DRUG THERAPY OF DIABETES (DR.Farooq Alam)

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DRUG THERAPY OF DIABETES (DR.Farooq Alam)
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• Insulin therapy of diabetes is more than simply
  replacement of a deficient hormone.
• First, the half-life of insulin is short it is
  readily metabolized and removed from circulation.
  
• Second, the complicated pattern of insulin
  secretion under neural, endocrine, and paracrine
  influences is difficult to mimic with exogenous
  hormone.
• Third, administration of insulin by injection
  differs from the normal secretion from the
  pancreas into the portal circulation.

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PREPARATIONS AND CLINICAL USE

• Insulin preparations differ mainly in their rate
  of absorption after subcutaneous injection.
• The rapidly absorbed and short-acting regular
  insulin is the only preparation that can be given
  intravenously and also in pregnancy.

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• All insulin preparations are available in
  strengths of 40 and 100 units/ml.
• Most insulins are administered two or three
  times daily often, in combinations of regular and
  intermediate-acting forms.

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MECHANISM OF ACTION

• Insulin acts by binding to specific receptors on
  the surface of insulin-sensitive tissue.
• The receptor is composed of four functional
  subunits, two alpha and two beta. The alpha
  subunit binds insulin, whereas the beta subunit
  is a tyrosine-specific kinase.

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• Stimulation of the receptor by insulin causes
  phosphorylation of the beta subunit and
  endogenous substrates, initiating a number
  biochemical events
• The insulin receptor complex can be internalized
  by endocytosis, which may be the means of
  inactivation.
• (e.g., facilitation of glucose transport into
  cells, enhancement of amino acid incorporation
  into proteins, increased lipid synthesis).

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DOSAGE

• The normal pancreas produces from 30 to 50 units
  of insulin per day.
• Usual non-pregnant adults theoretically require
  0.6 units/kg of insulin every 24 h.

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• co administration of other drugs may greatly
  alter the effectiveness of insulin. Those agents
  which reduce the effects of insulin, thus
  increasing the insulin requirements, include
• corticosteroids, dextrothyroxine, epinephrine,
  oral contraceptives, Thiazides diuretics, and
  thyroid hormones. Most of these act by increasing
  plasma glucose levels.

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• Agents enhancing the effect of insulin include
  
• ethanol (acute),
• guanethidine, and
• oral hypoglycemics, all of which decrease
  plasma glucose by altering carbohydrate
  metabolism.

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ADVERSE REACTIONS

• Hypoglycemia. A severe prolonged hypoglycemic
  reaction can, if untreated, lead to permanent
  cerebral damage, coma, or death.
• Allergic reactions to insulin can be either local
  or systemic.
• Local allergic reactions include the formation
  of an erythematous area at the site of injection.

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• Systemic allergy consists of
• angioedema,
• nausea, vomiting, diarrhea,
• bronchial asthma, and dyspnea.
• Hypotension, shock, and death are also produced
  occasionally.

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• To reduce the incidence of allergic reactions,
  it may be necessary to change to an insulin from
  a different source or to human insulin.
• Adverse reactions attributable directly to
  insulin administration are due to two factors
• (i) Impurities in insulin preparations and (ii)
  Species of origin

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• . These two factors are particularly important
  with respect to insulin allergenicity.
• Highly purified insulins are far less antigenic
  than impure insulins,
• and human insulins is less antigenic than
  porcine,
• which in turn is less antigenic than bovine.

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ORAL HYPOGLYCAEMIC DRUGS
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BIGUANIDES (METFORMIN PHENFORMIN)

• Type-2 OR NIDDM are mostly treated by oral
  hypo-glycemic drugs,but Now-a-days it is agreed
  that all type of DM should be treated by insulin.
• The two biguanides have similar actions potency
  differs due to pharmacokinetic differences.
• Metformin has been reported to improve lipid
  profile as well in type 2 diabetics.

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MECHANISM OF ACTION

• Metformin reduces hepatic glucose output, largely
  by inhibiting hepatic gluconeogenesis.
• It also slows intestinal absorption of sugars.
• A very important property of this drug is its
  ability to modestly reduce hyperlipidemia (LDL
  and VLDL cholesterol concentrations fall, and HDL
  cholesterol rises).

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• Some experts consider metformin to be the drug of
  choice for newly diagnosed Type 2 diabetics.
• It is the only Oral hypoglycemic agent proven to
  decrease cardiovascular mortality.
• Metformin may be used alone or in combination
  with one of the other agents, as well as with
  insulin.

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PHARMACOKINETICS AND FATE

• Metformin is well absorbed orally,
• is not bound to serum proteins,
• and is not metabolized.
• Excretion is via the urine.

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ADVERSE EFFECTS

• These are largely gastrointestinal.
• Metformin is contraindicated in diabetics with
  renal and/or hepatic disease, cardiac or
  respiratory insufficiency, a history of alcohol
  abuse, severe infection, or pregnancy.
• Rarely, potentially fatal lactic acidosis has
  occurred.
• Long-term use may interfere with vitamin B12
  absorption.

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• drug-drug interactions the effects of
  metformin may be enhanced by Cimetidine,
  Furosemide, Nifedipine, and other agents.

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OTHERS USES

• metformin is effective in the treatment of
  polycystic ovary disease. Its ability to lower
  insulin resistance in these women can result in
  ovulation and, possibly, pregnancy.

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SULFONYLUREA-MECHANISM OF ACTION

• Intact, pancreatic ß- cells are essential for the
  hypoglycemic action of sulfonylureas.
• Sulfonylureas do not affect the synthesis of
  insulin.
• ß- cells contain sulfonylurea receptors that
  appear to be linked to an ATPase-sensitive K
  channel.

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• Increased entry of Ca and intracellular
  binding to calmodulin could activate kinases
  involved in exocytosis of secretory granules.
• Additional mechanisms of lowering of blood
  glucose include release of somatostatin, which
  suppresses Glucagon secretion, and enhanced
  binding of insulin to target cell receptors.

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PHARMACOKINETICS

• When administered orally, the sulfonylurea
  drugs are completely absorbed from the small
  intestine and appear in the systemic circulation
  within 1 to 2 h.
• Close to 100 percent tolbutamide is absorbed
  after oral administration, with 88 percent bound
  to plasma protein.
• Tolbutamide is rapidly biotransformed to inactive
  products,
• Most of the drug is excreted in the urine.

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• Unlike other sulfonylureas, chlorpropamide
  products are excreted equally in the urine and
  bile. This is the advantageous in patients with
  renal impairment to prevent buildup of the drug,
  which would produce excessive hypoglycemic
  effects.

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ADVERSE REACTIONS

• Hypoglycemia and occurs more frequently with
  chlorpropamide, the longest-acting agent.
• It is more prominently observed in patients
  given large doses, with Impaired hepatic or
  renal function, and in patients failing to
  maintain a proper diet.
• A central nervous system syndrome of muscular
  weakness, vertigo, ataxia, and mental confusion
  following administration of very high doses of
  these drugs.

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• G.I.T symptom consist of heartburn, upper
  abdominal discomfort, nausea, lower abdominal
  cramps, and diarrhea.
• Exacerbation of peptic ulcer may occur.
• a history of gastrointestinal disease requires
  low dosage or avoidance of sulfonylurea drug
  therapy.

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• Hypersensitivity reactions have been described
  with all the sulfonylurea drugs.
• Skin reactions consist of photosensitivity,
  erythema, and morbilliform or maculopapular
  rashes.
• The hepatic reaction may be a simple elevation of
  alkaline phosphatase or cholestatic jaundice.

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• The hematopoietic effects consisting of
• leukopenia,
• thrombocytopenia,
• pancytopenia,
• agranulocytosis,
• hemolytic anemia,
• and aplastic anemia have been rarely reported.

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The sulfonylureas traverse the placenta, and can
deplete insulin from the fetal pancreas
therefore pregnant women with type 2-diabetes
should be treated with insulin.
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DRUG INTERACTIONS

• Several drugs may antagonize or potentiate the
  hypoglycemic action of the sulfonylureas.
• Drugs that impair glucose tolerance by a variety
  of mechanisms antagonize the effectiveness of the
  sulfonylureas. These includes

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• Corticosteroids, thyroid hormones, thiazide
  diuretics, Furosemide, and oral contraceptives.
• Other drugs, such as Phenylbutazone, clofibrate,
  dicumarol, and salicylates, potentiate the action
  of sulfonylureas, such as Tolbutamide, by
  displacing them from plasma or interfering with
  their biotransformation or excretion.

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• Monoamine oxidase inhibitors(e.g.,phenelzine,trany
  lcypromine) increase the hypoglycemic effect by
  reducing plasma glucose and by reducing hepatic
  metabolism of the drugs.
• Minor Disulfiram like symptoms may develop when
  alcohol is ingested in the presence of
  sulfonylureas, because of the inhibition of
  intermediary biotransformation of alcohol.

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• There can be an increased Hypoglycemic effect
  with ingestion of alcohol, particularly in
  fasting individuals, as a result of the
  suppression of gluconeogenesis.
• Also, a decreased hypoglycemic effect may occur
  with chronic alcohol abuse because of the
  biotransformation of the sulfonylurea increased .
• The sulfonylureas also interact with insulin,
  producing an exacerbated hypoglycemic effect.

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• Thank you