TREATMENT OF DIABETUS MELLITUS [D.M]
: -
A - insulin
:-
A small protein of 51 amino-acid arranged in 2 chains a& b connected to each other by
disulfide bridge (a= 21 amino-acid , b=30 amino-acid by s-s- disulfide bond ) . pro-insulin a long
single chain process with Golgi apparatus & package into granules on hydrolyzed give both insulin
& c-peptide in equi-molar amount of secretion . granules with beta cell store insulin in form of 2
atoms of zinc & 6 molecules of insulin . human pancrease contain upto 8 mg insulin=200
biological units .
Insulin secretion at low basal rates & at higher rate on response to various stimuli (glucose ,
mannose , certain amino-acid like leucine & ariginine , free fatty acid, glucagons , pancreatic
enzyme gastro-inhibitory polypeptide, cholinergic agent by enhance insulin secretion , adrenaline
& non-adrenaline via B2 stimulatory & alfe inhibitory ) . glucose increase ATP intracellular to
cause closing of ATP dependent potassium channel that cause a reduction in potassium outward
current that cause depolarization of beta cells that cause opening of voltage gate calcium channel
that increase intracellular calcium trigger thus stimulate insulin secretion from granules by
exogenous process . the liver & kidney are the most important organs in removing insulin from
circulation . as follow liver 60% & kidney 35-40% for endogenous insulin while for exogenous
insulin the ratio reverse as 60% by kidney & 35-40% by liver . its removal via hydrolysis of
disulfide bond between a& b chains by glutathione insulin transhydrogenase (insulinase) . the half
life of circulatory insulin 3-5 min.
= their mode of action via binding to specific insulin receptors found on the membrane of most
tissues this receptor consist of tow hetrodimers each containing alfa subunits extracellularly &
represent site of recognition + beta subunits that span the membrane & it containing tyrosine
kinase . on binding of insulin alfa unit stimulated & activate tyrosine kinase in beta portion that
activate many substrate that results in increasing entrance of glucose & other agents like amino-
acid & ions (K+ , Mg) into the cells to increasing the utilization of glucose by cell to be use as fuel
or storage energy as(glycogen , fat , protein) .
Insulin preparation availability : four principle types available including :-
1- ultra-short acting insulin of very rapid onset of action & very short duration of action .
2- short acting insulin with rapid onset of action & short duration of action .
3- intermediate acting insulin of slow onset & long duration of action .
4- long acting insulin of slow onset & long duration of action .
1& 2 as clear solution at neutral pH & contain small amount of zinc that improve their stability
(give it short duration of action ). While 3& 4 turbid solution or suspension at neutral pH prepare
either with protamine in phosphate buffer or in variant concentration of zinc in acetate buffer
(ultralente & lente ) .
ULTRA-SHORT ACTING INSULIN(insulin lispro) on S.C injection very rapidly absorbed
dissociated into monomers to reach peak serum level within 1 hour , give 5 min. before meal , use
in treatment of type 1 D.M , its duration of action seldom to be more than 3-4 hours .
SHORT ACTING INSULIN (regular insulin) : it is a short acting crystalline zinc insulin , their
onset of action after 30 min. of S.C injection , their duration of action 5-7 hours , should be
administrate as IV for treatment of diabetic keto-acidosis & when insulin requirement is changing
rapidly as in surgery & acute infection .
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INTERMEDIATE & LONG ACTING INSULIN (lente insulin consist of 30% of semilente of
rapid onset of action & 70% ultralente of delay onset of action + prolong duration of action ) so
lente insulin of rapid onset of action & long duration of action .
Species of insulin :-
1- animal insulin either from pork which defer by one aminoacid than human insulin or from
beef that defer by 3 aminoacid than human insulin , standard available form cosist of 70% of beef
& 30% of pork insulin .
2- human insulin by recombinant DNA technique by inserting proinsulin of human into E.Coli
or yeast then treating the extracting proinsulin to form human insulin molecules .
Concentration of insulin is 100 units / ml of available preparation & another rare concentration of
500 units /ml of regular insulin for sever insulin resistance state .
+++ insulin is the drug of choice in treatment of DM in the pregnant woman .
Delivery of insulin system :
1`- standard mode of insulin therapy is S.C injection .
2- coetaneous S.C injection infusion device (insulin pump) external open loop , the device has
programmable manual pump that deliver basal & bolus insulin re .
3- inhaled insulin under clinical trial .
4- portable pen injection by using of portable pen size injection these contain replaceable cartilage
100 units human insulin & ret ratable needle .
Complication of insulin therapy
: -
1-hypoglycemia ; most common complication of insulin therapy mostly occur in (elderly patient ,
if take too large dose , unusual physical exertion . ) give the sign & symptoms of autonomic
hyperactivity like sympathetic (tachycardia , palpitation , sweating ) + parasympathetic effects
(nausea , hunge ) which lead to convulsion & coma if not treated , their treatment as in mild
conscious state of patient that able to drinking glucose orally by give him orange juice or sugar
while in sever unconscious patients treatment include a- IV infusion of 50% glucose solution in
20-50 ml or / b- by 1 mg of glucagons as injection S.C or IM within 15 min. restore
consciousness & the patient able to take oral therapy or / c -small amount of honey or syrup
inserted into buccal cavity .
2- lipodystrophy at injection site which is atrophy of SC fatty tissues may occur at site of
injection .
3- immunopathology of insulin therapy including :
a- insulin allergy as immediate type hypersensitivity reaction .
b- immune insulin resistance low titer of IgG anti-insulin antibodies .
c-Somogyi effect (patient receive overdose of insulin can experience a hyperglycemic rebound
reaction via that hypoglycemia induce an acceleration releasing of glucagons , corticosteroid &
growth hormone , which antagonize the effect of insulin causing hyperglycemia) .
d-hypokalemia it is also possible since insulin facilitate intracellular uptake of potassium .
e-other effects like nausea , vomiting & sinus tachycardia .
ORAL ANTIDIABETIC AGENT
(oral hypoglycemic agents ) :-
Four categories of oral anti-diabetic agents available :-
1-Insulin secretagogues including Sulfonylurea & Meglitinides .
2-Biguanides . 3-Thiazolidinediones . 4- alfa- glucosidase inhibitors .
2
+++sulfonylurea & Biguanide longest available treatment of type 2 D.M .
►SULFONYLUREA :-
Their mode of action as follow 1- increase release of insulin via beta cells of pancreas via
activation of receptors on beta cells (when 70% of beta cells is damage the remain 30% by
sulfonylurea effect be sufficient to compensate the damage cells ). / 2- increase the sensitivity of
peripheral insulin receptors . / 3-enhance the action of insulin in liver , muscles & adipose
tissues ./ 4- reduction in glucagons concentration in serum .
= (Tolazamide ,Acetohexamide , Glyburid of diuretic effects while Chlorpropamide of anti-
diuretic effect ).
-their contraindication are [coma , pregnancy ,sever infection , renal disease , trauma , surgery .
diabetic ketoacidosis , elderly , but use in caution in patient with porphyria] .
-their adverse effects [agranulocytosis , anemia , blurred vision, confusion , fatigue , headache ,
hemolysis , hypoglycemia , hyponatremia , hypothermia , jaundice , irritability , pallor ,
palpitation , photosensitivity , pruritus , sinus tachycardia , tremor , pancytopenia &
thrombocytopenia ]
Sulfonylurea classified into:-
FIRST GENERATION :
Tolbutamide
(dose 0.5-2 g in divide daily doses of duration of action 6-12 hours) : well
absorbed & rapidly metabolite in the liver, its duration of action make is useful in treatment of
elderly patients , best give as 500 mg before each meal & at bedtime , & some need 1-2 tablets
daily .
chlorpropamide(
0.1-0.5g in single daily dose of duration of action upto 60 hours .
)
: its
half life 32 hours , slowly metabolite in the liver , 20-30 % excreted unchanged in urine , their
contraindication are hepatic & renal failure , their dose 250 mg daily as single daily dose .
tolazamide(
doses 0.1-1 g as single or daily divided doses of duration of action 10-14 hours .
) :
its potency like chlorpropamide , but of short duration of action , it is the more slower absorbed
sulfonylurea agent , , their half life 7 hours , , its effect appear after several hours , , if used in dose
more than 500 mg should be give in divide doses .
Acetohexamide(
0.25-1.5g in divide daily
doses of duration of action 12-24 hours
)
used as an adjunct to diet & exercise to lower blood
glucose , one –third potency of chporpropamide , twice potency of tolbutamide , its metabolite in
the liver into active agent hydroxyhexamide which can contribute to its prolong effect , exhibit
uricosuric activity make it useful in treatment of DM patient with Gout , rapidly absorbed via
GIT , , onset of action within one hour , their half life 1.3 hour of the parent drug while its
metabolite 6 hours , it with its metabolite excrete in urine .
SECOND GENERATION :
Glyburide
: in metabolite in liver , their dose 2.5 mg or less , average maintenance dose 5-10 mg
/day as single dose .
Glipizide
: of shorter half life 2-4 hours , the dose start with 5 mg/day upto
reach 15 mg/day as single daily dose on higher doses give in divide daily dose(maximum 40 mg
/day) , less to cause hypoglycemia due to their short half life , 90 % metabolite & 10% as
unchanged all excrete in urine .
Glimepiride
: used once daily as monotherapy or in combination
with insulin , of lowest dose of sulfonylurea agents (single dose of 1 mg/day upto 8 mg /day ) ,
their half life 5 hours , of long duration of action , their metabolite in liver .
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►Meglitinides : which is an insulin secretagogues agent that either use alone or in combination
with biguanides , its first drug included is Repaglinide use in dose 0.25-4 mg /day , maximum 16
mg/day before meal , their half life one hour & their duration of action for 4-5 hours , their mode
of action by modulate Beta cell insulin releasing by regulate potassium efflux through potassium
channels , of rapid onset of action within one hour & short duration of action , their hypoglycemic
occur in following state if delay meal or in case of inadequate in take of CHO .
►Biguanides
: -
it is include many agents like [
buformin
(used in dose of 0.05-0.3 g in divided daily doses their
duration of action 10-12 hours ) ,
metformin
(used in dose of 1-2..5 g in divided daily doses
their duration of action 10-12 hours , not metabolite & excreted as active compound in the urine ,
their half life 1.5-3 hours ) ,
phenformin
include DBI & meltrol-50(used in dose of 0.025-0.15
g in single daily dose or divided daily doses their duration of action 4-6 hours for DBI & 8-14
hours for meltrol ) ], their mode of action as follow : 1- direct stimulation of glycolysis in the
tissues that causing increase in the removal of glucose . / 2-reduce hepatic gluconeogenesis . / 3-
slower glucose absorption via GIT & increase conversion of glucose to lactate . /4-reduction of
plasma glucagons level .their clinical uses as 1- use in combination with the sulfonylurea in
treatment of type 2 DM . / 2-refractory obesity (hyperglycemia due to ineffective insulin) .
metformin use in dose 500 mg upto 2.5 g /day to be start with 500 mg at breakfast for several days
then 500 mg at evening added if tolerance develop then 500 mg at midday to be added if
hyperglycemia persist or use large dose 850 mg twice daily or even three times daily which is the
maximum dose that recommended . their adverse effects [ GIT disturbance as nausea , vomiting ,
diarrhea in 20% of patients , decrease absorption of B12 , lactic acidosis(less in absence of
hypoxia , renal or hepatic failure )] , their contraindication are hepatic ?& renal diseases ,
alcoholism , tissues anoxia .
►
Thiazolidindiones
: which include following agents [ proglitazone in dose of 15-45 mg
once daily , rosiglitazone in dose of 2-8 mg once daily & troglitazone in dose of 200-600 once
daily with the food ] . their mode of action by increasing target tissues sensitivity to the insulin &
decrease insulin resistance by increasing glucose uptake & metabolism by muscles & adipose
tissues .
►
Alfa –glucosidase
inhibitors : which include to agents [acarbose & miglitol both in dose of
25-100 mg /day before meal ] .only glucose or fructose can be absorbed by intestine so complex
starches broken via alfa-amylase & alfa-glucosidase into monosaccharide , both drug acts as a
competitive inhibitor of alfa-glycosidase enzyme . meglitol a seven times more potent than
acarbase , use each one as monotherapy or in combine therapy with sulfonylurea in treatment of
type 2 DM , their adverse effects [ flatulence , diarrhea , abdominal; pain , borborygmi &
elevation of hepatic enzymes level ] , their contraindication [inflammatory bowel disease , GIT
disease or obstruction , pregnancy , hepatic disease , breast-feeding , renal impairment & hiatus
hernia ] .
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