postprandial
Sleep Level
time of day GH
Pituitary (GH) Pharmacology
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GH IGF-1 release
Gluconeogenesis, Lipolysis
Glucose, Fat Uptake and Storage, Protein synthesis
PRO-INSULIN Growth Hormone Effects
IGF-1 has more constant serum levels (t1/2 > 12 hr*) – about 30x longer than GH
*when bound to IGF-1 carrier protein, IGFBP-3
IGF-1
GH
Pituitary (GH) Pharmacology
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Glucose synthesis, release
GH Low Glucose
t1/2 20-25 min
Glucose use, storage IGF-1
t1/2 >12 hr
more constant levels (vs. GH)
During hypoglycemia (or stress) spikes in GH release will make glucose available GH also increases IGF-1, then shuts-off this process (preventing hyperglycemia) If sugars get too low, more GH is released To prevent a vicious cycle causing hypoglycemia, IGF-1 feedback-inhibits GH
Pituitary (GH) Pharmacology
ANTI-INSULIN:
LESS:
GLUCOSE UPTAKE
MORE: GLUCONEOGENESIS
(new glucose biosynthesis) LIPOLYSIS (TG breakdown into FAs)
GH EFFECTS:
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Pituitary (GH) Pharmacology
GH
Anterior pituitary
Liver
IGF-1
IGF-1
Target Tissues
Target tissues: • Bone • Cartilage • Skeletal muscle • Cardiac muscle • Kidney
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IGF-1: Insulin-like Growth Factor-1
Pituitary (GH) Pharmacology
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GH Receptor
GH
PLC IP3 + DAG
Ca2+ (from ER)
HEPATOCYTE
GH Receptor is a TYROSINE KINASE
IGF-1 Gene Expression
IGF-1
Pituitary (GH) Pharmacology
Mediates GROWTH effects of GH
Carried by IGF-1 BINDING PROTEIN (IGFBP-3)
IGF-1 Receptor (IGFR) is also in the TYROSINE KINASE family receptor (like GH Receptor)
IGFR is VERY SIMILAR TO THE INSULIN RECEPTOR (IR) (60% sequence homology)
IGF-1
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Pituitary (GH) Pharmacology
IGF-1 EFFECTS
PRO-INSULIN
MORE: GLUCOSE UPTAKE GLYCOLYSIS (glucose utilization) GLYCOGEN SYNTHESIS (glucose storage)
LESS: LIPOLYSIS (less fat breakdown)
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Pituitary (GH) Pharmacology
IGF-1 EFFECTS
ANABOLIC
MORE: PROTEIN SYNTHESIS (growth)
Muscle Bone Cartilage
BONE Deposition
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Pituitary (GH) Pharmacology
a a
b b
S-S
S-S
S-S
IGF-1
IGF-1 Receptor
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PI3K
PIP2 PIP3 AKT
PROTEIN SYNTHESIS, GLYCOGEN STORAGE
ANABOLIC and PRO-INSULIN Effects
Pituitary (GH) Pharmacology
a a
b b
S-S
S-S
S-S
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a
b
S-S
S-S a
b
S-S
INSULIN Receptor
ONLY 1/10th AFFINITY OF INSULIN
MIXED Receptor
HETERODIMERS OF IR AND IGFR
IGF-1
IGF-1
Pituitary (GH) Pharmacology
• Growth Failure Disorders
• GH: USES, PHARMACOLOGY
• IGF-1: USES, PHARMACOLOGY
• IGF-1: Investigational uses
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PHARMACOTHERPY OVERVIEW
Pituitary (GH) Pharmacology
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(1°) GH RECEPTOR AND IGF-1 RELEASE
(2°) GHRH RECEPTOR AND GH RELEASE
(3°) GHRH PRODUCTION AND RELEASE
GHRH
Pituitary GH
Hypothalamus SST
IGF-1 Liver
LEVEL OF GROWTH DEFECT
NORMAL GROWTH
Pituitary (GH) Pharmacology
PRIMARY (1) “GH Insensitivity”
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Pituitary
Hypothalamus
Liver
GH HIGH GH
LOW IGF-1
GROWTH DEFICIENCY
IGF-1
GHRH HIGH GHRH SST
Pituitary (GH) Pharmacology
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SECONDARY (2) “GH Deficiency”
Pituitary
Hypothalamus
Liver
GH LOW GH
GHRH SST HIGH GHRH
IGF-1
GROWTH DEFICIENCY
LOW IGF-1
Pituitary (GH) Pharmacology
Pituitary Dwarfism (approx. 25% of short stature cases)
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TERTIARY (3) “GHRH Deficiency”
Pituitary
Hypothalamus
Liver
LOW GH GH
GROWTH DEFICIENCY
LOW IGF-1 IGF-1
Pituitary (GH) Pharmacology
GHRH LOW GHRH SST
GH CHILD USES: GROWTH FAILURE (BEFORE epiphysial closure!!)
Example CAUSES: • Pituitary Dwarfism • Prader-Willi syndrome • Turner syndrome • Chronic renal insufficiency • (SHOX) deficiency • Noonan syndrome
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Pituitary (GH) Pharmacology
• HIV-Wasting (cachexia)
• GH deficiency (usually pituitary tumor-related) Adult symptoms of GH deficiency:
• Low muscle mass • Asthenia (weakness) • Low cardiac output • Obesity
• Short-bowel syndrome (SBS)
GH ADULT USES:
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Pituitary (GH) Pharmacology
Brand name examples
Genotropin® (Pfizer) Omnitrope® (Sandoz) Humatrope® (Eli Lilly) Nutropin® (Genentech) Saizen®, Serostim®, Zorbtive® (Merck ) Tev-Tropin® (Gate) Norditropin® (Novo Nordisk) Accretropin® (Cangene)
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Pituitary (GH) Pharmacology
Growth Hormone (Somatropin, rGH)
PHARMACOKINETICS
ORAL BIOAVAILABILITY: NONE SQ INJ AVAILABILITY: 70% - 90% (product-dependent)
SERUM HALF-LIFE Circulating GH: 20-25 min BIOLOGICAL HALF-LIFE (SQ Admin) Time including release from site of injection: 2-4 hr
METABOLISM: Hepatic and Renal Peptidases
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Growth Hormone
Pituitary (GH) Pharmacology
Closed epiphyses (if used for short stature) Diabetic retinopathy Cancer (because it’s growth-promoting!) Critical illness or trauma
NOT USEFUL IN PRIMARY DEFECT (GH INSENSITIVITY)
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CONTRAINDICATIONS
DRUG INTERACTIONS
ANTI-INSULIN effect will MASK the onset of hypoglycemia caused by oral anti-diabetics or insulin (by transiently making sugars available in the blood) Means hypoglycemia is worse by the time it is noticed.
Growth Hormone
Pituitary (GH) Pharmacology
ANTIBODIES to GH a. Neutralize GH in blood - reduced efficacy of GH b. cause Hypersensitivity – i.e. flu-like reactions
FLUID RETENTION (EDEMA) and complications e.g. myalgia, arthralgia, paresthesia
HYPOTHYROIDISM UNMASKING of subclinical hypothyroidism
Leukemia? (see next slide)
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ADVERSE EFFECTS
Growth Hormone
Pituitary (GH) Pharmacology
vs.
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GH and Acute Lymphoblastic Leukemia (ALL)?
Growth Hormone
Pituitary (GH) Pharmacology
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Growth Hormone
Pituitary (GH) Pharmacology
Achondroplasia – approx. 70% of short stature cases GH does NOT work in these patients Caused by ONE COPY (heterozygous) mutation in fibroblast growth factor receptor 3 (FGFR3). (TWO COPY = homozygous, lethal) Fibroblast growth factor-1 and -2 (FGF-1, FGF-2) are endocrine/autocrine/paracrine proteins that like IGF-1 are important in growth and development.
IGF-1: USES
• PRIMARY 1 DEFECT in GH Axis (“GH Insensitivity” e.g. Laron syndome)
• Patients that have developed Neutralizing antibodies to GH (and GH is no longer effective)
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Pituitary (GH) Pharmacology
Rare, recessive gene (need 2 copies, homozygous) GH does NOT work in these patients
Laron Syndrome: Genetic Causes:
a. GHR mutation (DOES NOT BIND GH) b. GH cell signaling problems
(GH binds to GH Receptor, but NO SIGNAL)
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Laron syndrome has been linked to lower incidence of cancer. Limited data
Pituitary (GH) Pharmacology
Mecasermin rinfabate (Iplex®)
Recombinant IGF-1 + IGFBP-3 (binding protein)
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Mecasermin (Increlex®)
Recombinant IGF-1
Half-life: 6 hr
Half-life: > 12 hr
IGF-1: FORMULATIONS
Pituitary (GH) Pharmacology
RELATIVE RISK of hypoglycemia: Mecasermin >> mecasermin rinfabate
Monitor diet Avoid use in high risk (i.e. diabetic) patients
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IGF-1: ADVERSE EFFECTS
HYPOGLYCEMIA (INSULIN LIKE EFFECT!)
Pituitary (GH) Pharmacology
IGF-1: CLINICAL TRIALS Amyotrophic Lateral Sclerosis (ALS)
IGF-1, 0.1 mg/kg/day, SQ 330 patients Abandoned
Adenovirus-based delivery of IGF-1 gene directly to motor neurons in Preclinical Trials
Dotted line= Placebo Solid line = IGF-1
Mortality in treated vs. untreated patients 41/183 (22.4%) 262/1533 (17.1%) p = 0.14 IGF-1 PATIENTS DID WORSE!!
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Pituitary (GH) Pharmacology
• Excess Growth Disorders
• Somatostatin (SST) mimics - USES
• SST mimics - PHARMACOLOGY
• GHR antagonist
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OVERVIEW
Pituitary (GH) Pharmacology
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Pituitary TUMOR (secretes GH)
Hypothalamus
Liver
GHRH SST LOW GHRH
IGF-1
GROWTH EXCESS (Gigantism)
HIGH IGF-1
GH HIGH GH
Pituitary (GH) Pharmacology
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GHRH Receptor
AC
ATP cAMP
SOMATOTROPH (Anterior Pituitary)
GHRH
GH SYNTHESIS and RELEASE
SST
SST Receptor
Gai Gas
GHRH effect SST effect
Pituitary (GH) Pharmacology
SST t1/2 = 2-3 min
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TOO SHORT TO USE AS A DRUG
SST MIMETICS Synthetic peptide analogs with LONGER HALF-LIVES:
Octreotide (Sandostatin®) Lanreotide (Somatuline®)
MORE POTENT at SST receptor than SST LONGER HALF-LIFE than SST
MOA for acromegaly: inhibit GH secretion
Pituitary (GH) Pharmacology
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OTHER EFFECTS of SST MIMETICS:
INHIBIT secretion of MANY OTHER HORMONES (e.g. Gastrin, CCK, glucagon, insulin, PP, VIP, TSH, ACTH)
ALSO INHIBIT OTHER BODILY FUNCTIONS:
• Enzyme secretions (intestines and pancreas) • GI motility • Gallbladder contraction
Pituitary (GH) Pharmacology
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CUSHING’S SYNDROME:
Pasireotide (Signifor®) (FDA approved 2012) to treat Cushing’s syndrome (high ACTH secretion) caused by non-operable pituitary tumors
CANCER: • CARCINOID SYNDROME (5-HT Hypersecretion)
Large tumors (intestines, colon, pancreas, bronchioles) Hyperglycemia, Flushing, Cramps, Bronchospasm
• CARCINOID CRISIS (dangerous): Tachycardia, Hypertension, Severe Bronchospasm • VERNER-MORRISON syndrome (VIP Hypersecretion)
Hypersecreting VIPomas (pancreatic) Flushing, Abdominal cramps, Hypokalemia
OTHER USES of SST MIMETICS:
Pituitary (GH) Pharmacology
Excessive GH secretion
Pituitary TUMOR
Children: GIGANTISM
Adults: ACROMEGALY
ACROMEGALY from Greek: AKRON = extremities MEGA = large
• Soft tissue growth: hands, feet, face • Bone deformation, arthritis • Cardiac hypertrophy, heart failure • Diabetes • Muscular weakness • Vision problems (nerve compression) • Hypothyroidism or Addison’s
(due to compression of pituitary) 45
Pituitary (GH) Pharmacology
SST MIMETICS: Octreotide, Lanreotide
PHARMACOKINETICS
• ADMIN: INJ (Deep SQ or IM) • HALF-LIFE: ACETATE SALT (octreotide - SQ): 90-120 min DEPOT (long-acting, “autogel”): 3-5 weeks • BIOAVAILABILITY: Oral: NONE (digested) SQ: 100% Depot: 60-80% • METABOLISM: Hepatic (proteases)
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Pituitary (GH) Pharmacology
ADVERSE EFFECTS
MOST COMMON Bradycardia Headache, fatigue, nausea Abdominal cramps, diarrhea
LESS-COMMON Cholestasis (Block bile release = gall bladder sludge) Hypothyroidism (Block TSH secretion) QTc Prolongation (Acromegaly is associated with
long-QT anyways, due to cardiac hypertrophy and proliferation of interstitial fibers)
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SST MIMETICS: Octreotide, Lanreotide
Pituitary (GH) Pharmacology
• SST analogs INHIBIT CYP2D6 EXPRESSION (i.e. LEVELS) = REDUCED codeine effectiveness
= REDUCED metabolism of CYP2D6 substrates (RAISE LEVELS)
(e.g. some TCAs, Antipsychotics, b-blockers, etc.)
• SST analogs + Pegvisomant = LIVER TOXICITY
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codeine morphine CYP2D6
DRUG INTERACTIONS
SST MIMETICS: Octreotide, Lanreotide
Pituitary (GH) Pharmacology
GH ANTAGONIST: Pegvisomant (Somavert®)
GH
GHR
GH MUTANT protein G120K (Glycine to Lysine)
BINDS TO, but DOES NOT DIMERIZE GHR (receptor dimerization is needed for activation) Polyethylene glycol (PEG) derivative
(PEG increases half-life of protein)
Pegvisomant
GHR
NO DIMERIZATION = NO SIGNALING
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PLC JAK
STAT
Pituitary (GH) Pharmacology
SIGNALING
USE: Acromegaly (in patients resistant to or unable to tolerate other therapies)
PHARMACOKINETICS BIOAVAILABILITY (INJ): 57% HALF-LIFE: 6 days
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ADVERSE EFFECTS • Nausea, Diarrhea • Anti-GH antibodies Antibodies can cause flu-like symptoms Antibodies can neutralize the drug
GH ANTAGONIST: Pegvisomant
Pituitary (GH) Pharmacology
ADVERSE EFFECTS
Increases the HYPOGLYCEMIC caused by anti-diabetic drugs (dangerous!)
Why? Pegvisomant blocks GH release, (remember, GH has anti-insulin effect)
Pegvisomant + SST analogs = LIVER TOXICITY
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GH ANTAGONIST: Pegvisomant
Pituitary (GH) Pharmacology
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GHRH MIMETICS: Tesamorelin (Egrifta®)
USE: HIV Lipodystrophy (INJECTION) (etiology unclear, may be effect of medication)
often low in HIV patients
Tesamorelin GHRH
GH
Insulin
Fat Storage
result: high serum FAs and lipodystrophy in HIV patients (other mechanisms may also be important, e.g. PPARs)
Pituitary (GH) Pharmacology
COLLOID SPACE
FOLLICULAR EPITHELIUM
CROSS SECTION
THYROID DISORDERS: HYPOthyroidism HYPERthyroidism
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I- (RDA) = 150 mcg/day (UL = 1100 mcg/day) Thyroid use = 75 mcg/day, remaining urinary excretion
TARGET CELLS
TSH (from anterior pituitary)
I- TH (T4 + T3)
Thyroid Pharmacology
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TRH: Thyrotropin Releasing Hormone
3 amino acids, made in hypothalamus Cleaved from TRH precursor protein
Thyroid Pharmacology
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TRH Receptor
TSH
THYROTROPH (Anterior Pituitary)
TRH
TSH Gene Expression
Ca2+
P
TSH
ATP cAMP
AC Gas
Thyroid Pharmacology
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Glycoprotein hormone a-chain
TSH b-chain
TSH: Thyroid Stimulating Hormone
a-chain + b-chain Similar structure to FSH, LH, hCG
(2a + 2b) functional protein
Thyroid Pharmacology
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NORMAL THYROID HORMONE AXIS
Thyroid Pharmacology
Pituitary TSH
TRH Hypothalamus SST
T3,T4 Thyroid
NORMAL METABOLISM
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T3, T4 BIOSYNTHESIS
Tg
Tg: Thyroglobulin LARGE, 660 kDa protein
Tg Tg
Tg
Thyroid Follicles
Thyroid Pharmacology
I-
I-
I-
I-
Tg(I)
Tg(I)
Thyroid Peroxidase
Colloid lumen
BASOLATERAL
APICAL
Circulation NIS
Na+ I-
Na+ I-
Parafollicular Epithelial Cells
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I-
Pendrin
Cl-
Thyroid Pharmacology
Thyroid Oxidase
O2 O2-
SOD
H2O2
H2O2 + I-
Thyroglobulin Tyrosines
T3, T4 BIOSYNTHESIS
Thyroglobulin Tyrosine residue
Colloid Space
HIGH [I-] Wolff-Chaikoff
Effect
STEP 1. Thyroglobulin Ioidination
Di-iodotyrosine (DIT)
Mono-iodotyrosine (MIT)
1.
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Thyroid Pharmacology T3, T4 BIOSYNTHESIS
lysosome
Lysosomal Proteases
Follicular Epithelial Cell
Triiodothyronine (T3)
Thyroxine (T4)
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Thyroid Pharmacology
STEP 2. Coupling
T3, T4 BIOSYNTHESIS
Exocytosis
20% T3 80% T4
T4
POTENCY: T3 = 1 x T4 = 1/10 x T3
HALF-LIFES: T3 = 1 day T4 = 7 days
COMPARISON: T3, T4
62 reverse T3 (rT3) T2
INACTIVE metabolites
Thyroid Pharmacology
T4 can be thought of as a prohormone, as it is much less active (but longer-lived) and is converted into the active hormone T3
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Thyroid Pharmacology COMPARISON: T3, T4
T3
T4
TOTAL: 70-130 ng/dl FREE: 0.2-0.4 ng/dl (0.4% OF TOTAL T3 IS FREE)
TOTAL: 5,000-12,000 ng/dl FREE: 0.8-2.0 ng/dl (0.04% OF TOTAL T4 IS FREE)
Total T4 is about 50-fold > Total T3 Free T4 is about 5-10-fold > Free T3
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TBG: Thyroid hormone binding globulin (carries 70%) • HIGH AFFINITY • LOW PROTEIN AMOUNT • INDUCED by E2 during pregnancy
TTR: Transthyretin (carries 15%) • LOW AFFINITY • HIGH PROTEIN AMOUNT • Also carries: retinol, drugs, aromatic toxins
Serum albumin: (carries 15%) • VERY LOW AFFINITY • VERY HIGH PROTEIN AMOUNT
Thyroid Pharmacology CARRIER PROTEINS
T4 T3
rT3
Type I Deiodinase
T2
T2
Glucosyltransferases
T4, T3, rT3, T2 Inactive
Glucuronide Conjugates
METABOLISM, EXCRETION
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Thyroid Pharmacology
Urine
T3
T4 target cell
Deiodinase
Hsp90
Hsp90
TR TR RXR
Gene Expression
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GENE EXPRESSION
Thyroid Pharmacology
• MORE MITOCHONDRIA • MORE GLUCOSE UPTAKE • SIMULTANEOUSLY MORE glycolysis and gluconeogenesis (aka FUTILE CYCLING)
CARBOHYDRATE METABOLISM
METABOLIC EFFECTS
TSH
Thyroid
T4, T3 HIGHER METABOLIC RATE
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TRH
Pituitary
drop in core temperature
Thyroid Pharmacology
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FUTILE CYCLING
fructose-1,6-bisphosphatase
Gluconeogenesis
Fructose 6- phosphate
phosphofructokinase
ATP ADP + Pi + HEAT
Glycolysis
Fructose 1,6- bisphosphate
Thyroid Pharmacology METABOLIC EFFECTS
MORE LIPOLYSIS (Fat breakdown) = higher serum FAs MORE BETA OXIDATION (Fatty acid catabolism)
Q. Will extra T3/T4 help you LOSE WEIGHT?
A. Not recommended for people with normal thyroid function = ADVERSE EFFECTS! (BLACK BOX WARNING)
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LIPID METABOLISM
In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
Thyroid Pharmacology METABOLIC EFFECTS
FASTER HEART RATE (+ chronotropic effect)
STRONGER HEART CONTRACTION (+ inotropic effect)
HIGHER CO ( systole 10-15 mm Hg)
LOWER SVR ( diastole) Why? Higher metabolic rate raises lactic acid, which causes vasodilation and lower resistance
Result = wider pulse pressure
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Thyroid Pharmacology CARDIOVASCULAR EFFECTS
CARDIAC OUTPUT
Thyroid Disorders and DRUG SENSITIVITY
ANTICOAGULANTS
(Warfarin)
HYPER-thyroidism HYPO-thyroidism
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Thyroid Pharmacology
LESS SENSITIVE MORE SENSITIVE
SEDATIVES
(Benzodiazepines, Opiates)
LESS SENSITIVE MORE SENSITIVE
CARDIAC GLYCOSIDES
(Digoxin)
LESS SENSITIVE MORE SENSITIVE
HYPO-THYROIDISM
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LEVEL OF DEFECT
Thyroid Pharmacology
TRH
Pituitary TSH
Hypothalamus SST
T3,T4 Thyroid
LOW METABOLISM
(1°) THYROID GLAND NOT FUNCTIONING (85% of cases)
(2°) TRH RECEPTOR AND TSH RELEASE
(3°) TRH PRODUCTION AND RELEASE
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HYPO-THYROIDISM: PRIMARY (1°)
Thyroid Pharmacology
Pituitary
Hypothalamus HIGH TRH TRH SST
Thyroid
TSH HIGH TSH
T3,T4
LOW METABOLISM
LOW T3, T4
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Thyroid Pharmacology
HIGH TRH TRH
Pituitary (lactotrophs)
PRL
Hypothalamus SST
T3,T4
HIGH PRL
Breast Tissue • Gynecomastia • Lactation
HYPO-THYROIDISM: PRIMARY (1°)
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Thyroid Pharmacology
HIGH TRH TRH
Pituitary (lactotrophs)
PRL
Hypothalamus SST
T3,T4
Dopamine Agonists (e.g. Bromocriptine)
ADMIN: Oral ONSET: 1-2 hr HALF-LIFE: 12 hr
HYPO-THYROIDISM: PRIMARY (1°)
AUTOIMMUNE: Hashimoto’s disease
RADIATION destruction of thyroid (e.g. Cancer Therapy)
SURGICAL removal of thyroid
DRUGS: amiodarone, lithium, fluoride, cytokines (IFN-a)
LOW DIETARY IODINE: Endemic Goiter
MUTATIONS: Iodoperoxidase deficiency (low T3/T4 synthesis) Deiodinase deficiency (low T4 to T3 bioconversion)
CONGENITAL: Cretenism
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Thyroid Pharmacology HYPO-THYROIDISM: ETIOLOGY
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Thyroid Pharmacology HYPO-THYROIDISM: HEART DISEASE
• Reduced Cardiac Output (LOW CO) • High Diastolic Pressure • High SVR (endothelial dysfunction)
• Dyslipidemia: High total cholesterol High serum LDL High triglycerides
HEART DISEASE
Levothyroxine T4 (Synthroid®, Levoxyl®, Unithroid®, etc)
L-Thyroxine isoform D-isoform of thyroxine only has 4% activity!
PHARMACOKINETICS
• ADMIN: ORAL, IM, IV
• ORAL BIOAVAILABILITY: hard to predict (40-80%)
• HALF-LIFE: 7 days (in euthyroid patients)
LONGER if HYPO-thyroid (10 days) SHORTER if HYPER-thyroid (3 days)
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Thyroid Pharmacology THYROID AGENTS
Liothyronine T3 (Cytomel®, Triostat®, etc)
PHARMACOKINETICS
• ADMIN: ORAL, IV
• ABSORPTION: intestinal, complete
• HALF-LIFE: 1 day
• Precaution: Has a stronger stimulatory effect on the heart than T4 (potentially “cardiotoxic”)
• Interesting use: hormonal resuscitation for organ transplant
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Thyroid Pharmacology THYROID AGENTS
Liotrix (Thyrolar®) (4:1 mix T4:T3)
Desiccated Thyroid
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THYROID AGENTS
Armour Packing Plant St. Louis, MO
Thyroid Pharmacology
GRAVE’S disease (Toxic Diffuse Goiter) Thyroid-stimulating immunoglobulins (TSI) AUTOIMMUNE Stimulate T3/T4 synthesis/secretion in absence of TSH LONG HALF-LIFE (TSI = 12 hr vs. TSH = 1 hr)
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GOITER, EXOPTHALMOS SYSTOLE DIASTOLE TREMOR, WEIGHT LOSS
Thyroid Pharmacology HYPER-THYROIDISM
PLUMMER’S disease (Toxic Nodular Goiter) • Hypersecreting thyroid nodules
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Thyroid Pharmacology
Pituitary
Hypothalamus LOW TRH TRH SST
Thyroid
TSH LOW TSH
HIGH T3, T4 T3,T4
HIGH METABOLISM
HYPER-THYROIDISM: PRIMARY (1°)
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Thyroid Pharmacology
LOW TRH TRH
Pituitary
Hypothalamus SST
T3,T4
LOW PRL PRL
Breast Tissue (difficulty with lactation)
HYPER-THYROIDISM: PRIMARY (1°)
A. THIOAMIDES • Propylthiouracil • Methimazole
B. IODIDES
C. IODINATED CONTRAST MEDIA
• Diatrizoate • Iohexol
D. RADIOACTIVE IODINE • I131
E. b-blockers
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ANTITHYROID AGENTS
Thyroid Pharmacology
Propylthiouracil (PTU)
Methimazole (MMI, Tapazole®)
RELATIVE POTENCY 0.1X 1X
HALF-LIFE 1.5 hr 6 hr
BIOAVAILABILITY 50-70% 80-95%
Safety in pregnancy
SAFER More protein-bound
LESS SAFE Less protein bound,
Crosses placenta, TERRATOGENIC
PROTEIN BINDING 80% 0%
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ADMIN ORAL ORAL
Thyroid Pharmacology ANTITHYROID AGENTS
MECHANISM: interfere with T3, T4 biosynthesis)
1. INHIBIT Iodination of Thyroglobulin
2. INHIBIT “Coupling” reaction
3. Propylthiouracil ALSO INHIBITS the Deiodination of T4 to T3 in target tissues (methimazole does not, it only affects the thyroid)
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Propylthiouracil, Methimazole
CAUSE depletion of iodinated Tg and T3, T4 levels, but only after WEEKS of continued use
Thyroid Pharmacology ANTITHYROID AGENTS
ONSET 3-4 weeks (need to wait for HORMONE DEPLETION)
ADVERSE EFFECTS
• EARLY IN THERAPY: Nausea, GI distress • COMMON: Maculopapular RASH (6%) • RARE (but serious):
HEPATOTOXICITY: Liver inflammation Cholestatic jaundice AGRANULOCYTOSIS (0.1-0.5% of patients)
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Propylthiouracil, Methimazole
Thyroid Pharmacology ANTITHYROID AGENTS
Potassium Iodide (KI)
Potassium Iodide and Iodine (aka: Strong Iodide Solution, Lugol's solution)
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IODIDE USES:
• Endemic GOITER • Reduce thyroid VASCULARITY prior to thyroidectomy Wolff-Chaikoff effect: reduces T3, T4 synthesis and causes thyroid atrophy • Compete with RADIOACTIVE iodide uptake
Thyroid Pharmacology ANTITHYROID AGENTS
IODIDE ADVERSE EFFECTS (called ‘IODISM’)
Acneiform rash (similar to chloracne)
Goiter
Flu-like symptoms (fever, aches)
Swelling of salivary glands
Mucous membrane ulcerations
CNS: Confusion, Depression
GI: Nausea, Diarrhea
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Thyroid Pharmacology ANTITHYROID AGENTS
IODIDE DRUG INTERACTIONS
• WORSEN the hyperkalemia caused by potassium-sparing diuretics
(e.g. spironolactone)
• INHIBIT the anticoagulant effect of Vitamin K antagonists (e.g. warfarin)
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Thyroid Pharmacology ANTITHYROID AGENTS
APPROVED USES: • Angiography • Cystourethrography • Myelography • GI tract examination …etc.
Hyperthyroidism NOT a labeled indication, BUT: has been used in management of THYROID STORM
Diatrizoate (Gastrografin®, Cystografin®)
IONIC
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Iohexol (Omnipaque ®)
NON-IONIC
Thyroid Pharmacology ANTITHYROID AGENTS
Non-ISA b-blockers RESPONDING symptoms:
Tremor Tachycardia Arrhythmia Sweating (not a direct effect, b/c sweating is cholinergic)
Propranolol Metoprolol Atenolol Esmolol
NON-RESPONDING symptoms:
Exopthalmos Goiter Weight loss TH levels
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Thyroid Pharmacology ANTITHYROID AGENTS
Esmolol (Brevibloc®)
USE: THYROID STORM, ER/ICU
Rapid ONSET (2-10 min) Short DURATION (10-20 min) Short HALF-LIFE (9 min)
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(aka THYROTOXIC CRISIS, life-threatening) High fever Tachycardia Arrhythmias Vomiting, Diarrhea
Thyroid Pharmacology ANTITHYROID AGENTS
USES:
LOW dose (5-15 mCi) for Hyperthyroidism (toxic nodular goiter)
HIGH dose (30-150 mCi) for Thyroid cancer (thyroid ablation)
t½ = 8 days Absorption: rapid Emission: b particle
Penetration: 0.4-2 mm Decay product: Xe131
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Thyroid Pharmacology ANTITHYROID AGENTS
Sodium I131
ADMIN: Oral
BIOAVAILABILITY: 100%
CONTRAINDICATIONS:
• NOT for under 30 years old (for hyperthyroidism) • NOT for PREGNANT or LACTATING women
Radioactive T3, T4 CROSS PLACENTA, secreted into MILK
DRUG INTERACTIONS: • Antithyroid Agents, Amiodarone: INTERFERE with I131
ACUTE EFFECTS: • Necrosis (tissue death), Thyroid Swelling (inflammation)
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Thyroid Pharmacology ANTITHYROID AGENTS
Sodium I131