Part 2 Thyroid hormones and antithyroid drugs

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• Part 2Thyroid hormones and antithyroid drugs

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A. Thyroid hormones
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Metabolism of thyroid hormones
1. Uptake of iodide 2. Activation of iodide
(peroxidase), and iodination and coupling of
tyrosine 3. Formation of thyroxine (T4) and
triiodothyronine (T3) from iodotyrosine 4.
Secretion of thyroid hormones (proteolytic
enzymes) 5. Regulation by thyroid stimulating
hormone (TSH), T4, T3
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Metabolism of thyroid hormones
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Formation of thyroxine (T4) and triiodothyronine
(T3) from iodotyrosine

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Secretion of thyroid hormones ( lysosomal
proteolytic enzymes )
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Regulation of the secretion of thyroid hormones
(feedback inhibition)
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Pharmacology of thyroid hormones

• 1. Normalizing growth and development
• 2. Promoting body metabolism
• Body temperature energy levels, ect.
• 3. Enhancing sympathetic activity

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Action of thyroid hormones interaction with
their receptors in the nuclei
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Clinical uses of thyroid hormones

• 1. Treatment of hypothyroidism
• (1) cretinism (???)
• (2) myxoedema (?????)

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Clinical uses of thyroid hormones

• 2. Simple goiter (???????)

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B. Antithyroid drugs
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Symptoms of the patient with hyperthyroidism
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• Therapeutic drugs for Hypothyroidism
• antithyroid drugs thiourea derivatives
• iodine
  and iodides
• ?
  receptor antagonists
• surgery
• radioiodines 131I, 125I

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B. Antithyroid drugs

• Thiourea derivatives
• Propylthiouracil ?????
• Methimazole (tapazole) ????
• Carbimazole ????
• Iodine and iodides
• ? Receptor antagonists
• Radioiodide (131I)

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B. Antithyroid drugs

• Thiourea derivatives

????Thiamazole
?????
????
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B. Antithyroid drugs

• Thiourea derivatives
• 1. Pharmacological effects
• (1) Inhibiting the formation of thyroid hormones
  by interfering with iodination inhibiting
  peroxidation, then the iodination and coupling
• Symptom relieving 23 weeks
• Basic metabolic rate returning 12 months
• (2) Inibiting peripheral deiodination of T4 T4 ?
  T3 ? (propylthiouracil)
• (3) Goitrogenic action (goiter) TSH ?

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Mechanism of inhibition of thyroid hormone
synthesis by thiaureas Thiaureas are oxidized by
thyroid peroxidase (TPO)
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Mechanism of inhibition of thyroid hormone
synthesis by thiaureas
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B. Antithyroid drugs

• 2. Clinical uses
• (1) Non-operative therapy of hyperthyroidism 13
  month latent period
• (2) Preoperative therapy of hyperthyroidism
  combined with larger dose of iodide
• (3) Thyrotoxic crisis combined with larger dose
  of iodide, propylthiouracil
• 3. Adverse effects
• (1) Agranulocytosis (0.30.6)
• (2) Hypersensitivity (3) GI reactions

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B. Antithyroid drugs

• Iodine and iodides
• 1. Pharmacological effects
• (1) Small doses simple goiter
• (2) Larger doses inhibiting the release of
  thyroid hormones (proteolysis ?) and synthesis
• After iodide use, the thyroid vascularity is
  reduced, and the gland becomes much firmer, the
  cells become smaller (inhibiting TSH release).

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Mechanism of iodides
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Wolff-Chaikoff ??
Mechanism of iodides
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B. Antithyroid drugs

• 2. Clinical uses
• (1) Preoperative therapy of hyperthyroidism
  combined with thiourea derivatives (for 2 weeks)
• (2) Thyrotoxic crisis combined with thiourea
  derivatives (propylthiouracil)
• Lugols solution 5 iodine and 10 potasium
  iodide

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B. Antithyroid drugs

• 3. Adverse effects
• (1) Acute effects hypersensitivity, angioedema,
  swelling of the larynx
• (2) Chronic intoxication (iodism)
• (3) Thyroid dysfunction exacerbation of
  hyperthyroidism, goiter

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B. Antithyroid drugs

• ? Receptor antagonists
• 1. Pharmacological effects
• (1) Heart ?1 block
• (2) CNS relieving anxiety
• (3) Presynaptic ?2 receptor NE release ?
• (4) Inhibiting the conversion of T4 to T3
• 2. Clinical uses
• Adjuvant therapeutic drug

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B. Antithyroid drugs

• Radioiodine
• 131I, 125I, 123I
• Destroying thyroid tissue
• Diagnosis
• Careful use

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• Part 3Insulin and oral hypoglycemic drugs

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Pancreas
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Pancreas cells
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Diabetes mellitus Insulin ? or its responses ? ?
blood glucose ? ? Acute or chronic symptoms
Catecholamines
Glucose metabolism and the regulation by insulin
and glucogan
Glucocorticoid
Growth hormone
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Insulin promotes glucose utilization
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???
???
???
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Different forms of diabetes mellitus
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Complications of diabetes mellitus

• Acute complications
• Diabetic ketoacidosis
• Hyperosmotic nonketotic coma
• Chronic complications
• Cardiovascular diseases
• Renal damage
• Retinal damage
• Nerve degeneration
• Infection
• Myopathy
• etc.

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A. Insulin and its enhancers
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Structure of insulin
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Biochemistry of insulin
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Secretion of insulin
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A. Insulin and its enhancers
Insulin 1. Pharmacological effects (1)
Carbohydrate metabolism reducing blood glucose
levels by glycogenolysis ?, glycogen synthesis ?,
gluconeogenesis ? (ketone badies ?) (2) lipid
metabolism fat synthesis ?, lipolysis ?, plasma
free fatty acids ? (3) Protein metabolism active
transport of amino acids ?, incorporation of
amino acids into protein ?, protein catabolism
? (4) Mechanism of insulin actions
Interacting with insulin receptor
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Structure of insulin
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Interaction between insulin and its receptor IRS
insulin receptor substrate tyr tyrosine P
phosphate
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Insulin promotes the translocation of glucose
transporters into the membrane
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A. Insulin and its enhancers
2. Clinical uses (1) Insulin-dependent patients
with diabetes mellitus (type 1 diabetes mellitus)
(2) Insulin-independent patients failure to
other drugs (3) Diabetic complications diabetic
ketoacidosis (?????), hyperosmotic nonketotic
coma(?????????) (4) Critical situations of
diabetic patients fever, severe infection,
pregnancy, trauma, operation (5) Others
promotion of K uptake into the cells,
pshychiatric disorders
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A. Insulin and its enhancers
3. Preparations
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3. Preparations

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Actions of different insulin preparations
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A. Insulin and its enhancers
4. Adverse effects (1) Hypersensitivity treated
with H1 receptor antagonist, glucocorticoids
(2) Hypoglycemia adrenaline secretion
(sweating, hunger, weakenss, tachycardia, blurred
vision, headache, etc.), treated with 50
glucose (3) Insulin resistance acute, chronic
(4) Lipoatrophy localized in injection sites
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Insulin resistance
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A. Insulin and its enhancers
Insulin action enhancers Thiazolidinediones
(TDs) ???????? Rosiglitazone ????
Pioglitazone ???? Troglitazone ????
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A. Insulin and its enhancers
Rosiglitazone ????
Pioglitazone ????
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A. Insulin and its enhancers
Insulin action enhancers 1. Pharmacological
effects Selective agonists for nuclear
peroxisome proliferator-activated receptor-?
(PPAR?, ?????????????), increasing glucose
transport into muscle and adipose tissue. (1)
Lowering insulin resistance (2) Lipid metabolism
regulation TG, free fatty acid ? (3)
Antihypertensive effects (4) Effect on vascular
complications in type 2 patients
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A. Insulin and its enhancers
2. Clinical uses used for treatment of
insulin-resistant diabetic patients or type 2
patients 3. Adverse effects Edema, headache,
myalgia, GI reactions, hepatic damage
(troglitazone)
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B. Oral hypoglycemic drugs
Sulfonylureas(????) Biguanides(???) ?-Glucosidase
inhibitors(?????????) Others
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B. Oral hypoglycemic drugs
Sulfonylureas(????) Tolbutamide (D860)
???? Chlorpropamide ???? Glibenclamide ????
(???) Glipizide ???? Gliclazide ???? (???)
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B. Oral hypoglycemic drugs
1. Pharmacological effects Blocking K channel
Ca2 inflow ?, insulin release ?, Stimulating
insulin secretion Increasing insulin sensitivity
(long-term use)
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Action of sulfonylureas
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B. Oral hypoglycemic drugs
2. Clinical uses (1) Insulin-indenpedent
diabetic patients (type 2) alone or combined
with insulin (2) Diabetes insipidus (???)
Chlorpropamide (????) antiuretic hormone (ADH)
?
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B. Oral hypoglycemic drugs
3. Adverse effects (1) GI reactions (2) CNS
reactions (3) Hypoglycemia especially in
elderly, hepatic or renal insufficiencies (4)
Others leukopenia, cholestatic jaundice, hepatic
damage
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B. Oral hypoglycemic drugs
4. Drug interactions (1) Potentiation of
hypoglycemic effects replacement in plasma
protein binding salicylic acid, sulfates,
indomethacin, penicillin, warfarin, etc.
inhibition of hepatic microsomal enzymes
chloramphenicol, warfarin (2) Attenuation of
hypoglycemic effects induction of hepatic
microsomal enzymes phenytoin, phenobarbital,
etc. interactions in pharmacodynamics
glucagon, thiazides, etc.
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B. Oral hypoglycemic drugs
Biguanides(???) Metformin
????(???) Phenformin ????(????)
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B. Oral hypoglycemic drugs
1. Pharmacilogical effects increasing glucose
uptake in fat tissues and anaerobic glycolysis in
skeletal muscles decreasing glucose
absorption in gut and glucagon release  2.
Clinical uses mild insulin-independent
patients with obesity   3. Adverse effects
severe lactic acidosis (less for metformin),
malabsorption of vitamin B12 and folic acid 
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B. Oral hypoglycemic drugs
?-Glucosidase inhibitors(?????????)
Acarbose ???? Reducing intestinal
absorption of starch (??), dextrin (??), and
disaccharides (??) by inhibiting the action of
intestinal brush border ?-glucosidase
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Acarbose ????
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B. Oral hypoglycemic drugs
Others Repaglinide ???? Oral
insulin secretagogue