PHARMACOLOGY OF TYPE 1 PHARMACOLOGY OF TYPE 1 DIABETES MELLITUS - DIABETES MELLITUS - INSULIN INSULIN Dr. CHANDANE R. D. Dr. CHANDANE R. D. Asst. Professor Asst. Professor Dept. Of Pharmacology Dept. Of Pharmacology Govt Medical College, Govt Medical College, Akola Akola
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PHARMACOLOGY OF TYPE 1 PHARMACOLOGY OF TYPE 1
DIABETES MELLITUS - DIABETES MELLITUS -
INSULININSULIN
Dr. CHANDANE R. D.Dr. CHANDANE R. D.Asst. ProfessorAsst. Professor
Dept. Of PharmacologyDept. Of Pharmacology
Govt Medical College, AkolaGovt Medical College, Akola
DIABETES MELLITUSDIABETES MELLITUS
Group of syndromes characterized by Group of syndromes characterized by hyperglycemia; altered metabolism of lipid, hyperglycemia; altered metabolism of lipid, CHO & Proteins and increase risk of CHO & Proteins and increase risk of complications from vascular diseasescomplications from vascular diseases
Sushruta – ayurvedaSushruta – ayurveda
Aeretaeus – Diabetes - first centuryAeretaeus – Diabetes - first century
Dobson – sugar in urine 1755Dobson – sugar in urine 1755
Classification of Diabetes MellitusClassification of Diabetes Mellitus
I) Type 1 DM ( IDDM )I) Type 1 DM ( IDDM ) a) Autoimmune (Type 1 A)a) Autoimmune (Type 1 A) b) Non autoimmune/ idiopathic (Type 1 B)b) Non autoimmune/ idiopathic (Type 1 B)
II) Type 2 DM (NIDDM)II) Type 2 DM (NIDDM)
III) Type 3 DM (Other specific types of DM)III) Type 3 DM (Other specific types of DM)A) Specific defined gene mutationA) Specific defined gene mutation a) Maturity onset diabetes of youth (MODY)a) Maturity onset diabetes of youth (MODY) i) MODY-1: Hepatic nuclear factor 4i) MODY-1: Hepatic nuclear factor 4αα (HNF4A) gene mutation (HNF4A) gene mutation ii) ii) MODY-2: GlucokinaseMODY-2: Glucokinase gene mutation gene mutation iii) iii) MODY-3: Hepatic nuclear factor 1MODY-3: Hepatic nuclear factor 1αα gene mutation gene mutation iv) iv) MODY-4: Insulin promotor factor 1MODY-4: Insulin promotor factor 1 (IPF1) gene mutation (IPF1) gene mutation v) v) MODY-5: Hepatic nuclear factor 1MODY-5: Hepatic nuclear factor 1ββ (HNF1B) gene mutation (HNF1B) gene mutation vi) vi) MODY-6: Neurogenic Differentiation 1MODY-6: Neurogenic Differentiation 1(NEUROD1) gene mutation(NEUROD1) gene mutation vii) vii) MODY-X: Unidentified gene mutationMODY-X: Unidentified gene mutation b) Insulin b) Insulin gene mutationgene mutation c) Insulin receptor gene mutationc) Insulin receptor gene mutation
Classification…….Classification……. B) Diabetes Secondary to Pancreatic diseasesB) Diabetes Secondary to Pancreatic diseases i) Chronic Pancreatitisi) Chronic Pancreatitis ii) Surgeryii) Surgery iii) Tropical Diabetes (Chronic Pancreatitis with nutritional/ toxic factors)iii) Tropical Diabetes (Chronic Pancreatitis with nutritional/ toxic factors)
C) Diabetes secondary to EndocrinopathiesC) Diabetes secondary to Endocrinopathies i) Cushings Disease i) Cushings Disease ii) Glucocorticoid administrationii) Glucocorticoid administration iii) Acromegalyiii) Acromegaly
D) Diabetes secondary to immune suppressionD) Diabetes secondary to immune suppression E) Diabetes associated with genetic syndromesE) Diabetes associated with genetic syndromes
Prader willi syndromePrader willi syndrome
F) Diabetes associated with Drug therapyF) Diabetes associated with Drug therapy
IV) Type 4 DM Gestational diabetes mellitus (GDM)IV) Type 4 DM Gestational diabetes mellitus (GDM)
PATHOPHYSIOLOGY OF TYPE 1 DMPATHOPHYSIOLOGY OF TYPE 1 DM
A)A) AUTOIMMUNITYAUTOIMMUNITY- - Condition where ones own immune system attack Condition where ones own immune system attack
structure in one’s own bodystructure in one’s own bodyCirculating antibodies against b-cells and insulin Circulating antibodies against b-cells and insulin Cytoplasmic & membrane bound Ag IAAS GAD HSP etcCytoplasmic & membrane bound Ag IAAS GAD HSP etcInsulitisInsulitisBoth humoral & cell-mediated immunity are stimulatedBoth humoral & cell-mediated immunity are stimulatedtriggered by reaction to infectiontriggered by reaction to infection
B) B) GENETIC FACTORSGENETIC FACTORS Ethnic differences, Familial clustering, High concordance Ethnic differences, Familial clustering, High concordance rate in twins 25-50%rate in twins 25-50%HLA on Chromosome 6- HLA on Chromosome 6-
HLADR3/HLADR4HLADR3/HLADR4
C) ENVIRONMENTAL INFLUENCEC) ENVIRONMENTAL INFLUENCE
Faulty nerves in pancreas- Faulty nerves in pancreas-
HONEYMOON PERIODHONEYMOON PERIOD
Due to b-cell reserve optimal function & initiation of insulin Due to b-cell reserve optimal function & initiation of insulin therapy.therapy.
Leads to normal blood glucose level without exogenous insulin.Leads to normal blood glucose level without exogenous insulin.
Observed in 50-60% of newly diagnosed patients & it can last up to Observed in 50-60% of newly diagnosed patients & it can last up to one year but it always ends.one year but it always ends.
MANAGEMENT OF TYPE 1 DMMANAGEMENT OF TYPE 1 DM
EducationEducation
Diet and meal planningDiet and meal planning
Insulin therapyInsulin therapy
MonitoringMonitoring
Educate child & care givers about:Educate child & care givers about: DiabetesDiabetes InsulinInsulin Life-saving skillsLife-saving skills Recognition of Hypo & DKARecognition of Hypo & DKA Meal plan Meal plan Sick-day managementSick-day management
Diet and Meal planningDiet and Meal planning
Susrate and Charaka- 2,500 years agoSusrate and Charaka- 2,500 years ago John Rollo -eighteenth century John Rollo -eighteenth century
Frederick Allen -modern history of the diabetic diet Frederick Allen -modern history of the diabetic diet
Regular meal plans with calorie exchange options are Regular meal plans with calorie exchange options are encouraged.encouraged.
50-60% of required energy to be obtained from complex 50-60% of required energy to be obtained from complex carbohydrates.carbohydrates.
Distribute carbohydrate load evenly during the day preferably Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars.3 meals & 2 snacks with avoidance of simple sugars.
Encouraged low salt, low saturated fats and high fiber diet.Encouraged low salt, low saturated fats and high fiber diet.
INSULIN
HISTORY1500 BC Sushruta – ayurveda Diabetes First Described In Writing that flies and ants were attracted to urine of people with a mysterious disease that caused intense thirst, enormous urine output, and wasting away of the body-
250 BC Apollonius of Memphis coined the name "diabetes” meaning "to go through" or siphon. Latin word for honey is mellitus
150 BC Aretaeus the Cappadocian - melting down of the flesh and limbs into urine
Early Diabetes Treatments
1000- Greek physicians recommended horseback riding to reduce excess urination
1800s- bleeding, blistering, and doping were common
1915- Sir William Osler recommended opium
Overfeeding - compensate for loss of fluids and weight
Early 1900s Dr. Frederick Allen, recommended a starvation diet
Early Research
1798- John Rollo - excess sugar in the blood and urine
1813-Claude Bernard linked diabetes to glycogen metabolism
1869- Paul Langerhans- a German medical student, discovered islet cells in the pancreas
1889-Joseph von Mehring and Oskar Minkowski created diabetes in dogs by removing the pancreas
1910-Sharpey-Shafer of Edinburgh suggested a single chemical was missing from the pancreas. He proposed calling this chemical "insulin."
Pancreas Extractors
1908- a young internist in Berlin, Georg Ludwig Zuelzer created a pancreas extract named acomatrol. Try in dying diabetic patient
1911 - E. L. Scott was partially successful in extracting insulin with alcohol
1916-1920 - R. C. Paulesco, made an extract from the pancreas that lowered the blood glucose of dogs.
Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset
1922 BANTING & BEST1922 BANTING & BESTFrederick Banting & Charles Best – ligate pancreatic Frederick Banting & Charles Best – ligate pancreatic duct extract islets with alcohol and acid-↓BSL in dogduct extract islets with alcohol and acid-↓BSL in dogLeonard Thompson- age14-year wt 64 lb injected Leonard Thompson- age14-year wt 64 lb injected their extract - blood glucose to fall from 520 to 120 their extract - blood glucose to fall from 520 to 120 mg/dL in 24 hoursmg/dL in 24 hoursLeonard lived a relatively healthy Leonard lived a relatively healthy
life for 13 years before dying life for 13 years before dying of pneumonia (no Rx then) at 27of pneumonia (no Rx then) at 27
Macleod & J B Collip – stable extractMacleod & J B Collip – stable extract
Nobel PrizeNobel Prize 1923 – 1923 – Banting & MacleodBanting & Macleod nobel prize for nobel prize for
physiology /medicinephysiology /medicine 1930- Hagedorm – protamine1930- Hagedorm – protamine 1950- T.Scott & Fisher – added zinc1950- T.Scott & Fisher – added zinc 1955- 1955- SangerSanger- primary struct Nobel prize in - primary struct Nobel prize in
ChemistryChemistry 1969- 1969- HodgkinHodgkin- Tirtiary struct - Tirtiary struct 1977-1977-YalowYalow- Radioimmunoassay for insulin- Nobel - Radioimmunoassay for insulin- Nobel
prize in Medicineprize in Medicine 1978- Insulin gene cloned-Recombinant DNA Insulin1978- Insulin gene cloned-Recombinant DNA Insulin 1983 Intranasal1983 Intranasal 1988- Long acting insulin analogues1988- Long acting insulin analogues
Structure & ChemistryStructure & Chemistry
PancreasPancreas – – Islets 2% of PancreasIslets 2% of Pancreas
BeefBeef HighHigh AlanineAlanine ValineValine AlanineAlanineHuman Insulin – Human sequence insulin as primary structure Human Insulin – Human sequence insulin as primary structure identical to human insulin, chemical conversion of porcine insulin, identical to human insulin, chemical conversion of porcine insulin, - Synthesis by E.coli & Yeast cultures - Synthesis by E.coli & Yeast cultures
A- high mol wt contaminantA- high mol wt contaminant
B- Proinsulin & intermediate product of proinsulinB- Proinsulin & intermediate product of proinsulin
C- Insulin MonomersC- Insulin Monomers
Antigenicity – A&B Component – eliminate →purified C insulinAntigenicity – A&B Component – eliminate →purified C insulin
Animal insulin production – need large no. of animalsAnimal insulin production – need large no. of animals
DNA Technology research – identical to human insulinDNA Technology research – identical to human insulin
1)1) Enzymatic Modified Pathway – EMPEnzymatic Modified Pathway – EMPEnzymatic conversion of porcine to human insulinEnzymatic conversion of porcine to human insulinAlanine replaced by ThreonineAlanine replaced by Threonine
33 PurityPurity Proinsulin foldProinsulin fold Proinsulin & other prProinsulin & other pr
44 ImmunogenicityImmunogenicity Less Less More More
55 PH of soluble PH of soluble insulininsulin
Neutral Neutral Acidic (2.5-3.5)Acidic (2.5-3.5)
66 MixibilityMixibility Possible Possible Not possibleNot possible
77 Compatibility Compatibility CompatibleCompatible Less CompatibleLess Compatible
CHARACTERISTICS OF NEWER INSULINCHARACTERISTICS OF NEWER INSULIN
Absorbed faster, Gap between sc inj & food shorterAbsorbed faster, Gap between sc inj & food shorter
Duratio & onset of action –shorter-fasting hypoglycemia-so Duratio & onset of action –shorter-fasting hypoglycemia-so inj given post dinnerinj given post dinner
More pure more effectiveMore pure more effective
Neutral PH-more stable mixing & less painfullNeutral PH-more stable mixing & less painfull
Potency – more on wt basisPotency – more on wt basis
Less AntigenicLess Antigenic
Not cause LipodystrophyNot cause Lipodystrophy
Now cost is lowNow cost is low
Disadvantage:-Disadvantage:-
Hypoglycemic unawarenessHypoglycemic unawareness
INDICATIONS OF NEWER INSULINSINDICATIONS OF NEWER INSULINS
1.1. Newly diagnosed DM ptNewly diagnosed DM pt
2.2. Pt t/t intermittently with insulin – surgery infection etcPt t/t intermittently with insulin – surgery infection etc
-Substituting aspartic acid for histidine at B10 -Substituting aspartic acid for histidine at B10 -mitogenic experimentally -mitogenic experimentally
2) INSULIN LISPRO- 2) INSULIN LISPRO-
First genetically engineered – clinical useFirst genetically engineered – clinical use
Sequence of proline at B28 & lysine at B29 reversed to lysine Sequence of proline at B28 & lysine at B29 reversed to lysine at B28 & proline at B29 ( Lis Pro)at B28 & proline at B29 ( Lis Pro)
3) INSULIN ASPART –3) INSULIN ASPART –
Proline of B28 replaced by Aspartic acidProline of B28 replaced by Aspartic acid
4) INSULIN GLUISINE-4) INSULIN GLUISINE-
Lysine replace aspargine at B23 & Glutamic acid replace Lysine replace aspargine at B23 & Glutamic acid replace lysine at B29lysine at B29
LONG ACTING –LONG ACTING –1) NOVOSOL BASAL – 1) NOVOSOL BASAL – Contains Arginine, Glycine ThreonineContains Arginine, Glycine Threonine Low bioavailability, so high doses reqLow bioavailability, so high doses req2) INSULIN GLARGINE –2) INSULIN GLARGINE – Contains Arginine at carboxyterminus of B chain, Glycine Contains Arginine at carboxyterminus of B chain, Glycine
replaces arginine at A21replaces arginine at A21 Peakless effect given ODPeakless effect given OD Fasting & interdigestive BSL ↓ irrespective of time of dayFasting & interdigestive BSL ↓ irrespective of time of day Not mixable , Not control mealtime glycemiaNot mixable , Not control mealtime glycemia Lower night time hypoglycemiaLower night time hypoglycemia3) INSULIN DETEMIR – Fatty Acid acetylated insulin3) INSULIN DETEMIR – Fatty Acid acetylated insulin Most recent, Threonine dropped from B30 & Mysteric acid is Most recent, Threonine dropped from B30 & Mysteric acid is
attached to B29 Lysine, Less hypoglycemiaattached to B29 Lysine, Less hypoglycemia Onset of action 1-2 Hrs Duration >24hrs Onset of action 1-2 Hrs Duration >24hrs
ADVERSE REACTIONSADVERSE REACTIONS
1) HYPOGLYCEMIA-1) HYPOGLYCEMIA- Most common, Occurs in any diabetic -Most common, Occurs in any diabetic - Inadvertent inj of large doses, Missing meal, Inadvertent inj of large doses, Missing meal, Vigourous exerciseVigourous exercise Counter regulatory sympathetic regulation- sweating anxiety Counter regulatory sympathetic regulation- sweating anxiety
atrophy- immune response to insulinatrophy- immune response to insulin
Lipohypertrophy- enlarge subcut fat-→ lipogenic action of Lipohypertrophy- enlarge subcut fat-→ lipogenic action of high local conc. Insulin high local conc. Insulin
T/t- To change site of inj regularly T/t- To change site of inj regularly
Purpose- Purpose- Restore metabolism to normalRestore metabolism to normalPrevent death & alleviate symptomsPrevent death & alleviate symptomsPrevent acute & chronic complications Prevent acute & chronic complications Achieve biochemical controlAchieve biochemical control
DM controlled by diet & exercise DM controlled by diet & exercise need insulin whenneed insulin when
Not controlled by diet & exercise Not controlled by diet & exercise OHA prim/sec failure or not toleratedOHA prim/sec failure or not toleratedUnder wt ptUnder wt ptAny DM complicationAny DM complicationTemporary tide over infection, Trauma, Surgery, Pregnancy, Temporary tide over infection, Trauma, Surgery, Pregnancy, Perioperative monitoringPerioperative monitoring
Regular insulin- sc before mealRegular insulin- sc before mealRequirement – assess by BSL & Urine sugarRequirement – assess by BSL & Urine sugar Type 1 – 0.4-0.8 U/kg/dayType 1 – 0.4-0.8 U/kg/day Type 2- 0.2-1.6 U/kg/dayType 2- 0.2-1.6 U/kg/dayRegimens- Regimens- 1) Typical split mixed regimen- reg/lispro/aspart & intemediate 1) Typical split mixed regimen- reg/lispro/aspart & intemediate
acting (NPH/Lente) twice daily before breakfast & dinneracting (NPH/Lente) twice daily before breakfast & dinner2) In above evening dose of NPH/Lente is delayed at bed time2) In above evening dose of NPH/Lente is delayed at bed time3) Long acting insulin Glargine OD for basal coverage & rapid 3) Long acting insulin Glargine OD for basal coverage & rapid
acting at meal timeacting at meal time
4) Premeal short acting & Long acting NPH/Lente at breakfast & 4) Premeal short acting & Long acting NPH/Lente at breakfast & bed timebed time
1) Insulin- regular insulin, 0.1-0.2 U/kg iv bolus f/b 0.1 U/kg/hr 1) Insulin- regular insulin, 0.1-0.2 U/kg iv bolus f/b 0.1 U/kg/hr infusion, fall in BSL 10% per hr adequateinfusion, fall in BSL 10% per hr adequate
when BSL 300mg/dl – 2-3U/hr , after full conscious sc therapywhen BSL 300mg/dl – 2-3U/hr , after full conscious sc therapy
2) IV Fluids- correct dehydration2) IV Fluids- correct dehydration
NS 1L/hr, ↓ 0.5L/4hr depend on dehydration, NS 1L/hr, ↓ 0.5L/4hr depend on dehydration,
Stabilize pt (BP HR) ½ NS Stabilize pt (BP HR) ½ NS
when BSL 300mg/dl 5% Glucose in ½ NS – when BSL 300mg/dl 5% Glucose in ½ NS –
i. BSL ↓ before ketones clearedi. BSL ↓ before ketones cleared
ii. For restore depleted hepatic glycogenii. For restore depleted hepatic glycogen
3) KCl- 400 meq K3) KCl- 400 meq K++ lost, intracellular store replace, after insulin K lost, intracellular store replace, after insulin K++ driven intracellularly →Hypokalemia driven intracellularly →Hypokalemia
After 4hr 10-20meq/hr add to iv fluidAfter 4hr 10-20meq/hr add to iv fluid
4) Sodium Bicarbonate- 50 meq till PH>7.2 4) Sodium Bicarbonate- 50 meq till PH>7.2