phpp 516 (it-ii) spring 2016 jacobs wednesday, jan 20 2:00 … · pituitary gh hypothalamus ghrh...

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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


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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

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


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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:


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GHRH Receptor

ATP cAMP

SOMATOTROPH (Anterior Pituitary)

GHRH

GH Gene Expression

Ca2+

P

Gas AC

GH GH

GH

GH


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


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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


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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


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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


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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


ANTI-INSULIN:

LESS:

GLUCOSE UPTAKE

MORE: GLUCONEOGENESIS

(new glucose biosynthesis) LIPOLYSIS (TG breakdown into FAs)

GH EFFECTS:

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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


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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


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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IGF-1 EFFECTS

PRO-INSULIN

MORE: GLUCOSE UPTAKE GLYCOLYSIS (glucose utilization) GLYCOGEN SYNTHESIS (glucose storage)

LESS: LIPOLYSIS (less fat breakdown)

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IGF-1 EFFECTS

ANABOLIC

MORE: PROTEIN SYNTHESIS (growth)

Muscle Bone Cartilage

BONE Deposition

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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


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


• Growth Failure Disorders

• GH: USES, PHARMACOLOGY

• IGF-1: USES, PHARMACOLOGY

• IGF-1: Investigational uses

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PHARMACOTHERPY OVERVIEW


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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


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


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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 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


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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• 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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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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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


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


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


vs.

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GH and Acute Lymphoblastic Leukemia (ALL)?

Growth Hormone


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Growth Hormone


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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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


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


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!)


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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• Excess Growth Disorders

• Somatostatin (SST) mimics - USES

• SST mimics - PHARMACOLOGY

• GHR antagonist

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OVERVIEW


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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


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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


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


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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


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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:


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


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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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 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



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


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


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


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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)


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


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TRH Receptor

TSH

THYROTROPH (Anterior Pituitary)

TRH

TSH Gene Expression

Ca2+

P

TSH

ATP cAMP

AC Gas


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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


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NORMAL THYROID HORMONE AXIS


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


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 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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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


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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Urine

T3

T4 target cell

Deiodinase

Hsp90

Hsp90

TR TR RXR

Gene Expression

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GENE EXPRESSION


• 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


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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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LESS SENSITIVE MORE SENSITIVE

SEDATIVES

(Benzodiazepines, Opiates)


CARDIAC GLYCOSIDES

(Digoxin)


HYPO-THYROIDISM

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LEVEL OF DEFECT


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°)


Pituitary

Hypothalamus HIGH TRH TRH SST

Thyroid

TSH HIGH TSH

T3,T4

LOW METABOLISM

LOW T3, T4

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HIGH TRH TRH

Pituitary (lactotrophs)

PRL

Hypothalamus SST

T3,T4

HIGH PRL

Breast Tissue • Gynecomastia • Lactation


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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


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


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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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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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


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


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


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


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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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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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

91

Iohexol (Omnipaque ®)

NON-IONIC


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

92


Esmolol (Brevibloc®)

USE: THYROID STORM, ER/ICU

Rapid ONSET (2-10 min) Short DURATION (10-20 min) Short HALF-LIFE (9 min)

93

(aka THYROTOXIC CRISIS, life-threatening) High fever Tachycardia Arrhythmias Vomiting, Diarrhea


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

94


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)

95


Sodium I131

phpp 516 (it-ii) spring 2016 jacobs wednesday, jan 20 2:00 … · pituitary gh hypothalamus ghrh...

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