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Pharmacological applications Of drugs ‘mimic or block’
•Replacement therapy •Antagonists for diseases of excess •Diagnostic tool
GROWTH HORMONE (SOMATOTROPIN)
Mediation of Its effects: IGF-1, IGF-2 Pituitaries of human cadavers. Contaminated with prions -cause Creutzfeldt-
Jakob disease GH has a half-life of 20-25 minutes
Somatropin Somatrem rhGH----36 hours. 4-6/week Uses: 1. GH Def----- 2. Idiopathic short stature????? 3. Catabolic
states 4. Anti aging 5. Banned drug-sports 6. Cattle-Milk production ADE↑ICT MECASERMINrhIGF-1 & rhIGFBP-3
GROWTH HORMONE ANTAGONISTS Somatostatin
USES
Octreotide-analog
Acromegaly
Bromocriptine-DA ago Pegvisomant-GH Rec.Anta
Gigantism
? MOA
Hormone secreting
tumors-Carcinoid ADE Gallstones Bradycardia
Answer:
Q.
•Octreotide, 50200 mcg given s.c 8th hourly
•Octreotide acetate injectable long-acting suspension -slow-release microsphere formulation [After effect is established by short acting]
Q.
Answer:
•Somatrem •Somatropin
GONADOTROPIN-RELEASING HORMONE & ITS ANALOGS
Gonadorelin
-acetate salt of synthetic human GnRH. Synthetic analogs Goserelin, Histrelin, Leuprolide, Nafarelin Triptorelin. Route; I.v, i.m, s.c. Nasal
PD; Pulsatile i.v: Stim.-FSH &
Lh Continuous Biphasic respones 7-10 daysStimulation
GnRH-Uses Inhibition
Controlled ovarian Hyperstimulation To ↓ LH surge
Stimulation-Not common use Female infertility Male infertility Diagnosis of LH
responsiveness
Endometriosis Uterine fibroids Prostate cancer Central precocious puberty
GnRH Rec. Antagonists
Ganirelix and cetrorelix Competitive antagonists of
GnRH receptors Used to Prevent the LH surge during controlled ovarian hyperstimulation Advantages and disadvantages over GnRH agonists????????
Answer: •Endometriosis •Assisted reproduction •Central precocious puberty
Q:
Diabetes mellitus Types 1, 2, 3, 4 Insulin Oral anti-diabetic drugs
Endocrine secretions of pancreas Alpha Beta
Glucagon, proglucagon Insulin, C-peptide, proinsulin, amylin Somatostatin
Delta F(PP)
Pancreatic polypeptide (PP)
Control of insulin release from the pancreatic B cell by Glucose [Chemical][Hormonal, Neural are other stimuli]
Oral>i.v
First phase- Within 2 minutes Delayed phase
Insulin Degradation Endogenous
Liver[60%]
Kidney[40%]
s.c
Liver?? [40 %]
Kidney?? [60%]
Glut 1
All tissues
Glut 2
Pancreas
Glut 3
Brain, kidney
Glut 4
Muscle, adipose [Insulinmediated uptake of glucose] Gut, kidney
Glut 5
The Insulin Receptor
TRANSLOCATION
Phosphorylation of tyrosine residues on the β subunits and tyrosine kinase activity directed at cytoplasmic proteins
Gluconeogenes is IN LIVER Glycogenolysis In su Insulin [-] lin
Absorption
[-]
No actio n
Blood
Processes add glucose [Hyperglycemia] Processes utilize glucose [Hypoglycemia]
in l u
In
su
l in
[+ ] Protein Synth. In Muscles
[+ ]
s In
Insuli [+ n ]
Peripheral utilization
Lipogenesis
Sources and insulin preperations Species
A Chain
B Chain
8th AA
10th AA
30th AA
Human
THR
ILEU
THR
Pork
THR
ILEU
ALA
Beef
ALA
VAL
ALA
1. Highly purified pork Insulins • Monocomponent insulins
Conventional prep. •Impurities •Antigenic •Less expensive
•Replaced by 2.Highly purified pork Insulins 1. Human insulins 4.Human insulins • Recombninant DNA 5.Insulin analogs Technology[E.Coli, porcine, Yeast] 3. Insulin analogs Changing or replacing AA sequences 3. Lispro 4. Aspart 5. Glulisine 6. Glargine 5. Detemir
Principal Types and Duration of Action of Insulin Preparations Type
Duration]
Onset
Peak
Appearance
Rapid acting I.Lispro
3-5
Clear
I.Aspart
3-5
Clear
I.Glulisine
2-4
Clear
6-8
Clear
Short acting Regular[Soluble ] Intermediate acting I.Zinc[Lente]
20-24
Cloudy
Isophane.I [NPH]
20-24
Cloudy
24-36
Cloudy
Long acting Protamine zinc I. [Ultra lente] I.Glargine
24
Clear
Complications of insulin therapy Hypoglycemia
Lipodystroph y
Diagnosi Atrop
s Treatme nt
hy Hypertrop
hy
Immunopathology
•Insulin allergy •Insulin resistance
Q Answer:
•Regular human insulin •NPH Human insulin •70/30 Human insulin
Q
Answer: •Non-antigenic, less allergenic •Less lipodystrophy, •Preferred in insulin resistance
Why? •Infection •DKA •Chronic tt with conventional Q
Answer:
What to do? •Treat the cause •Use newer preparations
When insulin requirement is > 200 i.u
Q
Answer: •Regular insulin •Intravenous •Bolus [0.1-0.2u/kg] →Infusion [0.1u/kg/hr.]
Q Why shoud serum potassium be monitored with Insulin therapy in diabetic ketoacidosis? Answer:
+
•Though K is lost in urine in DKA + serum K is normal [Intracellular exchange] •Insulin→ DKA subsides → + K is driven intracellular →Hypokalemia •So, after 4 hrs →10-20mEq/hr KCL to i.v.fluid
ORAL ANTIDIABETIC [ Insulin Biguanide secretagog s Metformin ues 1.
HYPOGLYCAEMIC
Sulfonylureas
I Gen •Tolbutamide, •Chlorpropamide •Tolazamide II Gen •Glibenclamide •Glipizide •Gliclazide •Glimepiride
2. Meglinitides •Repaglinide
3. Dphenylalanine derivative
] AGENTS
Thiazolidinedion es •Rosiglitazone •Pioglitazone •aglucosidase inhibitors. •Acarbose •Miglitol
Sulfonylureas :Mechanism of Action ACUTE ADMINISTRATION: INSULIN RELEASE FROM PANCREATIC Beta CELLS↑
CHRONIC ADMINISTRATION:
1. Down regulation of sulf.receptors on pancreas
Insulinaemia decreased But antidiabetic action maintained?????????
Increase in the insulin receptors in target tissues 2.Reduction of serum glucagon concentrations…. [Minor action]
Biguanides :Metformin [-]
mi n
or
Glycogenolysis
M et fo rm in
[-]
Me
tfo r
s Ab
on i t p
Gluconeogenesis
Processes add glucose [Hyperglycemia]
Blood
Processes utilize glucose [Hypoglycemia]
o
f t e
in rm
[+ ]
M
Blood sugar reduced
Peripheral utilization Protein Synth.
Lipogenesis
Pio Glitazon es
THIAZOLIDINEDIONES (Tzds) Bind to nuclear PPAR-γ Rec.
Reduce blood glucose by • Increasing Glu tpt into muscles and adipose tissues • Inhibiting hepatic gluconeogenesis • Promoting lipogenesis
Peroxisome ProliferatorActivated Receptor-gamma (PPAR-γ),
ALPHA-GLUCOSIDASE INHIBITORS Oligosaccharides and Disaccharides
Monosaccharide [Glucose Fructose ]
Acarbos e Miglitol
Not Absorbe d
Uses: Add on drugs in Type 2 ADE: Flatulence, diarrhea, and abdominal pain
Q: Answ er
•Fewer adverse effects and drug interactions •More potent •Longer acting
Q:
Answer:
Anorexic-Clinical relevance???? Does not promote weight gain Reduces plasma triglycerides . nsulin sensitizer-Obesity + Insulin resistance
Q:
Answer:
•Reduces postprandial glycemic elevations •Fewer episodes of hypoglycemia
Q:
Answer: •Increase in weight-edema •Expansion of plasma volume •Reduction in renal sodium excretion •↑ Vascular permeability
Q:
Answer:
Unacceptable levels of hyperglycemia n who respond initially to a sulfonylurea hange in drug metabolism, rogression of β-cell failure, hange in dietary compliance, Misdiagnosis of a patient with slow-onset type 1 DM.
Q:
Answer:
•Levothyroxine of 10 to 15 µg/kg •Life long
Q:
Answer: •Carbimazole •Radioactive iodine
Grave’s disease ↓ Hyperthyroidism ↓ Thyrotoxicosis ↑ Thyrotoxicosis Without Hyperthyroidism ↑ Thyroiditis