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1
Thyroid Disorders
Hyperthyroid Disorders
Graves Disease: Toxic diffuse goiter
Pituitary adenomas
Toxic adenoma
Toxic multinodular goiter
Subacute thyroiditis
Drug--induced (amiodarone, thyroid
Drug
replacement)
247
Hypothyroid Disorders
Hashimotos Disease
Thyroid surgery / Ablative therapy
Iodine deficiency y
Secondary causes
Drug
Drug--induced (amiodarone, lithium)
247-248
2
Thyroid Labs / Diagnosis
Free T4 and TSH tell most of the story
Hyperthyroid:: Low TSH, elevated free T4
Hyperthyroid
Hypothyroid:: High TSH (lack of negative
Hypothyroid
feedback), suppressed free T4
TSH may be low or normal in secondary
causes
Thyroid antibodies
Radioactive iodine uptake
248
Clinical Presentation
(Hyperthyroid)
Hyperthyroid)
Appetite increased
Weight loss
Goiter
Heat intolerance
Fine hair
Palpitations / tachycardia
Anxiety / insomnia / nervousness
Moist skin / sweating
Exophthalmos (bulging eyes)
248
Clinical Presentation
(Hypothyroid)
Hypothyroid)
Weight gain
Dry skin
Cold intolerance
Weakness / fatigue / lethargy
Bradycardia
Slow reflexes
Coarse skin / hair
248
3
Thyroid Disorder: Goals
Improve quality of life
Minimize or eliminate symptoms
Minimize long-
long-term damage
Normalize free T4 / TSH
249
Hyperthyroid Pharmacotherapy
Usual indications
Not surgical (adenomas) or ablative therapy
candidate (tx
(tx of choice in Graves disease)
Surgery / ablative therapy unsuccessful
Mg
Mg--Mg: methimazole is 10x more potent
249
4
Thioureas (aka Thioamides)
ADRs:
Hepatotoxicity with PTU (black box warning)
Arthralgias
Fever
Rash
Transient leukopenia
Agranulocytosis
Beta--blockers
Beta
Primarily for symptomatic improvements
Most commonly employed: propranolol /
nadolol
Block manyy manifestations of hyperthyroidism
yp y
(tachycardia / anxiety / tremor / palpitations) -
some T4 to T3 conversion blocked
Very poor remission rates: 20-
20-30%
Significant role in thyroid storm
249-250
Iodines
Lugols Solution / SSKI
Block release ((not
not synthesis)
synthesis) of hormone / May
help in reducing size and vascularity of gland
prior to surgery
ADR: Metallic taste / hypersensitivity / oral
soreness or burning
Primary uses:
uses: Pre
Pre--surgery to shrink gland size /
post-
post-ablative tx to reduce release stored
hormone (less thyroiditis) / thyroid storm
Only used short-
short-term (1(1--2 weeks): Gland will
eventually begin to leach hormone
250
5
Hypothyroid Pharmacotherapy
Drug of Choice:
Choice: Synthetic T4 ((levothyroxine
levothyroxine))
Cost / antigenicity profile / potency / ADR
profile
Initial dose: 50-
50-75 micrograms
Common maintenance dose: 1.6- 1.6-1.7 mcg/kg/day
Titrate based on T4/TSH and symptoms
6 weeks to reach steady state (usual titration
schedule)
ADRs: Hyperthyroidism / angina / MI
250
Hypothyroid Pharmacotherapy
Synthetic T3 ((liothyronine
liothyronine):
): Less
attractive alternative (higher CV ADR
p
profile))
Liotrix / Desiccated thyroid: Not used
much anymore
251
6
Pituitary Disorders
Limit treatment discussion to Acromegaly /
Hyperprolactinemia
Acromegaly pharmacotherapy often reserved
for:
Pre
Pre--surgery/irradiation (control symptoms)
Not a surgical candidate
254
Acromegaly Therapy
Cause: Growth
Growth--Hormone (GH) secreting
pituitary adenoma
Goal: Decrease IGF
IGF--1 and GH, mortality,
symptoms
y p
Dopamine Agonists (paradoxical decrease in
GH production)
Bromocriptine / cabergoline
ADRs: Nervousness / fatigue / dizziness / GI
~50% get symptom relief (10% obtain normal IGF-
IGF-
253-254 1)
255
Acromegaly Therapy
Somatostatin analog (octreotide
(octreotide))
Block GH secretion
Dosed subcutaneously three times daily initially
Can be switched to long-
long-acting formulation (once
monthly) if responsive to tx
ADR: Lot of GI / hypothyroidism / arrhythmias /
glucose abnormalities / biliary tract disorders
Good symptomatic relief (50-
(50-60% IGF
IGF--1
normalization)
GH Receptor antagonist pegvisomant
Very good IGF-
IGF-1 normalization / long-
long-term trials
needed
7
Hyperprolactinemia Therapy
Prolactinomas
Drug
Drug--induced: SSRIs, anti-
anti-psychotics
DC offending agent
Case
C where
h ddrug therapy
h may b
be b
better
than surgery
Dopamine agonists
Cabergoline More effective than bromocriptine
Bromocriptine
255
Adrenal Disorders
(Cushings Syndrome)
Hypersecretory cortisol disease
Adrenocorticotropic hormone (ACTH)
(ACTH)--
dependent
80% of cases / Excessive ACTH secretion
Most common form: Pituitary corticotroph
adenoma (Cushings disease)
Adrenocorticotropic hormone (ACTH)
(ACTH)--
independent
20% of cases / Exogenous steroid use or
excessive cortisol secretion 256
Cushings Syndrome
Clinical presentation (similar to excessive / long-
long-
term use of exogenous corticosteroids):
HTN / Osteo / Obesity / Moon face / Glucose
abnormalities etc
Treatment Options (all aimed at inhibiting
cortisol production)
Ketoconazole: Gynecomastia / GI / LFT increases
Mitotane: Ataxia / GI / Lethargy / Anorexia
Etomidate (IV): Usually reserved for acute cases
257-258
8
Hyperaldosteronism
70% cases: Bilateral adrenal hyperplasia
30% cases: Aldosterone-
Aldosterone-producing
adenoma
Dx: Elevated plasma aldosterone : renin
ratio
S/S: HTN / fatigue / HA / polydipsia
Obesity
Obesity - Classification
Classification BMI
Normal 18.5-24.9
Overweight 25.0-29.9
25.0 29.9
Class I 30.0-34.9
Class II 35.0-39.9
Class III 40+
260
9
Obesity Therapy
Sibutramine (Meridia)
Meridia) pulled from market 2010
Orlistat Inhibits gastric and pancreatic lipases
>> reduced fat absorption
Rx
R (Xenical
((X
Xenical):
X i ll)):) 120 mg three
h times
i daily
d il (up
( to 1 hour
h
prior to meals)
OTC (Alli
(Alli):
): 60 mg three times daily (up to 1 hour
prior to meals)
LOTS GI ADRs: flatulence, oily stool, loose stool
261
262
10
PCOS Therapy Options
Clomiphene citrate
Selective estrogen receptor modulator (improves
LH--FSH secretion)
LH
ADRs: Flushing
Flushing, GI discomfort,
discomfort vaginal dryness,
dryness
multiple pregnancies
Recombinant FSH or GRH (+/-
(+/- clomiphene)
clomiphene)
May result in multiple pregnancies
Metformin
263
Diabetes Mellitus
231
11
Patient Case
(Does this patient have diabetes?)
56 yo Hispanic female with complaints of
symptoms consistent with vaginal fungal
infection. Seen last month with similar
complaints.
Weight 220 lb (BMI 42 kg/m2 ), BP 148/84, ht
rate 88, temp 98.8
PMH: Gestational DM, HTN, else
unremarkable
Labs: Chem 7 glucose (fasting) 142 mg/dL, else
wnl (fasting glucose last month was 136 mg/dL)
Diabetes Classification
Type 1 Diabetes Mellitus (5
(5--10% of DM)
Pancreatic beta
beta--cell destruction / insulin required
Type 2 Diabetes Mellitus (90
(90--95% of DM)
Insulin resistance + decreased pancreatic insulin
output
Gestational diabetes
Maturity--onset diabetes of the young (MODY)
Maturity
Others (pancreatitis, drug induced, genetic
defects)
231
232
12
Screening for Diabetes
Gestational DM:
DM:
Previously dependent on risk (high /
average / low)
2010/2011 Recommendations by
ADA
24-
24-28 weeks of gestation
75 gram Oral Glucose Tolerance Test
232
232
13
Type 1 and 2 DM Diagnosis
Elevated Plasma Glucose Post
Post--OGTT
2 hours after 75 g oral glucose
ingestion
> 200 mg/dL
mg/dL
Plasma Glucose if abnormal should be
repeated on subsequent day
232
Patient Case
(Should this patient be screened?)
56 yo Hispanic female with complaints of
symptoms consistent with vaginal fungal
infection. Seen last month with similar
complaints.
Weight 220 lb (BMI 42 kg/m2 ), BP 148/84,
148/84, ht
rate 88, temp 98.8
PMH: Gestational DM DM,, HTN,
HTN, else
unremarkable
Labs: Chem 7 glucose (fasting) 142 mg/
mg/dL
dL,, else
wnl (fasting glucose last month was 136 mg/dL
mg/dL))
Patient Case
(Does this patient have diabetes?)
56 yo Hispanic female with complaints of
symptoms consistent with vaginal fungal
infection. Seen last month with similar
complaints.
Weight 220 lb (BMI 42 kg/m2 ), BP 148/84, ht
rate 88, temp 98.8
PMH: Gestational DM, HTN, else
unremarkable
Labs: Chem 7 glucose (fasting) 142 mg/dL
mg/dL,, else
wnl (fasting glucose last month was 136 mg/dL
mg/dL))
14
Goals of Therapy in DM
PREVENT ACUTE AND CHRONIC
COMPLICATIONS !
Acute:
Acute: Hypoglycemia / DKA / HHNS
Chronic:
Chronic:
Microvascular
Microvascular:: Retinopathy / Neuropathy /
Nephropathy
Macrovascular
Macrovascular:: Cardiovascular /
Cerebrovascular / Peripheral vascular disease
233
Post--prandial (1
Post (1--2 hours after meal): < 180 mg/dL
mg/dL
Glycemic goals in gestational DM much more
aggressive
233-234
234
15
Benefits of Good DM Control
Glycemic Control
Reduces microvascular complications
Cholesterol Control
Patient Case
(Glycemic Control)
56 yo Hispanic female, one month later
Last month placed on metformin 500 mg once
daily for one week, then bid since
A1 llast month
A1c h ((at di
diagnosis):
i ) 88.6%
6%
Fasting morning BGs per patient log over this
past week:
148,152,144,198, 178, 164
Thiazolidinediones (pioglitazone )
16
Oral Agents For Type 2 DM
Alpha
Alpha--glucosidase Inhibitors (acarbose
/ miglitol)
miglitol)
Dipeptidyl Peptidase
Peptidase--4 (DPP-
(DPP-4)
Inhibitors (sitagliptin,
sitagliptin, saxagliptin)
saxagliptin)
Colesevelam
Bromocriptine
Glucosidase Inhibitors
DDP-4 Inhibitors
Incretin Mimetics
Bromocriptine
Metformin
TZDs TZDs
Metformin
Sulfonylureas
Meglitinides
DPP-4 Inhibitors
DPP-4 Inhibitors
Incretin Mimetics
Incretin Mimetics
Sulfonylureas
May affect both fasting and post-
post-prandial
glucose
Side Effect Profile
Weight gain
Hypoglycemia
Rash
HA
GI complaints
SIADH (rare)
234-235
17
Meglitinides
Better Focus on Post-
Post-prandial BG than
sulfonylureas
Repaglinide likely better than nateglinide
Side Effect Profile
Hypoglycemia (less than with sulfonylureas)
sulfonylureas)
Weight Gain
URI
Precautions
Concurrent use of gemfibrozil (increases repaglinide
levels) 236-237
Metformin
Initial Drug of Choice per ADA
Side Effect Profile
Common
Gastrointestinal: Cramping, Diarrhea, N/V
Severe
S (b
(but rare))
Lactic acidosis
Other
Hypoglycemia (uncommon with monotherapy)
monotherapy)
Weight Loss
Triglyceride reduction
235-236
Metformin
Precautions
High cardiovascular risk / Hypoxic state
235-236
18
Metformin
Contraindications
Increased serum creatinine
1.4+ in women, 1.5+ in men
Thiazolidinediones (TZDs)
Side Effect Profile
Hypoglycemia (uncommon with monotherapy)
monotherapy)
Weight gain
Peripheral
p edema
HDL increase / TG decrease (pioglitazone
(pioglitazone))
Bone fracture risk (women)
236-237
Thiazolidinediones (TZDs)
Contraindications
Heart Failure (NYHA Class III and IV)
Liver impairment (ALT >2.5
2.5 times uln)
uln)
237
19
Glucosidase Inhibitors
Post
Post--prandialglucose focus
Side Effect Profile
LOTS of GI side effects: Flatulence,
Flatulence diarrhea,
diarrhea
cramping, pain, etc
Reason for slow titration
237
Glucosidase Inhibitors
Precautions
Lowerdosage in patients with renal
impairment
Contraindications
Inflammatory bowel disease, ulcerative colitis,
intestinal obstruction
237
Colesevelam
Mild reductions in A1c
Side Effects
Constipation / dyspepsia / nausea / myalgia
Precautions / Contraindications
Elevated triglycerides
Bowel obstruction
Difficulty swallowing
238
20
Bromocriptine
Small reductions in A1c
Side Effects
Fatigue / dizziness / nausea / vomiting / headache
/ hypotension / syncope
Precautions/Contraindications
h/o syncopal migraines
Nursing mothers
Limits effectiveness of antipsychotics
238
Alpha cells:
Postprandial
glucagon secretion
Liver:
Glucagon reduces hepatic
Beta cells: glucose output
Enhances glucose-dependent
insulin secretion
Stomach:
Helps regulate gastric
emptying
239-240
DPP--4 Inhibitors
DPP
Side Effect Profile
GI complaints
Hypersensitivity (angioedema
(angioedema,, exfoliative skin
conditions,, anaphylaxis)
p y )
Precautions
Renal impairment (dose adjust)
History of pancreatitis
237-238
21
Injectable DM Agents
Incretin Mimetics
GLP
GLP--1 analog (in Type 2 DM)
Exenatide (Byetta) Twice daily
Liraglutide (Victoza) Once daily
Weight Loss
Nausea
Vomiting
GI discomfort
Pancreatitis risk
239
22
Exenatide and Liraglutide
Precautions
Existing gastroparesis
History of pancreatitis
Exenatide
Exenatide:: Moderate renal impairment (<50
ml/min)
Contraindications
Exenatide
Exenatide:: CrCl
CrCl<30
<30 ml/min
Liraglutide:
Liraglutide: Medullary thyroid carcinoma
239
23
Treating Type 1 DM
75
Breakfast Lunch Dinner
n (U/mL))
50
Plasma
Insulin
25
Time
Treating Type 1 DM
241
24
Treating Type 1 DM
241
242
Type 1 DM Case
42 yo WF with Type 1 DM x 22 years: A1c last
week = 7.6%
Current insulin regimen
Detemir 60 units once daily at bedtime
Lispro:: 6 units before breakfast, 5 before lunch, 8
Lispro
before dinner (very consistent diet/dosing)
Fasting am BGs: 162, 155, 168, 140, 166
Post--prandials
Post prandials:: 172, 176, 154, 166, 170, 142, 133
No bouts of daytime or nocturnal hypoglycemia
Patient Case 3 page 242
25
Treating Type 2 DM
Step 3
Lifestyle and Metformin and
Intensive Insulin Therapy
242
Diabetes Care 2009;32:193
Metformin Metformin
Sulfon + Pioglit Basal Insulin
26
Assessing Therapy and Dosage
Adjustment
Patient Case
(Glycemic Control)
56 yo Hispanic female, one month later
Last month placed on metformin 500 mg
once daily for one week, then bid since
A1c last month (at diagnosis): 8.6%
All post-
post-prandial BGs < 180 mg/dl but fasting
BGs consistently elevated over the last 3 weeks
27
Treatment of Diabetes
Complications
Hypoglycemia
Treatment depends on degree of hypoglycemia
Plasma glucose < 70 mg/dl (+/-
(+/- symptoms)
Mild--moderate low BGs: 15-
Mild 15-20 gm oral glucose
or equivalent
i l
Severe (cognitive impairment, requires help):
1 mg IM glucagon
IV Dextrose
243
Diabetic Ketoacidosis
Significantly elevated BG / ketoacidosis /
dehydration
Signs/symptoms: Thirst, abdominal pain, mental
status changes,
changes fruity breath,
breath tachycardia,
tachycardia low Na
/ high K, ketones in urine/serum
Most common causes: infection/acute illness or
inappropriate/inadequate insulin therapy
243-244
28
DKA--Treatment (see ADA statement)
DKA
Find and fix underlying cause (if known)
NOT about normalizing blood glucose
Fluid Replacement (IV Na% depends on serum
Na)
IV insulin: 0.1 unit/kg bolus, 0.1 unit/kg/hr
drip (double drip rate if minimal response)
Hold if baseline serum K < 3.3 meq
meq/L
/L until
corrected
Potassium supplementation: Depends on
baseline K
244 Diabetes Care 2009;32:1335-43
244
244-245
29
Diabetic Nephropathy
Urine albumin / creatinine
(mg/g or mcg/mg)
Normal < 30
Microalbuminuria 30-
30-300
Macroalbuminuria > 300
(Proteinuria / overt
nephropathy)
244
Treatment DM Nephropathy
Type 1 DM / HTN / any degree of
nephropathy : ACE
ACE--Inhibitor
Type 2 DM / HTN / microalbuminuria:
ACE--Inhibitor or ARB
ACE
Type 2 DM / HTN / proteinuria / serum
Cr > 1.5: Angiotensin Receptor Blocker
244
Diabetic Neuropathies
Neuropathic Pain
TCAs (smaller doses than in depression)
Desipramine / Nortriptyline /
Amitriptyline
Anticonvulsants
SSRIs / SSNRI
Duloxetine
245
30
Diabetic Neuropathies
Gastroparesis
Often symptomatic post-
post-prandially (N/ V)
Non
Non--pharmacologic treatments:
Smaller,
Smaller more frequent meals
Homogenize food
Pharmacologic treatments:
If LDL-
LDL-C still not below 100 mg/dL despite statin
therapy, 30-
30-40% reduction is alternative
246
31
Questions ???
32