Pharmacology of Endocrine System G3FR_

Pancreatic Hormones
1. Alpha (α) cells (20%) 2. Beta (β) cells (75%) 3. Delta (δ) cells (3-5%) 4. G cells (1%) 5. F (PP) cells (1 %)
secret glucagon that counters insulin & produces hyperglycemia secret insulin, C-peptides and amylin secret somatostatin that inhibit α cells and β cells of pancreas secret gastrin Secrete pancreatic polypeptide (PP) !" digestive processes
Diabetes Mellitus (DM)
Chronic metabolic disorders develop due to relative or absolute deficiency of insulin characterized by sustained abnormal elevation of blood glucose level (hyperglycemia), hyperlipidemia and ketoacidosis in sever deficiency of insulin.
Types of DM
A) Primary DM B) Secondary DM C) Gestational DM
Type I Type II Type III Type IV
l. Name IDDM NIDDM 2ry to another cause that increase blood glucose level: • Diagnosed for the first time during pregnancy
2. Age of onset Usually# 30 Y Usually " 30 Y • Pancreatitis or surgical removal of pancreas •In some females the placental hormones
3. Insulin deficiency Severe Moderate, variable • Drug therapy with one of the followings: develop insulin resistance in the last trimester.
4. Ketosis Marked Absent 1. Immunosuppressive: inhibit insulin synthesis
5. Islet cell antibodies Yes NO 2. Inhibitors of Insulin Release: α2-Agonists. β2-Antagonists. Thiazide, diuretics, Diazoxide & Phenytoin
6. Body weight Non-obese Obese (85 %) or non-obese (15%) 3. Counter-regulating hormones e.g. Glucagon. Glucocorticoids. GH, Thyroid, Oral CCPs &Catecholamines
7. ttt with insulin Always necessary Usually not necessary
1- Insulin
Origin Relation between insulin concentration & receptor number Absorption and fate
• Insulin synthesized in β-cells of pancreas as proinsulin (insulin+ C- peptide). 1. "insulin concentration !#receptor number (down regulation) & resistance to insulin • Not effective orally (polypeptide), so given usually SC.
• Insulin: two polypeptide chains of 51 aa (chain A 21 aa & chain B 30 aa) connected by 2 (s-s) 2. #insulin concentration !"receptor number (up-regulation) & "sensitivity of receptor • Soluble insulin can be given IM or IV.
bridges, integrity of these bridges is essential for activity ! stored in specific granules in β-cells 3- In obese (NIDDM) patients: • Metabolized in liver and kidney by glutathione insulin
• Amylin: single polypeptide chain of 37 aa ! synthesize and stored in β-cells ! delay gastric • Overeating !hyperglycemia !"insulin secretion !#number of insulin receptors!insulin resistance transhydrogenase enzyme (insulinase) that breaks the disulphide
emptying & modules both insulin and glucagon release •#food intake ! diminishes hyperglycemia !#insulin secretion !" receptors number & sensitivity bridges ! degraded by proteolytic enzyme
Pramlintide (Amylin analogue) Pharmacological actions of insulin Methods of parenteral Administration
• given S.C injections with insulin in diabetes to delay gastric emptying & inhibit glucagon 1. Rapid transport effects: • Disposable plastic syringes.
release !# postprandial hyperglycemia • SE: hypoglycemia anorexia, nausea & vomiting • (+) Receptor !sends signals to increase glucose transporter 4 vesicles on cell membrane !"uptake • Pen injection device. • Insulin pump + Glucose sensor
Insulin release • Insulin enhances cellular uptake of K+, Ca++ & phosphate !#in their plasma levels Assessment of Diabetic Control
Released from pancreatic β-cells at a low basal rate and at higher stimulated peaks during meals 2. Gradual (delayed) effects: • Urine analysis for glucose + ketone by bodies using test strips.
1. High blood glucose after meals enters β-cells by GLUT-2 ! phosphorylated by glucokinase A- Carbohydrates: Insulin decreases blood glucose level through: • Blood sugar monitoring (Home or Laboratory)
2. products of glucose metabolism (glycolysis) enter mitochondrial respiratory chain ! ATP. • "cellular uptake & utilization of glucose • long term control: glycosylated hemoglobin (HbA1c) every 3-months
3. increase ATP levels !blockade of ATP dependent K+ channels preventing K+ efflux ! • "glycogen storage in liver by "glycogenesis and # glycogenolysis. • #gluconeogenesis & serum fructosamine every 1 months
membrane depolarization ! open voltage gated Ca++ channels ! Ca++ influx ! exocytosis of B- Protein: anabolic: Factors that increase insulin requirements
insulin C peptide amylin. 4. Daily output of insulin is 30-40 U. • "cellular uptake of a.a by skeletal ms for protein synthesis •#protein degradation. •#gluconeogenesis
• Infection, Operation, Pregnancy & Trauma
C- Fat: increases lipogenesis and triglyceride storage-through:
Regulation of insulin secretion • Treatment with counter- regulation hormones or drugs
• (+) extracellular lipoprotein lipase !clean up plasma Triglyceride (gut chylomicrons or hepatic VLDL)
1. Food: !"release specially glucose, amino acids (leucin & arginine) and fatty acids. • Severe liver dysfunction, normally live secrete insulin inhibitor
• (-) intracellular triglyceride lipase ! preventing degradation of triglyceride (lipolysis)
2. GIT hormones: GLP-1, GIP, cholecystokinin & glucagon !"release of insulin ,-./01 123451 • antagonists· e.g. High insulinase activity & insulin Ab formation
3. Systemic hormones: • Glucagons & GH !"release. • somatostatin !#release. N.B Triglycerides 6⎯⎯⎯⎯⎯⎯⎯⎯⎯8 glycerol(Gluconeogenesis) + FFA (Ketone bodies), So insulin has Factors that decrease insulin requirements
4. PGE-1: !#insulin secretion. anti-ketotic effect !#FFA !#ketone body e.g. acetone & acetoacetic & β-hydroxybutyric acid l. Physical exercise !" Glucose uptake & utilization by tissues. Daily
5. Autonomic receptors: a) (+) β2 & M!"secretion while, (+) α2!#secretion. Sources of insulin insulin requirements are inversely proportional to degree of physical
b) # β & M receptors !#secretion while, # α2 receptors !"release. 1. Animal insulin: a. Bovine: 3 Amino-acids differences from human ! Antigenic. 2. A decrease in caloric intake, diet regulation & weight reduction !
6. Hypoglycemia (fasting, starvation) !# secretion due to (+) sympathetic transmitter release. b. Porcine: 1 Amino-acid difference from human ! Less antigenic. resumes sensitivity to insulin
7. Drugs: Sulphonylurea !"release while phenytoin, diazoxide, thiazide & verapamil !# 2. Humanized insulin: Modification of animal insulin ! Human insulin. Complications of insulin therapy (adverse effects)
release 3. Recombinant insulin: a. Human b. Analogues e.g. Lispro & Glargine, aspart & glulisine. 1. Hypoglycemia (The most common) caused by: a. increased exercise.
P/D “Mechanism of action” Insulin preparations b. Application of LD of insulin or bad timing
c. Delayed or missed meals or little food intake
1. Insulin receptor: preparations onset peak duration route
2. • Lipoatrophy (treated by changing the insulin type) or
• Glycoprotein consists 2 α and 2 β-subunits linked by disulphide bonds. A) Rapid acting (Human analogue) • Hypertrophy (treated by changing the injection site)
• The two α -subunits are located on the external surface while, the two β subunits crossing the • Lispro insulin • Insulin aspart • Insulin glulisine 5-15 min One h 3-5 h SC 3. Insulin allergy: common with animal or protamine insulin
cell membrane and project extracellularly and intracellularly. B) Short acting • local: reaction at injection site • Systemic: urticaria, anaphylactic reactions.
2. Insulin binds to α subunit !phosphorylation of proteins and enzymes, receptors undergo • Regular insulin (human) 30 min 2-3 h 6-8 h SC. IV, IM ttt: - change protamine insulin (isophane) to lente insulin - use human insulin
conformational changes and become internalized inside cells. C) Intermediate acting: 4. immunologic insulin resistance: caused by:
3. Receptors are degraded and some of them are recycled into plasma membrane. • Neutral protamine Hagedorn (NPH) (isophone insulin) 2h 5-6 h 18-24 h • formation of anti-insulin antibodies • high activity of insulinase enzyme.
4. Action is mediated through Tyrosine kinase ! changes in enzyme activity ! gene expression Treatment: change to human insulin.
• Zinc insulin (lente)
and translocation of glucose transporter 4 !"glucose uptake by adipose tissue and skeletal ms 5. Weight gain.
D) Long acting: 6. Somogyi effect (pseudo -resistance):
Glucose transporters “GLUT” • Protamine zinc insulin (P.Z.I) 4-6 h 6-12 h 24-36 h • Insulin-induced evening hypoglycemia followed by morning hyperglycemia.
4-6 h SC
Transporter Tissues Functions • Extened zinc insulin (Ultra Lente) • Caused by release of counter regulatory hormone glucagon and adrenaline.
• Insulin glargine (insulin analogue) 2-5 h peakless 18-24 h • Treatment: Decrease evening insulin dose.
GLUT-1 All tissues, especially RBCs, brain Basal uptake of glucose across BBB
GLUT-2 β-cells, liver, Kidney, gut Regulate insulin release, glucose homeostasis E) Premixed insulin: Uses of insulin
GLUT-3 Brain, kidney, placenta Uptake into neurons, other tissues • mixtard and humalin (70 NPH/ 30 regular) 30 min 2-6 h 18-24 h 1. IDDM
GLUT-4 Muscle. adipose insulin-mediated uptake of glucose • all except insulin lispro and insulin aspart increase in duration with increase in dose 2. NIDDM in the following conditions
GLUT-5 Gut, kidney Absorption of fructose • Regular insulin of 2 types either acidic or neutral and PZI is alkaline and other preparations are neutral. So, do a) Failure of oral hypoglycemic or trauma. b) During severe infection
not mix acidic regular insulin with PZI in one syringe. • Insulin glargine is acidic in nature c) Surgical interference, Pregnancy e) Ketoacidosis & lactific acidosis
• Lispro insulin (ultrashort acting insulin) has shorter duration of action more rapid than regular insulin 3. Hyperkalemia
 2- Glucagon G3FR_
• Single chain polypeptide of 21 amino-acids, Synthesized, stored & released from α -cells of islets of Langerhans & from Upper GIT
Mechanism of action Regulation of release Pharmacological actions
• (+) specific membrane receptors 1.#Plasma level of glucose & fatty acids or "amino-acids e.g. L-arginine !"glucagon release l. "glycogenolysis & gluconeogenesis (in liver Not Skeletal muscle) !"blood glucose level & "lipolysis & catabolic (skeletal ms)
! activate Adenylcyclase 2. (+) β2 & M receptors !"release. ! counter regulatory to insulin ! useful SC & IM in treatment of Hypoglycemic coma when IV glucose is not available.
!"cAMP 3. insulin& Somatostatin !#release. 2. Stimulates heart leading to +ve Inotropic & +ve chronotropic effects. !used in heart failure induced by β-blockers.
3. It has smooth muscle relaxant effect ! useful before radiological examination.
Hyperglycemic Coma “Diabetic Ketoacidosis” Diagnosis of hypoglycemia
Diabetic ketoacidosis is a life threating medical emergency, which occurs in people with type 1 diabetes and rarely with type 2 diabetes 1) Sympathetic discharge cause sweating , tremors. tachycardia and pallor
Causes Clinical manifestations 2) Neuroglycopenia: Hunger, weakness. irritability, confusion, blurred vision, convulsions and coma if not treated .
1. Excess food intake. 1. Deep coma with deep and slow (Kussmaul) breathing 3) If prolonged coma, lead to brain cell damage and death.
2. Inadequate or absent insulin replacement. 2. Dehydration [dry tongue]. 4) Laboratory diagnosis: low blood sugar & urine is negative for glucose.
3. Stressful conditions as sepsis, pancreatitis or high-dose steroid therapy . 3. Tachycardia, hyperglycemia and ketonuria.
Treatment Management of hypoglycemia
1. Regular insulin: the usual dose is 0.1 U/kg/hr. with frequent reevaluation and modification. 1) If the patient is conscious, cooperative and able to swallow safely. Is treated with oral glucose, orange juice or any sugar containing
2. Correction of dehydration & acidosis by normal saline & sodium bicarbonate. Administration of glucose 5% when blood glucose < beverages or food.
250 mg/dL to avoid hypoglycemia and brain edema. 2) In severe hypoglycemia where the patient unconscious is treated with: • Glucose. 50 ml of 50 % solution IV or.
3. KCI to avoid hypokalemia. 4. Antibiotic for infection. • Glucagon l mg SC or IM.
 Oral Antidiabetic Drugs G3FR_
I- Insulin Secretagogues (Oral hypoglycemic drugs) II- Insulin Sensitizer
1- Sulphonylurea drugs “SU” 2- Meglitinides “D-phenylalanine derivatives” 3- Dipeptidyl-peptidase IV inhibitors 1-Biguanides (2) Thiazolidinediones (TZDs) or
First generation Second generation Repaglinide & Nateglinide Sitagliptin & Vildagliptin Metformin Glitazones
• Tolbutamide Short (6-12) • Glipizide Short (6-10) • Troglitazone
• Acetohexamide Intermediate (8-10) • Gliclazide Intermediate (12-18) • Rosiglitazone
• Chlorpropamide Long (24- 72) • GlibenclamideLong(18-24 )Potent
• Pioglitazone (only used now)
• Glimepride Long(12-24)Potent
P/ • absorption: Well from G.I.T. with better absorbed when taken 30 min • rapidly acting (15-30 min) • Well absorbed orally, not affected by food • well absorbed from G.I.T. peak after 2 h • Pioglitazone: well absorbed orally bound to serum
K before meals. Peak after 2-3 h • Metabolism: by CYP450 enzyme to inactive • Excreted unchanged in urine !dose must be • No PPB albumin, undergo hepatic Metabolism by CYP450 &
• Distribution: all over the Body, BBB & placental barriers, PPB to 95% product! used cautiously in hepatic impairment adjusted for patient with renal dysfunction • not undergo biotransformation have some active metabolites
• Metabolism: inactivated in liver (except acetohexamide converted to • Rapidly eliminated: Repaglinide by kidney & • T1/2 = 12 h • eliminated by kidney (90% within 12 h) • Excretion: drug & metabolites !biliary excreted
active hydroxyhexamide) Nateglinide by biliary secretion • T1/2 = 2-4 hour
• Excretion: kidneys excrete the metabolites with some unaltered drug . • short acting: Repaglinide 8 h & Nateglinide 4 h
+
1. "insulin release from β-cell by: bind to and block ATP-sensitive K channel !#K+ efflux ! membrane depolarization • inhibits DDP-4 enzyme which responsible l. "peripheral glucose uptake & utilization • bind to specific nuclear receptor (Peroxisome-
!activate voltage gated sensitive Ca+2 channel !Ca+2 efflux ! insulin release by exocytosis of inactivation of GIT hormones, glucagon “glycolysis” in skeletal muscle Proliferator-Activator Receptor-Gamma= PPAR-y)
2- #serum glucagon concentration by increase somatostatin release like peptide-1 (GLP-1) & glucose dependent 2."sensitivity of insulin receptors. in adipose, skeletal muscle & liver ! activate gene
M
3- Enhance insulin action in cells and stimulate synthesis of glucose transporter insulin peptide (GIP) “incretin” !"levels of 3.#hepatic glucose production & expression ! synthesis of cellular molecules
O 4- Extra-pancreatic effect: "number & sensitivity of insulin receptor !potentiate peripheral action of insulin e.g. lipogenesis GLP-1 & GIP ! prolong their activity to gluconeogenesis important for insulin signaling, in fat synthesis and
A in adipose tissue and suppress haptic gluconeogenesis & glycogenolysis #glucagon release, "insulin secretion 4.#intestinal glucose absorption. CHO metabolism !"insulin sensitivity.
- Glimepride ! rapid association with receptors ! rapid reduction in !decrease gastric emptying !#blood - This drug is actually euglycemic and not • Hyperglycemia, insulin resistance & elevated
blood glucose level & rapid dissociation from receptors-!less glucose level hypoglycemic. HbA1C are improved
hyperinsulinemia with less risk of hypoglycemia.
- 2nd generation Potent 100 times & less SE compared to first generation
• NIDDM patient who are not controlled by diet regimen and biguanide • Preventing postprandial hyperglycemia. • As monotherapy in type 2 diabetes (oral 1. NIDDM if dietary regimen is not 1. As monotherapy or in combination with
U • ttt of cranial diabetes insipidus “Chlorpropamide” • Before meal as mono therapy or combined with single dose not related to food) sufficient for control of blood glucose Sulphonylurea or metformin in NIDDM.
metformin • combined with Metformin or 2. NIDDM in non-obese whom diet control 2. relief of insulin resistance in polycystic ovary
S
• should not be used in with Sulphonylurea due to thiazolidinediones and sulfonylurea fails to control diabetes syndrome can cause ovulation in premenopausal
E overlapping in their molecular site of action. 3. polycystic ovary disease women
S Meglitinide have 2 binding sites on common with
the Sulphonylurea and one unique binding site
1. Allergic reactions (skin rash) . 2. GIT upset - Repaglinide !Nausea, headache & • Severe allergic reaction (skin lesion). Side effect
3. Weight gain. 4.Teratogenicity. hypoglycemia but less than with Sulphonylurea • Vildagliptin produces blistering skin lesion 1. GIT (up to 20% the patients) !anorexia, 1. Troglitazone ! hepatotoxic (obsolete).
5. Hypoglycemia esp with long acting (Chlorpropamide & Glibenclamide) & pancreatitis
S nausea, diarrhea & abdominal discomfort. 2. Rosiglitazone ! Heart failure (obsolete).
6. cholestatic jaundice & leucopenia: rare • Nasopharyngitis, upper respiratory infection These may be transient, avoided by initially 3. Pioglitazone !"hepatic enzymes So, measure
E 7. Failure of drug: • Primary failure: in l0-15% of NIDDM. • headache
• Secondary failure: after long use due to exhaustion of β-cells prescribing small doses with meals. liver enzyme level initially & periodically during ttt
l. Displacement from PPB by salicylate & sulfonamide !hypoglycemia 1. Repaglinide: produce severe hypoglycemia In contrast to sulfonylureas, metformin does 4· "body weight due to increase subcutaneous fat
2. #renal elimination (e.g. allopurinol. salicylates) when used with gemfibrozil “fibrates group” not cause hypoglycemia if given alone. or fluid retention.
3. Thiazides and diazoxide (K+ channel opener), Adrenaline, Thyroxine, 1- enzyme inducer (barbiturate, carbamazepine, 2. lactic acidosis, though the risk is low, so 5. Fluid retention may lead to edema and anemia.
corticosteroids & contraceptives!#Sulphonylurea action rifampicin) ! opposite the effect of meglitinides the drug is CI in Hepatic impairment 6. Glitazones reduce plasma concentrations of
D 4. Propranolol !"hypoglycemia by decrease hepatic glycogenolysis 2- enzyme inhibitor (azole, erythromycin, 3. Long-term use of metformin decrease estrogen-containing contraceptives ! Women
I & mask sympathetic manifestation of hypoglycemia !silent coma clarithromycin, cimetidine, omeprazole) may absorption of Vit B12. taking oral contraceptives may become pregnant
5. metabolism:"by enzyme inducers: rifampicin, carbamazepine, & enhance glucose lowering effect of meglitinides
#by enzyme inhibitors (e.g. cimetidine. allopurinol & chloramphenicol)
1. Known sensitivity to sulfonamides. • Renal impairment: it is totally eliminated III- Other oral anti-diabetic drugs
C 2. pregnancy & lactation: Sulphonylurea pass placental barrier ! by the kidney)
1- Alpha glucosidase inhibitors
I teratogenic & secreted in milk !hypoglycemia of neonate • Hepatic impairment: normal liver cells
3. Insulin dependent diabetes. extract the excess lactate, thereby, inhibits Acarbose & miglitol
4. NIDDM during stress periods e.g. infection. surgery or trauma. the possible lactic acidosis induced by drug MOA
5. Severe hepatic or renal disease • Reversibly inhibit a glucosidase in intestinal brush
Advantages of Nateglinide Advantages of Metformin over SU border !#absorption of CHO. So, decrease
1. safe in patients with renal impairment 1. No weight gain. postprandial hyperglycemia.
2. less incidence of hypoglycemia of all 2. It is euglycemic not hypoglycemic. • Unlike other oral antidiabetic agents, these drugs
Secretagogues as it act in response to "glucose & 3. Not bound to plasma protein. don't stimulate insulin release
not affect normoglycemia 4. It is eliminated as such though the kidney. nor increase insulin action. They don't cause
3. less CVS risks as it is more selective (300 5. Not depend on functioning β-cell of hypoglycemia if used alone
times) on pancreatic β-cells K+ channel pancreas. USES
NIDDM either alone or in combination with
Sulphonylurea not metformin.
SE
abdominal pain, flatulence and diarrhea.
 Thyroid Hormones G3FR_
• The thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function. • Two major thyroid hormones: triiodothyronine(T3), the active form and thyroxine (T4).
• Although the thyroid gland is not essential for life, inadequate secretion of thyroid hormone (hypothyroidism) results in bradycardia, poor resistance to cold, and mental and physical slowing (in children, this can cause mental retardation and dwarfism).
• If, however, an excess of thyroid hormones is secreted (hyperthyroidism), then tachycardia and cardiac arrhythmias, body wasting, nervousness, tremor, and excess heat production can occur. Note: The thyroid gland also secretes calcitonin a serum calcium -lowering hormone
Synthesis Action Uses of thyroid hormones
l. Iodide trapping: T.S.H. stimulates active uptake of iodide (decreased by anaerobic 1. Growth & differentiation: required for growth and maturation of all body tissue especially 1. Hypothyroidism: due to
conditions, monovalent ions and digitalis) CNS Its deficiency in early life ! irreversible mental retardation Infant: Cretinism “L-Thyroxin”
2. Oxidation: of iodide to iodine by peroxidase enzyme 2. Caloric effect: "B.M.R. Adult: a. Drugs: Prolonged use of antithyroid dugs b. post thyroidectomy
3. Organification: iodine + tyrosine → mono & diiodotyrosine (MIT& DIT) 3. Metabolic actions: c. irradiation: Destruction of gland by radioactive isotope d. Hashimoto’s disease
4. Coupling: of iodotyrosines to Tetra iodothyronine (T4) iodothyronine (T3). • Carbohydrate: "Glycogenolysis. 2. #TSH secretion which causes thyroid enlargement in:
4. Storage: T4 & T3 + thyroglobulin ! storage in follicles • Lipid: "lipolysis & metabolism of cholesterol to bile acids ! hypercholesterolemia • Single goiter. • Thyrotropin dependent carcinoma
5. Release: proteolysis of thyroglobulin by protease enzyme releasing T3 and T4. • Protein: Catabolic effect & osteoporosis due to calcium mobilization 4. Hypercholesterolemia
5. In blood: T4 → T3 (more active) 4. CNS: Anxiety & tremors due to "NM excitability • Use d-thyroxin in euthyroid patient. • Use L-thyroxin in hypothyroid patient
Control of thyroid hormones 5. CVS: • Direct: "HR & V.D. • Indirect: Supersensitivity α & β receptors ! V.C. &"HR 5. Infertility and amenorrhea
• Hypothalamus ! thyrotropin releasing hormone (TRH) !pituitary !"TSH 6. GIT:"appetite with #body weight ("BMR) 6. Resistant depression.
• TSH ! trapping of iodine, increase size and vascularity of the gland 7.Kidney: Diuretic effect ("COP)
• Autoregulation: -ve feed back of iodine trapping Preparations Side effects
• Thyroid stimulating Abs “Grave's disease” l- synthetic manifestations of hyperthyroidism
Fate of thyroid hormones - D-Thyroxin: Not used in replacement therapy but potent hypocholesterolemic l. Intolerance to heat: warm flushed patient
l. Conjugation: with glucuronic acid by the liver and excreted into the bile. - L-Thyroxin sodium (T4):• Long duration & slow onset • completely absorbed orally 2. Precipitation of angina pectoris as it "H.R. & BP ! extra systoles & atrial fibrillation
2. Oxidative deamination in kidney. 3. Deamination • uses: myxedema & cretinism. • The dose increased in pregnancy up to 150 ug/day 3. Weight loss due to "BMR
4. Deiodination of T4 in tissues: T4 → T3 (more active) 3. Liothyronin sodium (T3 ):• highly potent with short duration • More rapid onset than T4 4. Tremors: fine tremors of hand due to increased NM excitability
• uses: myxedema coma 5. GIT: increase appetite & diarrhea
MOA 4. Liotrix (T4 + T3): (4: 1) similar to normal thyroid hormone. 6. Eye signs: lid retraction & exophthalmos
• Thyroid hormones pass cell membrane and bind to mobile cytoplasmic receptors 5. Thyroid extract & thyroglobulin (tablets): from animal
!DNA transcription !mRNA !synthesis of active enzymes.
Treatment of hyperthyroidism
• Hyperplastic nodule or diffuse hyperplasia of the gland (Grave 's disease) • The effects of hypersecretion are the same as side effects of thyroxin.
I. Antithyroid drugs II. Sympathetic depressants
1. Thioamides 2. Iodide 4. Radioactive iodine 2. Ionic inhibitors 1- Beta-blockers
+ 131 1. No I.S.A.
• Carbimazole • Methimazole • Propylthiouracil • Lugol's solution = 5% iodine + 10 % K iodide • 1 (Sodium Iodotope): oral or IV K+ perchlorate
• Na+ and K+ iodide tablets • K+ iodide solution • I132 2. Protects heart from tachycardia. angina &
P/K • Rapidly absorbed and peak after 1 h. • Rapid onset &short duration I131 is rapidly trapped by the thyroid gland and deposited arrhythmia of hyperthyroidism.
• Distributed all over the body BBB, pass placental barrier (CI • maximal effects are obtained after 10-15 days in the colloid of the follicles from which it is slowly 3. Pass BBB !#anxiety & tremors of
in pregnancy) liberated hyperthyroidism
• Carbimazole “DOC” prodrug metabolized in liver to 4. # Conversion of T4 to more active T3.
methimazole (active) Uses
• Excreted in urine and milk (CI in lactation) • Temporary relief manifestations: Orally
MOA inhibit formation of thyroid hormones by: 1. High iodide concentration !attenuate the effect of Actions block uptake of iodide into the gland till control of hyperthyroidism by antithyroid
1. #oxidation of iodide: (-) peroxidase enzyme and T.S.H. on cAMP !#thyroid hormones release • Effect appears 6-12 weeks after administration. !#synthesis of T3 and T4 drugs or thyroidectomy or radioactive iodide
2. #organification (iodination of tyrosine) • (-) protease enzyme, #proteolysis of thyroglobulin & • Two types of radiations are emitted: • Hyperthyroid crisis: IV in emergency
3. #coupling of MIT & DIT. Decrease endocytosis • β-rays in LD: destructive with low penetration 2- Guanethidine
4. #iodination of tyrosyl residues of thyroglublin The result will be: • Gama rays in SD: non-destructive with high Eye drop !#sympathetic stimulation to
5. Propylthiouracil !#peripheral deiodination of T4 to T3 • #B.M.R. • #size and vascularity of gland penetration. muscle that cause eye lid retraction.
- The onset of these agents is slow (3-4 weeks). • Accumulation thyroglobulin in follicle.
USES 1. Treatment of mild hyperthyroidism. short-term only: 1. Hyperthyroidism in: • old & heart disease. Treatment of exophthalmos
2. With radioiodine to hasten recovery. 1. Preoperative: before thyroidectomy to reduce size and • Recurrence after subtotal thyroidectomy • Guanethidine eye drops!#exophthalmos.
3. Propylthiouracil in thyroid crisis. vascularity of the gland (7 -10 days). 2. No remission after prolonged ttt with antithyroid • Corticosteroids & surgical decompression
2. thyroid crisis: with Propylthiouracil & Propranolol drugs (failure of treatment) may be needed
3. Saline expectorant: in chronic bronchitis 5. Propranolol or antithyroid with I131 to hasten recovery
6. I131: • thyroid cancer • testing thyroid function
7. I132: diagnosis of thyroid disorders (t1/2 = 2 h)
Toxici 1. Allergy: skin rash. fever. 1. Iodism 1. Hypothyroidism. Treatment of thyroid crisis
ty & 2. Pain, headache and stiffness in joints 2. With continuous treatment, the hyperthyroidism may 2. Not used in childhood and pregnancy
SE 3. nausea Hepatitis and nephritis. return due to increasing of T.S.H. so, restricted only “thyroid storm”
4. "T.S.H. release !"size & vascularity of the gland. Also. preoperative 1. Propylthiouracil.
releasing of exophthalmos producing factor !" 2. Lugol's iodine.
exophthalmos 3. Propranolol (I.V.)
5. Agranulocytosis: appear in 1st few months of therapy (sore 4. Hydrocortisone (I.V.).
throat or fever) most dangerous. So, frequent blood count may
be needed.
6. In lactation and pregnancy !cause cretinism (Not used in
pregnancy and lactation)
Propylthiouracil only Thioamides allowed in pregnancy
 Parathyroid Gland G3FR_
Parathormone is a polypeptide hormone secreted by the parathyroid glands and its release is regulated by the calcium level in blood and its main function is hypercalcemic hormone
MOA The action of P.T.H. is mediated through activation of Adenylcyclase enzyme in bone and renal cells !"Ca+2 by:
1. Bone: "resorption by: a) Increase Glycogenolysis !" lactic acid ! local acidosis ! solubilize Ca+2 b) "lysosomal activity ! bone digestion ! mobilization of fixed calcium.
+2 +2
2. Kidney: "reabsorption of Ca and Ca excretion of phosphate.
3. GIT: "absorption of Ca+2 stimulated by vitamin D3 (calciferol)
Hypoparathyroidism Hyperparathyroidism
Cause • idiopathic or due to thyroid surgery • Primary: adenoma. • Secondary: due to failure or decreased vitamin D.
Symptoms • Hypofunction ! phosphate retention and hypocalcemia. • bradycardia, arrhythmia, and urinary stones. Soft tissue calcification fragile bone "bone resorption"
• Tetany occurs when the plasma calcium level falls below 7 mg % (normal level 9-11 mg %).
ttt 1. Ca++ gluconate 10 ml 10% IV, followed by supplementary oral administration. • Primary: X ray or surgical removal ''partial". • Secondary: Treat the cause.
4. Ca++ Diet rich as milk
2 Parahormone 100 units daily but after repeated use become ineffective
3. Vit. D3 (Calciferol) stimulate s Ca++ absorption from the gut.
Osteoporosis Hypercalcemia
Def: #bone mass with distortion of the microarchitecture (osteopenia: #mineral content ). It leads to CNS depression & may be fatal
Manifestation: osteoporotic bone can fracture easily after minimal trauma Treatment:
Causes: • postmenopausal deficiency of estrogen & age-related deterioration in bone homeostasis. 1. Loop diuretics:"Ca+2 excretion
• secondary to rheumatoid arthritis, excessive thyroxine or glucocorticoid administration. 2. Cortisone:!#absorption of Ca+2 it is acting as anti-vitamin D.
• 50% of patients on long-term oral glucocorticoid therapy can suffer fractures due to excessive bone loss. 3. Phosphate and calcitonin
• ttt:• Antiresorptive: bisphosphonates and raloxifene (anti-estrogen 4. Disodium edetate IV. or dialysis, 5- Mithramycin and Etidronate
• Anabolic: stimulate bone formation (PTH, teriparatide)
Agents affecting calcium homeostasis
1- PTH 2- Vitamin D 3- Calcitonin 4- Non-hormonal agents
Anti-Rickets effect • polypeptide hormone formed & stored by Biophosphonates Mithramycin Glucocorticoids Thiazide Fluoride Estrogens
parafollicular cells "C cells" of the thyroid gland. • Pamidronate • Alendronate
•"Ca+2 in blood, glucagon & cAMP !"released
• Na+ clodronate
Action & • "Ca+2 absorption from GIT. • #renal calcium and phosphate reabsorption stimulate osteoclasts apoptosis, so cytotoxic antibiotic !# •#Ca+2 absorption •#renal Ca+2 excretion
MOA potentiated by P.T.H. • #decrease the rate of bone turnover inhibit bone resorption. bone resorption • "bone resorption
• "active bone resorption. • has analgesic effect.
• "Ca+2 reabsorption in kidney
Uses • Paget's disease of bone •Paget's disease orally • Paget's disease idiopathic • preventing prevent resorbing
• hypercalcemia • hypercalcemia associated with • hypercalcemia due to hypercalciuria dental caries effect of PTH in
malignancy malignancy • #frequency of early menopause.
• postmenopausal osteoporosis. fracture when
supplemented
with Ca+2
SE • GIT disturbances, peptic ulcer
• esophagitis.
• Bone pain.
 Adrenal gland G3FR_
Cortex: Histologically divided into three zones: Medulla
1- Zona glomerulosa 2- Zona fasciculata 3- Zona reticularis Secretes epinephrine and norepinephrine.
• produces mineralocorticoids (aldosterone), responsible for regulating salt & water metabolism synthesizes Glucocorticoids (cortisol) , involved with normal metabolism and resistance to stress secretes adrenal androgens.
• Production of aldosterone is regulated primarily by rennin-angiotensin system • Secretions controlled by pituitary ACTH which is released in response to the hypothalamic corticoptropin-releasing hormone
(CRH; also called corticotrophin-releasing factor) • Glucocorticoids serve as feedback inhibitors of corticotrophin and CRH secretion.
Molecular mechanism of action of corticosteroid hormone
• adrenocorticoid bind to specific intracellular cytoplasmic receptors ! DNA transcription ! genes expression ! mRNA ! protein synthesis ! response
• This mechanism requires time to produce delayed effect, while glucocorticoids have immediate effects, such as their interaction with catecholamines to mediate relaxation of bronchia smooth muscle or lipolysis.
Corticosteroids
Preparations
A) Short Acting (8 -12 h) B) Intermediate Acting (12 - 36 Hours) C) Long Acting (36-72 h) D) Mineralocorticoids
Corticosteroid Cortisol Cortisone (prodrug) Prednisone (prodrug) Prednisolone Methyl-Prednisolone Triamcinolone Betamethasone Dexamethasone Aldosterone Desoxycorticosteron “D.O.C.A” Fludrocortisone
Gluco- 1 4 5 25 ± No 10
Mineralo- 0.8 0.5 No No 500 50 125
Daily requirement Not used
20 mg 25 mg 5 mg 4 mg 0.75 mg S.L. 2 - 6 mg Oral 0.1-0.3 mg
• Prednisone is preferred in pregnancy (t1/2 = 12-36 h )
because it has minimal effects on the Fetus.
P/K Absorption Distribution Metabolism excretion
well form GIT, IV, IM, intra-articularly, topically, or aerosol 90% PPB, most to either corticosteroid-binding globulin or albumin. by liver microsomal-oxidizing enzymes, metabolites conjugated to glucuronic acid or sulfuric acid by kidney
Pharmacological actions of glucocorticoids Therapeutic uses of corticosteroids Contraindications of Glucocorticoids
1- General metabolic and systemic effects: 1) Replacement therapy for: 1- Abrupt withdrawal. 2- Cushing's disease. 3- Diabetes melilites.
• Carbohydrates:#uptake & utilization of glucose while "gluconeogenesis ! hyperglycemia a. 1ry adrenocortical insufficiency (Addison's disease): 4- Osteoporosis. 5- Repeated intra-articular injections.
• Protein: #synthesis & "breakdown. Particularly in muscle, and this can lead to wasting • Hydrocortisone: 2/3 dose in the morning & 1/3 in afternoon
6- HTN & Heart failure. 7- thromboembolic disease. 8- Digitalis toxicity
• Lipids: • Fludrocortisone: glucocorticoid + mineralocorticoid action
- "Lipolysis: glucocorticoids !(+) synthesis of cAMP-depended kinase !lipase activation. b. 2ry adrenocortical insufficiency: - Hypothalamus: #CRH - Pituitary: #ACTH 9- urogenital infection. 10- During pregnancy.
- LD of glucocorticoids over a long period !redistribution of body fat “Cushing syndrome” • synthesis of mineralocorticoids in the cortex is less affected than glucocorticoids, so 11- Glaucoma. 12- Peptic ulcer. 13- Psychological disturbances.
• Minerals: - mineralocorticoid actions ! Na+ retention & K+ loss. hydrocortisone is used for treatment of these deficiencies Precautions during long-term glucocorticoid therapy
- decreasing Ca2+ absorption in GIT and "its excretion by kidney !osteoporosis. c. Congenital adrenal hyperplasia: l. Gradual withdrawal. 2. Test for glucose in urine
2- Increases resistance to stress through: • enzymatic defect in synthesis of one or more of the adrenal steroid hormones.
• "plasma glucose levels ! provide the body with the energy required to face stress caused, by • may lead to virilization in females due to overproduction of adrenal androgens.
3. Routine X-ray spine. 4. Add anabolic.
trauma, fright, infection, bleeding or debilitating disease. • administration corticosteroids !#ACTH and CRH ! normalize hormone levels 5. Weight estimation. 6. Measure blood pressure.
• "blood pressure by V.C effect of adrenergic stimuli on small vessels. 2) Diagnosis of Cushing syndrome: 7. Avoid in Digitalis toxicity. 8. Increase dose in stress.
3- Blood: •#eosinophils, basophils, monocytes and lymphocytes by redistributing them from • Cushing syndrome: hypersecretion of glucocorticoids either due to adrenal tumor or 9. Diet should be Rich in Proteins K+ & Ca+2 & Low in NaCL
circulation to lymphoid tissues. 2ry to excessive release of corticotrophin from anterior pituitary Withdrawal
• #circulating lymphocytes and macrophages !#body's ability to fight infections. However, • dexamethasone suppression test used to diagnose & differentiate the cause • Withdrawal from these drugs can be a serious problem because, if the patient has
this property is important in the treatment of leukemia. 3) Relief inflammatory symptom: experienced HPA “Hypothalamic-pituitary-adrenal” suppression, abrupt removal of the
• "erythrocytes, platelets and polymorphonuclear leukocytes. • as in rheumatoid and osteoarthritis & inflammatory conditions of the skin corticosteroids causes an acute adrenal insufficiency syndrome that can be lethal.
4- Anti-inflammatory and immunosuppressive effects: including redness, swelling, hotness and tenderness
• When large doses of glucocorticoids are required over an extended period of time (more
- #T and B lymphocytes, !#Ab formation & Ag-Ab reaction • enumerate the mechanism of anti-inflammatory action
than 2 weeks) suppression of the HPA axis and adrenal atrophy occurs
- #ability lymphocytes & macrophages responds to mitogens and antigens 4) Anti-allergic: (immunological disorders)
• To prevent this adverse effect a regimen of alternate-day administration of the
- #basophils. eosinophils and monocytes • as bronchial asthma, allergic rhinitis, drug, serum, and transfusion allergic reactions.
adrenocortical steroid may be useful. This schedule allows the HPA axis recover/function
- #phospholipase A2 (Indirect via lipocortin) !# PG & LTs • These drugs are beneficial but not curative.
on the days the hormone is not taken. • Also, gradual withdraw is beneficial
- interfere with mast cell degranulation !#histamine release and capillary permeability 5) Acceleration of lung maturation: Fetal cortisol is a regulator of lung maturation.
- Redistribution of leukocyte to other body compartment • Two doses of dexamethasone ! IM to mother 48 & 24 h before delivery.
- "concentration of neutrophils Adverse Effects of Glucocorticoids Adrenostatics
5- Negative feedback effects on the anterior pituitary and hypothalamus: 1. Abrupt withdrawal after long use ! acute Addisonian crisis. Def: Drugs which decrease adrenocortical activity (Useful in ttt of Cushing's disease)
• Both endogenous & exogenous glucocorticoids ! negative feedback effect on CRH & ACTH. 2. Iatrogenic Cushing's disease (moon face & buffalo hump). A. ACTH-Dependent Cushing's:
• exogenous glucocorticoids !#CRH & ACTH !#secretion of endogenous glucocorticoids ! 3. Hyperglycemia ! Worsens DM due to their Anti-Insulin effect. 1- Cyproheptadine 2- Bromocriptine
adrenal atrophy 4. Osteoporosis ! Collapse of vertebrae & anemic fracture neck of femur. Antihistamine (#H1) + Anti-serotonin Direct dopamine agonist (#release of ACTH)
• prolonged therapy, may take many months to return to normal function when drugs are slopped 6. Anti-vitamin D ! Hypocalcemia !Aggravate Osteomalacia & Osteoporosis B. ACTH-Independent Cushing’s
6- Others: • Kidney: maintain GFR 5. Subluxation of joints after repeated intra-articular injections. Mitotane Ketoconazole Aminoglutethimide Metyrapone (Mitopirone)
• Stomach: High doses stimulate gastric acid & pepsin production ! peptic ulcer. 7. Myopathy & muscle weakness.
• affect mental and psychic status. Destruction of #Conversion of Cholesterol ! (-) 11- β-Hydroxylase !#
7. Retardation of growth in children. 8. Delays healing of wounds. adrenocortical Pregnenolone (1st step in steroidogenesis) Synthesis of Aldosterone &
Pharmacological actions of mineralocorticoids 9. Teratogenicity (less with prednisone). cells Cortisol !"ACTH.
• Kidney: acts on tubules and collecting ducts ! Na+, H2O retention & K+, H+ excretion 10. Eye: Cataract & " Intra-ocular pressure ! Glaucoma.
• GIT mucosa, sweat and salivary glands: the same (Na+, H2O reabsorption) 11. CVS: Hypertension, HF & Thromboembolism a. Useful in Cushing's disease • Uses: 1- Cushing's disease
• "aldosterone levels may cause alkalosis and hypokalemia whereas, 12. hypokalemia ! Worsens Digitalis toxicity. b. Inoperable + Amino-glutethimide.
Na+, H2O retention !" blood volume and blood pressure 13. Edema & weight gain. adrenocortical 2- Test function of anterior
• Hyperaldosteronism is treated with spironolactone. 14. Mask manifestations of bacterial & viral infections, carcinoma pituitary to secrete A.C.T.H.
• Mineralocorticoid receptors interact with the hormones in a manner of glucocorticoid receptor. 16. Immunosuppressant !"Susceptibility to infection & reactivation of latent T.B.
15. GIT: Peptic ulcer. 18. CNS: Psychological disturbances.