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Thyroid Hormone
. 5003097
.
5003110
.
Outline
Thyroid hormone
- Physiology
- Pathophysiology:
Hyperthyroidism
Hypothyroidism
Euthyroidism
-
Hyperthyroidism
Hypothyroidism
Parathyroid hormone
- Physiology
- Pathophysiology:
Hyperparathyroidism
Hypoparathyroidism
Hyperparathyroidism
Hypoparathyroidism
205
Thyroid Hormone
Physiology
2
isthmus 2,
3 cricoid 15-25 g
2
pharyngeal
pouches 1 2 endoderm
pharyngeal pouches 4 ultimobranchial body
pharyngeal pouch 5 parafollicular (C) cells
80120 mL/min ( 1
cardiac output) superior inferior thyroid (Superior
and inferior thyroid arteries)
Laryngeal pharyngeal
. Follicular cells (Follicles) 0.020.9
(villi) thyroid hormones Iodothyronines Thyroxine (T4) Triiodothyronine
(T3) metabolism thyroid follicle colloid
follicular cells thyroid hormones
2. Parafollicular cells C cells
follicles Thyrocalcitonin calcitonin
++
Ca
2
1. Thyroid hormones Iodothyronines tyrosine
206
thyroid hormones 4
1. thyroglobulin thyroglobulin glycoprotein tyrosine polysaccharide
Rough Endoplasmic Reticulum
2. (Iodide trapping) (I-)
Active transport autoregulation mechanism
3. tyrosine (Oxidation Organification)
peroxidase H2O2
tyrosine thyroglobulin monoiodotyrosine (MIT) diiodotyrosine (DIT)
organification
207
T4
DIT 2 T3 DIT MIT peroxidase
(Storage Secretion)
T4 T3
thyroglobulin thyroid
follicles TSH T4 T3 thyroglobulin Proteolysis
ECF (Secretion)
T4 T3 3 : 1 T4
7090 T3 1530
(Transportation)
T4 99.96 T3 99.5 3 thyroid-binding globulin
(TBG), thyroid-binding prealbumin (TBPA) albumin
thyroid hormone
T4
T3
Thyroid binding globulin (TBG)
70
77
Thyroid-binding prealbumin (TBPA)
10
8
Albumin
20
15
Thyroid binding protein
208
metabolism
- carbohydrate metabolism glycolysis gluconeogenesis
- protein metabolism thyroid Hormones
- fat metabolism lipolysis lipogenesis
- insulin
- thyroid hormone
- cardiac output
T4 T3 metabolised
Pathophysiology
(Thyroid disorder) 3 Hyperthyroidism Hypothyroidism
Euthyroid
1) Hyperthyroidism
Hyperthyroidism
hyperthyroidism
Thyrotoxicosis ( ) thyroid hormone
metabolism hyperthyroidism
thyroid hormone
209
Hyperthyroidism
1. Toxic diffuse goiter (Graves disease)
hyperthyroidism
Autoimmune disease
immunoglobulin Thyroid Stimulating Immunoglobulin (TSI) autoantibody
TSH receptor autoantibody
Graves ophthalmopathy
immunoglobulin Long Acting Thyroid Stimulator (LATS)
LATS LATS
TSH 12
2. Toxic multinodular goiter (Plummers disease Toxic adenomas)
(Toxic adenoma)
thyroid hormone
3. Thyroditis
thyroid hormone leak
4. Iodine-induced hyperthyroidism
thyroid hormone
5. thyroid hormone
Hypothyroidism
Hyperthyroidism
- (nervousness)
- (anxiety)
- (palpitations)
- (hand tremor)
-
- (emotion liability)
- (heat intolerance)
-
- (insomnia)
-
- -
- (thyromegaly) -
-
-exophthalmos Graves disease
tachycardia
210
2) Hypothyroidism
Hypothyroidism thyroid hormone
Hypothyroidism
1. Primary hypothyroidism thyroid hormone
1.1 Chronic autoimmune thyroiditis (Hashimotos disease)
Autoimmune disease antibodies enzyme thyroid
peroxidase, thyroglubolin thyroid cell TSH receptor
.
(Thyroid hypoplasia)
thyroid hormone
2. Secondary hypothyroidism
thyroid hormone
2.1 Pituitary disease
TSH
Pituitary tumor, , Postpartum pituitary necrosis (Sheehans syndrome)
2.2 Hypothalamic Hypothyroidism
TRH hypothyroidism
Hypothyroidism
Hypothyroidism
-
- (Depression)
- (Muscle cramps)
-
-(myalgia)
-
-
-
- (cold intolerance)
-
-
-
-Bradycardia
-
211
212
Hyperthyroidism Hypothyroidism
Hyperthyroidism Hypothyroidism
From: Damjanof I. Pathophysiology for the health professions. 3rded., Elsevier,2006
- - adrenergic receptor
- insulin
- basal metabolic rate
- goiter
-
- activity
- reflexes
-
-
-
- myxedema
-
Hyperthyroidism
Hypothyroidism
Hyperactive, insomnia
/
Lethargic ,somnolent
,
Hypercholesteroemia
3) Euthyroid
Euthyroid thyroid hormone TSH
Euthyroid
TSH
213
Drug
Dopamine, Glucocorticoids, Octreotide
Lithium Iodide, Amiodarone, Aminoglutethimide
Amiodarone
Colestipol, Cholestyramine, Aluminum hydroxide, Sucralfate,
Ferrous sulfate
Estrogens, Tamoxifen, Heroin, Methadone, Mitotane,
Fluorouracil
Androgens, Anabolic steroids (e.g. danazol),
Slow-release nicotinic acid, Glucocorticoids
Furosemide, Fenclofenac, Mefenamic acid, Salicylates
Phenobarbital, Rifampin, Phenytoin, Carbamazepine
Propylthiouracil, Amiodarone, Glucocorticoids,
Beta-adrenergicantagonist drugs
Interferon alfa, Interleukin-2
Thyroid disorders
- thyroid hormone thyroid hormone
- (Thyroid symptoms) (tenderness)
-
- Thyroid disorders
-
. TSH
TSH
. T4
T4
MCQ by MUPY RX39
214
Hyperthyroidism
Hypothyroidism
Primary
Secondary
TSH
T4
3. T3
T3 Hyperthyroidism
Hyperthyroidism Hyperthyroidism T3 T3
Hypothyroidism T3 thyroid hormone
215
Antithyroid Drugs
Thioamides propylthiouracil (PTU) methimazole adjuncts
primary treatment Iodide containing preparation, beta blocker, CCB, steroid
216
Thioamides
Mechanism of action
peroxidase
MIT DIT T4 T3 Propylthiouracil (PTU)
action Thyroid storm T4 T3 peripheral
Bioavailability
(%)
Propylthiouracil
Methimazole
80 95
80 95
Protein
binding
(%)
75 - 80
0
Transplacental
passage
Breast milk
level (M:P)
Half-life
(hr)
Low
High
Low (0.1)
High (1)
12
6 13
Excreted
in urine
(%)
< 35
<10
217
Side effect
- (pruritic maculopapular rash) (arthralgia)
( 4000 ) benign transient leukopenia
thioureas MMI 50
- rare side effect (agranulocytosis)
(fever) (gingivitis) (malaise)
(oropharyngeal infection) granulocyte 500 ,
(aplastic anemia), (Lupus-like syndrome), (polymyositis),
(GI intolerance), (hepatotoxicity),
(hypoprothrombinemia) 3
agranulocytosis antibiotic
granulocyte count G-CSF thiourea
granulocyte count, CBC
Drugs Interaction
- Anticoagulant ( ) hypoprothrombinemia bleeding
- -Blocker -Blocker
- Digitalis glycoside ( ) digitalis
- Theophylline () theophylline hyperthyroid (
theophylline hypothyroid
C/I
- Hypersensitivity
Iodide-containing preparation (Inorganic iodine)
thyroid hormone negative feedback thyroid hormone
Lugol s solution 6.3 SSKI (Saturated
solution of potassium iodide) 38 thyroid storm
7 14
Mechanism of action
- iodide organification
-
-
Dose
SSKI 3 10 ( 120-140 )
7 14
Pregnancy Risk Factor X
Side effect
hypersensitivity reaction (skin rashes) (drug fever)
(rhinitis) (conjunctivitis), (salivary gland swelling),
MCQ by MUPY RX39
218
(iodism)
,
(gynecomastia)
Beta blocker, CCB, Steroid
Thioamide hyperthyroidism beta
blocker
(thyrotoxicosis)
TSAb euthyroid
propranolol block converse T4 T3 beta blocker CCB
Steroid steroid block converse T4 T3 peripheral thyroid storm
side effect
-Blocker (I131)
Graves disease (toxic nodule) ,
-Blocker
Pregnancy Risk Factor C (manufacturer); D (2nd and 3rd trimesters - expert analysis)
Radioactive iodine
131I, 125I 131I
Side effect
- Hypothyroidism , , ,
- high dose
C /I
,
( second
trimester) , RAI euthyroid
Side effect
hypothyroidism,
219
2. Hypothyroidism
.
PE thyroid function test
- TT4 ( - mcg / dL), FT ( . . ng / dL), TT3 ( - ng / dL)
- TSH ( . - . mlU / L)
- RT3U ( %)
- cholesterol ( total, LDL-C), CK, LDH, AST
- Hct / Hb
- Na
- psychosis
- / creatine phosphokinase(CPK)
- CHD
-
.
Hypothyroidism
. Hypothyroidism thyroid hormone TSH
2. long term consequences
Thyroid hormone replacement
-
T3 T4 %
-
: thyroid extract ( T3 T4 ) T4 L
thyroxine sodium (Eltroxin ) T3
Levothyroxine (L-thyroxine, T4)
levothyroxine
Mechanism of action
T3 levothyroxine T4
T4 converse T3
Dose
. . 1 ( ) half life 9-10
Drugs Interaction
- Anticoagulant,oral ( ) anticoagulant
- Cholestyramine, colestipol ()
220
- , Dose
recommend mcg / day
- osteoporosis,
Parathyroid Hormone
Physiology
2
(inferior parathyroid gland) pharyngeal
pouch 3 (superior parathyroid gland)
pharyngeal pouch 4 inferior
thyroid
(trabeculae)
2
1. Chief cell
chief cell
++
++
PTH Ca Ca
Calcitonin Ca++ Chief cells 2 dark chief cell light
chief cell
2. Oxyphil cell chief cell chief cell
chief cell transitional cells chief oxyphil cells
MCQ by MUPY RX39
221
Chief cells
(Calcium sensing receptor) - PTH
PTH (Negative feedback)
chief cell preProPTH (
)
N ProPTH
N PTH
- osteoblast osteoclast
-
-
- 25(OH)D3 1,25(OH)2D3
Endocrine regulators 3
PTH thyrocalcitonin PTH thyrocalcitonin
Pathophysiology
2 Hyperparathyroidism Hypoparathyroidism
1) Hyperparathyroidism
Hyperparathyroidism PTH
Hyperparathyroidism
1. Primary hyperparathyroidism PTH
2.
Secondary hyperparathyroidism PTH
MCQ by MUPY RX39
222
- ( Kyphosis ) osteoclast
- (hypercalcemia) hypercalciuria
hypophosphatemia
- HCO3-
(metabolic acidosis)
-
2) Hypoparathyroidism
Hypoparathyroidism PTH PTH
Hypoparathyroidism
Hypomagnesemia aminoglycosides
-
-
-
-
Trouesseaus sign
- (carpopedal spasm )
- ( Trouesseaus sign)
- laryngospasm
1. Hyperparathyroidism
1.
parathyroid immunoassay
serum calcium primary hyperparathyroidism secondary
hyperparathyroidism
PTH
Serum Calcium
hyperparathyroidism
Primary
Secondary
tertiary hyperthyroidism PTH serum calcium primary
hyperthyroidism tertiary hyperthyroidism
223
hyperparathyroidism
facial
nerve (Chvosteks sign)
systolic ( Trouesseaus sign)
1.
(parathyroid adenoma)
hyperparathyroidism
secondary hyperparathyroidism
1.5
phosphate binding gel chronic alcoholism , malnutrition , aminoglycoside
( PTH
) calcitriol
- IV
D calcitriol
TH-One
(High Intensity Focused Ultrasound: HIFU)
primary hyperparathyroidism
secondary
hyperparathyroidism
calcimimetics cinacalcet primary
hyperparathyroidism secondary hyperparathyroidism
2. Hypoparathyroidism
2.
serum albumin
cAMP
hypoparathyroidism
- pseudohypoparathyodism (
) pseudopseudohypoparathyroidism (
pseudohypoparathyroidism
)
-
X
-
-
MCQ by MUPY RX39
224
(Electrocardiography: ECG)
facial nerve
(Chvosteks sign) systolic (
Trouesseaus sign)
.
calcium gluconate central venous catheter (
)
3 4 (
aminoglycoside )
phosphate binding gel
Teriparatide
hypoparathyroidism
Reference
1. , . Thyroid and antithyroid drugs Power point. :
; 2550.
2. . : , . .
3. : , 2535:288 294
3.
. . : . :
, 2551: 1-21.
4. . . : , 2550: 5-9.
5. . . : . : , 2551: 25-39.
6. . . : . : , 2551:
40-52.
7.
, . Thyroid diseases Power point. : ;
2550.
8. . . : , . . 3. :
, 2535: 187-206.
9. Joseph T., Robert L., Gary C. Yee, et al. Thyroid disorders. Pharmacotherapy 7th Ed. McGraw-Hill 2008; 78:1243-63
10. Laurence L., Keith L.Thyroid and anti thyroid drugs. Goodman&Gilmans. Manual of pharmacology and therapeutics. McGrawHill 2008; 981-94
225
DiabetesMellitus
. 5003026
. 5003027
. 5003092
5103003 5103010 5103075
Outline
Physiology
Physiology
Islets of Langerhans
1.
(A)cell islets ( %) glucagon
2.
(B) cell islets ( %) insulin amylin
3.
D cell
islets ( - %) somatostatin
4.
F cell
226
. Insulin cell islet of Langerhans
. Glucagon cell Islet of Langerhans
Struture metabolism
Insulin peptide pro-insulin endopeptidase enzyme pro-insulin
Polyribosome endoplasmic recticulum -cell
Pro-insulin peptides A B C amino acid , 30 (porcine)
peptide A intra-disulfide bond Cys6 Cys11 Inter-disulfide bond
A B Cys7 , Cys7 Cys20 , Cys19 Peptide C pro-insulin
endopeptidase insulin peptides 2 A B disulfide
bond A
227
Insulin 2
1. Basal insulin secretion insulin 0.5-1 unit/hr ( 70-120
mg/dl) (Preprandial glucose)
2. First and second phase insulin secretion insulin
(Prandial glucose) (Postprandial glucose)
first phase insulin secretion 5-10 second phase insulin secretion
glucose
Insulin
1. (glucose metabolism)
1) , ,
2) glycogen phosphorylase
3) glycogen synthase
4) glycerol ( gluconeogenesis)
2. (lipid metabolism)
1)
2) lipoprotein lipase triglycerides(TG) lipoprotein
3) lipoprotein
4) lipase TG TG
3. (protein metabolism)
1)
2)
3) ketone body
MCQ by MUPY RX39
228
Glucagon
glycogen adipose tissue
insulin uptake
(glycogen synthasis) glucagon receptor
glucagon (gluconeogenesis)
Glucose Homeostasis
50-100 mg%
Glucotoxicity (Glucotoxicity
insulin beta-cell beta-cell insulin first
phase insulin )
Glucose entry 2
1. exogenous glucose entry exogenous glucose entry
post prandial glucose 2
1) external factor
2) internal factor
GI tract, adipose tissue, adrenal gland )
2. endogenous glucose entry 2
gluconeogenesis gluconeolysis endogenous glucose entry fasting glucose
MCQ by MUPY RX39
229
Glucose utilization 2
1.
insulin
2.
(Polyuria) ,(Polydipsia) ,
(Polyphagia) , , ,,,
1 2
severe hyperglycemia insulin Counter regulatory hormone
catecholamines cortisol TG ketone body
Ketoacidosis
(dehydration) (hypotension) (tachycardia) (hyperventilation)
(hyperthermia) coma (~10%)
(Modifiable risk factors)
(Hyperglycemia) , (Hypertension BP>140/90) ,
(Dyslipidemia) ,Prothrombotic state , (Albuminuria) ,
(Smoking) , ,HDL <35, and/or TG>250 , (vascular dz.)
, cyst PCOS (polycystic ovarian syndrome) , other conditions associated with insulin
resistance , , 4 kg ,
American-African
- Type 1 diabetes
- Type 1.5 diabetes
- Type 2 diabetes
- Gestational Diabetes
- Other specific type , ,
Type 1 diabetes
- 1 cellular-mediated autoimmunity -cell T cell
-cell lymphocyte -cell -cell insulin insulin
insulin
- ketoacidosis( ketone glucose)
-
MCQ by MUPY RX39
230
- 1 (
40 ) 5-10% 1
- cellular-mediated autoimmune
- insulin
- Onset age < 40
- polyphagia(), polyuria(
), polydipsia()
-
-
- insulin
cellular-mediated autoimmune
1. HLA (Human leukocyte antigen)
.
-
autoreactive T cell
autoimmune
-
- regular T cell
- 1
Type 2 diabetes
2 Syndrome X Metabolic Syndrome
gout
ketoacidosis
macrovascular
microvascular
231
- (insulin resistant)
(insulin deficiency)
-
- Onset age > 40 ( - )
-
-
-
-
Type 1.5 diabetes
Slow onset type 1 Latent Immune Diabetes in Adults(LADA)
232
(random plasma glucose)
mg/dl(11.1 mmol/l)
2. ( )
mg/dl
(fasting plasma glucose:FPG)
3. (2-hPG) (oral glucose tolerance test: OGTT)
mg/dl ()
- OGTT (Specificity) (Sensitivity)
- FPG OGTT
plasma glucose
Diabetes
Diabetes
0
Mellitus
IGT
(pre-DM)
0
IFG
Mellitus
Normal
Normal
FPG
2h- PPG
233
3
Diabetic ketoacidosis (DKA) Hyperosmolar
hypergkyceneic state (HHS)
Pre-Diabetes
Pre-diabetes
artherosclerosis complication
pre-diabetis
234
.
.
.
. A1C
ADA
AACE
<80 or >140
<100 or >160
>
(cardiovascular system) (coronary heartdisease; CHD)
Fasting plasma glucose (FPG)
Postprandial glucose (PPG)
A1C
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides
male (BMI)
female
Blood pressure (BP)
80-120 mg/dl
80-160 mg/dl
<7%
<200 mg/dl
<100 mg/dl
>45 mg/dl
<150 mg/dl
20-25 kg/m2
19-24 kg/m2
130/85 mmHg
>140 mg/dl
>180 mg/dl
>8%
>250 mg/dl
>130 mg/dl
<35 mg/dl
>400 mg/dl
>27 kg/ m2
>26 kg/m2
>160/95 mmHg
235
(The Endocrine Society of Thailand)
()
Hemoglobin A1C
A1C (meanplasma
glucose; MPG) (pre- and post-meal glucose)
A1C A1C 1%
(microvascular complications) 35-40% A1C
<7% ( 6%) PPG <180 mg/dl A1C
(Life-style modifications)
1.
- (cholesterol
) - - > CHO: protein: lipid = 50-55%: 15-20%: <30%
-
-
saccharin, aspartame, cyclamate, acesulfame-K
- 2 1 - - >360
ml of beer , 100 ml of wine , 30 ml of whisky
-
2.
insulin
2 1
hypoglycemia (intensity)
(frequency) (duration) 30 3
(warm up) (cool down)
1.
A1c 1-2%
MCQ by MUPY RX39
236
2.
3.
4.
5.
6.
7.
8.
cholesterol TG,LDL
Drug class
. insulin
(Insulin secretagogues)
- Sulfonylurea (SU)
- Non-Sulfonylurea (NSU)
DPP-4
- DPP-4 inhibitor
.
insulin (Insulin sensitizers)
- Biguanides
- Thiazolidinedione(TZD)
-glucosidase Inhibitor
Mechanism of action
Metabolis
m
Insulin release
Pancreas
Hepatic
Carbohydrate absorption
Liver,Peripheral tissue
Sulfonylurea: SU
First generation :
Tolbutamide
Chlorpropamide
Second generation : Glibenclamide
Gliclazide
Glipizide
Glimepiride
Potency,Pharmacokinetics,
Safety first gen.
NO/YES
Yes
Hepatic
No
Peripheral tissue,Liver
Small intestines
Real excreate
of active
metabolite
Intestinal
Yes
237
Machanism Of Action
insulin SU SUR(sulfonylurea receptor) cell ATP-dependent K+ channel
K+ depolarize Ca + channel Ca +
Ca + insulin
SAR
SU acidic functional group(sulfonylurea) aromatic ring
alkyl group
Duration
Activity
O
O
R1
N
H
N
H
R2
Toxicity
238
sulfa sulfonamide
sulfa R4 H
SU R4 H
239
1.
Type 2 DM
. response FBS < 240 mg/dl
3.
.
* active metabolite
Tolbutamide
Chlorpropamide
Glibenclamide**
Glipizide**
Glicazide**
Glimepiride
Orinase
Diabinese
Daonil
Minidiab
Diamicron
Amaryl
(mg)
time to
peak (hr)
duration
(hr.)
(mg.)
,
,
. ,.,
,
6-10
24-72
20-24
12-24
10-15
24
500-3000
125-500
2.5-30
2.5-30
40-320
1-6
,,
**
gen lipophilic gr.( Glibenclamide, Glipizide, Glimepiride)
/
2-3
1
1-2
1-2
1-2
1
100%
100%*
50%*
85%
60-70%
60%
* NICE Guidline
1. Gliclazide : half life hypoglycemia
2. Glybenclamide : hypoglycemia
3. Glimepiride : second choice hypoglycemia
- phase 1
- dose -
- dose
240
-
-
Side effect
- Hypoglycemia
- 30
beta-adrenergicantagonist sulfonylureas betaadrenergic antagonist 15 g
- Weight gain
- hemolytic anemia
cholestasis
- sulfonylurea sulfa
- /(),
-
- Pancreatic diabetes
- ketoacidosis,hyperosmolar hyperglycemic coma severe hyperglycemia
- (teratogenicity)
(neonatal hypoglycemia) glibenclamide
-
Drug interaction hypoglycemia
- SU albumin : aspirin, fibrates, trimethoprim
- metabolism SU: H -blockers, anticoagulants, alcohol
- SU: probenecid,allopurinol
- sulfonylureas
calcium channel blockers, estrogen,
isoniazid, niacin, oral contraceptives phenytoin sulfonylureas
azole antifungals histamine-2 receptor
sulfonylureas
sulfonylureas sulfonylureas sulfonylureas
241
sulfonylureas
- Chlorpropamide Glibenclamide
- Chlorpropamide Glibenclamide active metabolite
- half-life inactive
- Chlorpropamide (hyponatremia) ADH
(antidiuretic hormone)
(antabuse effect- disulfuram)
- glipizide glibenclamide
Non-sulfonylurea
Repaglinide(Novonorm), Nateglinide
Machanism of Action
insulin beta cells SU SUR
SU ( SU)
SU
(postprandial hyperglycemia)
MCQ by MUPY RX39
242
SAR
carboxylic acid SU
insulin
hypoglycemia
Onset
(min)
Duration
(hr)
(mg)
(.)
Repaglinide
Novonorm
15-30
4-6
.,,
0.5-4
2-3
Nateglinide
Starix
20
60-120
2-3
Pharmacokinetics
non-sulfonylurea secretagogues sulfonylureas
nateglinide > repaglinide > glipizide, glimepiride, gliclazide >tolbutamide,
glibenclamide (micronized formulation) > chlorpropamide, glibenclamide (nonmicronizedformulation)
SU
Side effect
hypoglycemia ,
243
Type 1 diabetes mellitus
diabetes ketoacidosis
(Cat :C )
12
CYP 3A4
Drug Interaction
Repaglinide CYP450 3A4
Nateglinide CYP450 2C9, 3A4( In Vitro )
Gemfibrozil Repaglinide hypoglycemia
Biguanides
Metformin(Glucophage)
Machanism of Action
(decrease glycogenolysis decrease gluconeogenesis)
GLUT- [insulin-stimulated glucose transport in muscle cell]
glucose
SAR
guanidine 2
(BMI >25)
244
Pharmacokinetics
half-life reservoir
Bioavailability 50-60%
plasma proteins
hepatic metabolism
Time to peak
(hr)
(mg)
(.)
Metformin
Glucophage
500,850,1000
500-2500
2-3
- 500 mg -
- - - ( SU
)
- .
FPG -70mg/dl
A1C .5- %
LDL triglyceride 10- %
HDL
-
anorexia
hypoglycemia
Side effect
(metalic taste)
B12 B12
(Lactic acidosis)
Lactic acidosis ()
245
serum creatinine
Scr > 1.5 mg/dL, Scr > 1.4 mg/dL
lactic acidosis
( cat : B )
Drug Interaction
Thiazolidinedione (TZD)
Rosiglitazone(Avandia),Pioglitazone(Actos)
246
Machanism of Action
PPARv- (peroxisome proliferators-activated receptor-) insulin-responsive genes
carbohydrate lipid metabolism
insulin resistance
free fatty acid
adinopectin
SAR
- thiazolidine-2,4-dione
side chain
thiazolidine-2,4-dione
1.
Thiazolidinedione
2.
Methyl
3.
Phenyl
4.
O
2
2 Metformin
metformin
sulfonylurea
metformin 2
Pharmacokinetics
247
Time to peak
(hr)
Duration
(wk)
(mg)
(.)
Rosiglitazone
Avandia
1-2
>3-4
2,4,8
4-8
Pioglitazone
Actos
1-2
>3-4
15,30,45
15-45
-
-
- - ( )
- FPG 5-7
- ( ALT) ALT
- Monitor ALT (ALT)
- renal insufficiency
248
. NYHA (New York Heart Association) congestive HF class III IV ( Europe class)
.
.
. . -
. Congestive HF US FDA black box warning HF
6. Type 1 diabetes mellitus
7. diabetis ketoacidosis
- 4
-
- HF volume overload acute
exacerbation of heart failure
-
-
Drug Interaction
- rosiglitazone pioglitazone
CYP450 2C8 2C9 gemfibrozil
-glucosidase Inhibitor (AGI)
Acarbose(Glucobay), Voglibose(basen)
Machanism of Action
-glucosidase -glucosidase
oligosaccharide
monosaccharide (postprandial glucose)
249
.
.
SU metformin
.
.
1
5.
Pharmacokinetics
2%
1
51% 96
(mg)
(.)
Acarbose
Glucobay
25,50,100
25-100
Voglibose
Basen
0.2,0.3
15-45
GI side effect
.
, bowel obstruction
.
3.
4.
250
Potency
GI side effect
Drug Interaction
- glucosidase digoxin
antacid, bile acid resin, activated charcoal, digestive enzyme efficacy- glucosidase
corticosteroid
SU*
NSU
Metformin
TZD
AGI
time to peak(hr)
2-6
1
2-3
1-2
1-2
half life(hr)
5-10
4-6
1-5
3-7
2
duration
12-24
4-6 hr
>3-4 wk
>3-4 wk
4 hr
*Second generation
SU
NSU
Metformin
FPG HbA 1c
LDL
(.%)
(%)
60-70
1.5-2
60-70
1.5-2
60-70
1.5-2
- %
MCQ by MUPY RX39
HDL
Triglyceride
- %
251
TZD
AGI
60-70
0.9-1.6
16-20
0.5-1
Insulin
(-cells)
A B disulfide
bridge (S-S)
- 2
1st phase
Plasma
Insulin
mg/dl
80
2nd phase
60
40
20
.
.
.
Insulin
Insulin preparation
Rapid acting
- Lispro
- aspart
Short acting
- Regular
Intermediate acting
- NPH (isophane)
- Lente ( zinc )
15
30
45
60
75
Time (min)
trade names
onset of
action
peak of
action
Humalog
Novorapid
15-30min
15-30 min
1-2 hr
1-2 hr
3-4 hr
ActrapidHM,HumulinR
30-60 min
2-3 hr
3-6 hr
HumalinN,InsulatardHM
Monotard HM
2-4 hr
3-4 hr
4-6 hr
6-12 hr
8-12 hr
12-18 hr
effect duration
252
Long acting
- Ultralente
- Glargine
- Detemir
Combinations
-NPH/Regular
Ultratard HM
Lantus
6-10 hr
4-5 hr
2 hr
10-16 hr
No peak
6-9 hr
18-24 hr
22-24 hr
14-24 hr
Mixtard
Humulin80/20,70/30,
30-60 min
10-16 hr
Rapid acting
Lispro (Humalog) amino acid carboxy terminal B chain 29
proline lysine hexamer monomer
Aspart (Novolog) recombinant DNA aspart proline
Lispro
Short acting
Regular (Humarin R,Actrapid HM)
Intermediate acting
NPH [neutral protamine hagedorn insulin](Humalin N,Monotard) isophane insulin
protamine -
Lente insulin zinc
Slow acting
Glargine arginine 2 carboxy terminal B chain Isoelectric point pH 5.4
. asparagines glycine A chain analog
basal insulin
- Detemir treoninem B 30 myristic acid
albumin
Combinations
-
MCQ by MUPY RX39
253
Type 1 ( : / )
0.5-0.6
Honeymoon phase(
1
) 0.1-1.4
Split-dose therapy 0.5-1.2
With ketosis or during acute illness 0.5-1.0
Type 2 ( : / )
0.2-0.6
Split-dose therapy 0.5-1.2
With insulin resistance 0.7-2.5
1. [intermediate-acting insulin]
2. insulin mixture
3. 2 [intermediate-acting insulin]
2/3 1/3
4. insulin mixture hr
5. 3-4 [multiple injection] Regular insulin 3 Long-Acting Insulin
6. continuous subcutaneous infusion pump regular insulin
10-20 /
0.6 /../
3-7 2
1.
2. Sc
3. Pump
( basal line
)
4. Inhalation: Exubera inhaled insulin (dry powder inhalers; DPI)
.
.
.
.
MCQ by MUPY RX39
254
Side effect:
.
2. Lipodystrophy
.
.
aqueous humor
.
U100 1 cc. 100
10 cc. 1000
2-8 C 30 1
1.
2.
3.
4.
1.
2. ()
255
256
Pramlintide(Symlin)
human amylin -cell
HbA1c
ml 1
2 insulin therapy
1; mcg mcg -60 mcg
;
mcg max dose 120 mcg
:nausea and vomiting, anorexia, headache.
SGLT2 Inhibitors
Phlorizin, Dapaglizin, Sergliflozin, Remogliflozin
SGLT2 Inhibitors
Type 2 diabetes
SGLT2 transporter
- transporter early proximal tubule
- reabsorption %
MCQ by MUPY RX39
257
- affinity
- gene mutation transporter (renal glucosuria)
Mechanism of Action
- SGLT2 transporter
- reabsorp
-
-
- ()
Dose-dependent effect
-
-
-
-
Side effects
1.
2.
3.
4. Hypoglycemia ()
5.
6.
7. Hematocrit
8.
*side effect HTN, obesity
SGLT2 inhibitors
- insulin glucose metabolism hypoglycemia
-
-
- Side effects
- Mild osmotic diuretic CHF
258
( 2554)
259
Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check
A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C
is 7%. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. Insufficient clinical use to be
confident regarding safety.
Complications
Acute complication
1. Hypoglycemia
2. Hyperosmolar coma shock
3. Diabetic ketoacidosis
Chronic complication
(coronary heart disease: CHD)
260
Total cholesterol (./.)
LDL-cholesterol (./.)
<170
<100
>40
>50()
<150
18.5-22.9
<90
<80
HDL-cholesterol (./.)
<130/80
*
LDL-cholesterol 70(./.)
** 140-110/70
Ref : .2554
ACEI (angiotensin-converting enzyme
inhibitors) ARBs
Statin CHD CHD
aspirin 75-162 mg/d A1C %
- %
1. Microvascular: retinopathy (glaucoma,cataract), nephropathy,neuropathy
FPG
2. Macrovascular; cerebrovascular disease, CHD, peripheral vascular disease
(
FPG>100)
Microvascular
Retinopathy
MCQ by MUPY RX39
261
Treatment
1.
2. A1C < %
3.
-
-
Nephropathy
Microalbuminuria Macroalbuminuria
Treatment
1. ACEI(angiotensin-converting enzyme inhibitors) ARBs
ACEI Microalbuminuria ARBs
Macroalbuminuria
2. A1C < %
3. albumin
4. albumin
- -
-
Neuropathy
1. Peripheral neuropathy:
Amputation
Treatment: hyperglycemia, hypertension, dyslipidemia
: tricyclic antidepressants,Anti-convulsant
:
2. Autonomic neuropathy
- Cardiovascular: (> bpm), Orthostasis hypotension
- GIAutonomic neuropathy:
- Genitourinary:
UTI
- Sexual: Erectile dysfunction and/or Retrograde ejaculation
MCQ by MUPY RX39
262
Macrovascular
Cardiovascular disease Stroke
Cardiac disease: AMI,Ischaemia
1.
2.
3. ()
-
-
-
4.
5. , ,
, ,
cotton or wool
3-6
()
()
MCQ by MUPY RX39
263
6.
7.
8. ,
9.
Reference
1. Nature publishing group. Pharmacotherapy for the Treatment of Patients with
Type 2 Diabetes Mellitus: Rationale and Specific Agents. CLINICAL PHARMACOLOGY & THERAPEUTICS 2007;
81(5):636-649.
2. . 2.
; : - .
3. , ,.Inhaled Insulin: Exubera.Thai Pharm Health Sci J
2006;1(2):170-179
4. .
5. Kumar A,Nair R,Jagadish V,Oral hypoglycemic agents for treatment of type II Diabetes Mellitus
: A Review.
6. ADA recommended algorithm. Nathan DM et al. Diabetes Care. 2006;29:19631972 [19].
7. Matindale
8. Goodmangrillman
9. Pco tx handbook
10.
11. : . .
12. 2554 ,
13 .Medical Management of Hyperglycemia in Type 2 Diabetes : the American Diabetes Association and the
European
Association for the Study of Diabetes ; Diabetes Care. 2009 January; 32(1): 193203.
341
** !!
1
Menopause ()
(WHO)
(Menopause)
1. Natural menopause 12 ( 1
)
49-51
1.5
2. Surgical menopause
3. Premenopause
3 40
4. Perimenopause () 4-5
1
5. Postmenopause Natural Surgical menopause
6. Climacteric period Premenopause, Perimenopause Postmenopause
MCQ by MUPY RX39
342
(
)
estrogen estrogen
estrogen androgen
estrogen estrogen
Estradiol (estradiol-17 E2) estrone (E1) estrogen
- (Reproductive age) estrogen estradiol (estradiol-17 E2)
- (Menopause) estrogen estrone (E1)
343
(Short term)
1. Neuroendocrine system
1.1 Vasomotor symptoms (2 menopausal
symptoms) hot flushes hot flashes
1.2 Psychosexual symptom
2. Urogenital system
receptor estrogen
estrogen menopause (atrophy)
(vaginismus)
(dyspareunia) (uterovaginal prolapse)
(cystocele)
344
(Long term)
Osteoporosis & bone fracture
estrogen bone formation osteoblast ( )
bone resorption osteoclast ()
(bone mass) bone mineral density (BMD) BMD . SD
osteoporosis
Hormone
12 menopausal syndrome
estrogen
perimenopause
menopausal symptoms Hormone replacement therapy (HRT)
1. (Serum hormone levels)
Treatment
1.
MCQ by MUPY RX39
345
hot flushes
-
-
-
estrogen (phytoestrogen) ** **
hot flushes
Common ADR phytoestrogen
- Constipation
- Bloating
- Nausea
Vitamin E vitamin E 900 IU hot flushes
Antidepressants Venlafaxine , Paroxetine , Fluoxetine
endorphine
5
2.
2.1 Estrogens (Estrogen replacement therapy ERT)
menopausal symptoms
osteoporosis
estrogen proliferation
(endometrial) endometrial cancer ( ** estrogen
Conjugated estrogen(Premarin) 0.625-1.25 mg/day** ( ) cyclic
continuous
combined HRT progestogens
breast cancer)
conjugated estrogens (Premarin) 0.3 mg 17 -estradiol (Estrofem)
0.5 mg
estrogen
osteoporosis
0.625 mg
1-2 mg
Vasomotor Symptoms
Mild
Moderate & Severe
0.625 mg
1.25 mg
2-4 mg
346
2-4 mg
5-20 g
2-8 mg
1-2 mg
1 mg
50 g
50 g
100 g
25 g
25-50 mg
50-100 mg
25 mg
1.5 mg
25-50 mg
5-10 mg
25 g
- Prempak
(conjugated estrogen 0.625 mg 21
+ medrogestone 5 mg 10 )
- Cyclo-Progynova
(estradiol valerate 2mg 21 +
norgestrel 0.5 mg10)
- Climen
(estradiol valerate 2mg 21 +
cyproterone cetate1 mg10)
- 7
347
- ERT
- 7
-
-
Estrogens + Progestogens 2
2.2.1. Cyclic hormone replacement therapy Perimenopause
3 (E Estrogen, P Progestogen, A Androgen dose mg /
2.2.1 )
2.2.2 Continuous hormone replacement therapy Postmenopause 6
348
349
350
HRT: HRT
1.
2. ,
(severeoligo-amenorrhea)
- Turners syndrome
- Anorexia nervosa ()
3.
(premature menopause)
4. (bone mass) 1 SD peak bone mass
5.
osteoporosis
Types of Continuous HRT
1.Continuous unopposed E
( E
)
-Kliogest
(1 17-estradiol
2mg+norethisterone acetate 1
mg)
- ERT
-
menopausal symptoms
-Trisequens
(estradiol 2 mg 12 ,
Estradiol 2 mg+norethisterone
acetate 1 mg 10 ,
Estradiol 1 mg 6 )
- P
-Livial
(1 tibolone 2.5
mg tibolone
E,P,A)
MCQ by MUPY RX39
351
HRT
1. (hot flushes)
estrogen
80 3
2. urogenital symptoms
estrogen
(atrophic vaginitis) estrogen ,
3. Osteoporosis & bone fracture
estrogen
-
osteoclast activity cytokines & other bone affecting agent
- calcium
Ca2+absorption, renalCa2+excretion,PTH(parathyroid hormone) secretion,
calcitonin secretion
BMD bone fracture
( HRT treatment of choice osteoporosis
bisphosphonate estrogen
)
Calcitonin
PTH
4. colorectal cancer
estrogen estrogen
bile acid bile acid
estrogen estrogen receptor proliferation colorectal cancer
cell apoptosis cancer cell
5. endometrial cancer
** progestogen estrogen endometrial cancer **
352
HRT :
1. Coronary heart disease
conjugated equine estrogen (CEE) 0.625 . CEE 0.625 . +
Medroxyprogesterone acetate (MPA) 2.5 . atherosclerosis
coronary (coronary heart disease)
2. Stroke
WHI (2002) (Womens Health Initiative study) WHI (2004) estrogen +
progesterone estrogen stroke
3. * *Venous thromboembolism (VTE) **
estrogen estrogen+progesterone
venous thromboembolism
venous thromboembolism
4. Breast cancer
estrogen ductal epithelium meiotic activity
cells ducts connective tissue
sex hormone breast cancer
5. Ovarian cancer
estrogen 1.6 16 estrogen +
progestogen 1.1 11
9 Charla M.
Blacker, MD, FACOG Prevention and Treatment of Osteoporosis estrogen
(www.glowm.com) estrogen
estrogen+progestogen
6. Cognition & dementia
estrogen progestorone
dementia 65
7. Gallstone disease
estrogen
super saturated with cholesterol
cholesterol stone
cholecystectomy
gallbladder stone
% Oral CEE 2% Transdermal 1.3%
353
HRT
1. (hot flushes)
2. Urogenital symptoms
3. Osteoporosis
& fracture
4.
Colorectal cancer
5.
Endometrial cancer
Contraindication of Estrogens
1. (breast cancer)
estrogens proliferation Tamoxifen
( anti-estrogen estrogen tissue )
2. (endometrial cancer)
estrogens proliferation (endometrial)
endometrial cancer
estrogens
3. Severe liver dysfunction
metabolize estrogens
progestogens metabolize 2
4. Porphyria ( ) enzyme hemoglobin estrogen HRT
enzyme
5. Abnormal vaginal bleeding ()
6.
Contraindication of Progestogens
Meningioma : progesterone receptors progestogens
antiprogestogen
menopausal syndromes
hot flushes Estrogen
dose (Transdermal patch) dose
( )
354
(perimenopause) (early
postmenopause) estrogen
estrogen
Tamoxifen
Raloxifene
(Celvista, Evista 6omg/tab Dose: 60 mg/day)
Preg. Cat.: D
SERMs 1gen
Benzothiophene derivative
Preg. Cat.: X
SERMs 2gen
Indication
Indication
Estrogen antagonist
Estrogen agonist ,
Lipid profile cholesterol metabolism
355
Indication
- osteoporosis
- hot flushes vasomotor, psychological, and libido problems
Comparison of selected actions and side effects of estrogen, SERMs and STEAR
Side Effects
Estrogen Tamoxifen Raloxifene Tibolone
Hot flushes
Uterine bleeding
Risk of endometrial cancer
Prevention of postmenopausal bone
loss
Risk of breast cancer
Favorable pattern of serum lipids
Venous thrombosis
356
Reference
1.
, , .
. : - () , 2539
2. , . Menopause -
. 10700,
http://www.sirirajmedj.com/content.php?content_id=
3. , . . : , 2543.
4. , , , . . :
, 2548
5. ... , . . : ,
2545 . Hormone Replacement Therapy
6. . , . . :
.., 2551