ORAL ANTIDIABETIC AGENTS & NSAIDs

Nonsteroidal Anti-Inflammatory

Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout

THE IMMUNE RESPONSE

• Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents.

• Inflammation is the body’s effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair.

• When healing is complete, the inflammatory process usually subsides.

• However, inappropriate activation of the immune system can result in inflammation, leading to immune mediated diseases such as rheumatoid arthritis (RA).

• Normally, the immune system can differentiate between self and nonself.

• In RA, white blood cells (WBCs) view the synovium (tissue that nourishes cartilage and bone) as nonself and initiate an inflammatory attack.

• WBC activation leads to stimulation of T lymphocytes (the cell-mediated part of the immune system), which recruit and activate monocytes and macrophages

• These cells secrete proinflammatory cytokines, including tumor necrosis factor (TNF)-? and interleukin (IL)-1, into the synovial cavity

• In addition to T-lymphocyte activation, B lymphocytes are also involved and produce rheumatoid factor (inflammatory marker) and other autoantibodies with the purpose of maintaining inflammation.

• These defensive reactions cause progressive tissue injury, resulting in joint damage and erosions, functional disability, significant pain, and reduction in quality of life

THERAPEUTIC STRATEGIES

• The treatment of patients with inflammation involves two primary goals: first, the relief of symptoms and the maintenance of function, which are usually the major continuing complaints of the patient; and second, the slowing or arrest of the tissue damaging process

• Pharmacotherapy in the management of RA includes anti-inflammatory and/or immunosuppressive agents that modulate/reduce the inflammatory process, with the goals of reducing inflammation and pain, and halting or slowing disease progression.

NONSTEROIDAL

ANTI-INFLAMMATORY DRUGS

Chemistry & Pharmacokinetics

• All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.

• Most of these drugs are well absorbed, and food does not substantially change their bioavailability.

• Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone.

• NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver

• While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation).

• Most of the NSAIDs are highly protein-bound (~ 98%), usually to albumin.

• Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac)

• All NSAIDs can be found in synovial fluid after repeated dosing.

• Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives

Mechanism of action

• NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis

• Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized.

• The selective COX-2 inhibitors do not affect platelet function at their usual doses.

• The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved.

• On the other hand, selective COX-2 inhibitors increase the incidence of edema, hypertension, and possibly, myocardial infarction.

• Celecoxib has an FDA-initiated “black box” warning concerning cardiovascular risks.

• It has been recommended that all NSAID product labels be revised to mention cardiovascular risks.

• all newer NSAIDs are analgesic, anti- inflammatory, and antipyretic, and all (except the COX-2-selective agents and the non-acetylated salicylates) inhibit platelet aggregation

• NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin

• Nephrotoxicity, reported for all NSAIDs, is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins.

• Hepatotoxicity can also occur with any NSAID.

• Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically

• most are probably effective in RA, sero- negative spondyloarthropathies (eg, PA and arthritis associated with inflammatory bowel disease), OA, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout).

• Adverse effects are generally quite similar for all of the NSAIDs:

1. Central nervous system: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis.

2. Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction and congestive heart failure (CHF).

3. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding.

4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia.

5. Hepatic: Abnormal liver function test results and rare liver failure.

6. Pulmonary: Asthma.

7. Skin: Rashes, all types, pruritus.

8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.

ASPIRIN

• Aspirin is now rarely used as an anti-inflammatory medication and will be reviewed only in terms of its antiplatelet effects (ie, doses of 81–325 mg once daily)

• Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood

• Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.

• Mechanisms of Action: Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet)

• In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours.

• Clinical Uses: Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting

• Adverse Effects: In addition to the common side effects listed above, aspirin’s main adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers. Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses

NONACETYLATED SALICYLATES

• These drugs include magnesium choline salicylate, sodium salicylate, and salicyl salicylate.

• All nonacetylated salicylates are effective anti-inflammatory drugs, although they may be less effective analgesics than aspirin

COX-2 SELECTIVE INHIBITORS

• COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isozyme found in the GI tract, kidneys, and platelets.

• Clinical data suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the market.

1. CELECOXIB

• Celecoxib is a selective COX-2 inhibitor— about 10–20 times more selective for COX-2 than for COX-1.

2. MELOXICAM

• Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d.

• It is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective.

NONSELECTIVE COX INHIBITORS*

1. Diclofenac- phenylacetic acid derivative

2. Diflunisal- derived from salicylic acid

3. Etodolac- racemic acetic acid derivative

4. Flurbiprofen- propionic acid derivative

5. Ibuprofen- simple derivative of phenylpropionic acid

6. Indomethacin- indole derivative

7. Ketoprofen- propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase

8. Nabumetone- only nonacid NSAID in current use; it is given as a ketone prodrug and resembles naproxen in structure

9. Naproxen- naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer

10. Oxaprozin- another propionic acid derivative NSAID.

11. Piroxicam- an oxicam

12. Sulindac- sulfoxide prodrug; It is reversibly metabolized to the active sulfide metabolite

13. Tolmetin- not often used; ineffective in the treatment of gout

14. Other NSAIDs- Azapropazone, carprofen, meclofenamate, and tenoxicam are rarely used

• All NSAIDs, including aspirin, are about equally efficacious with a few exceptions— tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for AS.

• Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness ( ex. the GI and renal side effects of ketorolac limit its use.

• Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic.

• For patients with renal insufficiency, nonacetylated salicylates may be best.

• Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs.

• The relatively expensive, selective COX-2 inhibitor celecoxib is probably safest for patients at high risk for GI bleeding but may have a higher risk of cardiovascular toxicity

• Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for GI bleeding;

• The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person

OTHER ANALGESICS

• Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect.

• It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects.

• acetaminophen lacks anti-inflammatory properties

• The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is an effective analgesic

• In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occur.

• With larger doses, dizziness, excitement, and disorientation may occur.

• Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis

• Present data indicate that even 4 g acetaminophen is associated with increased liver function test abnormalities. Doses greater than 4 g/d are not usually recommended and a history of alcoholism contraindicates even this dose.

• Dosage: Acute pain and fever may be effectively treated with 325–500 mg four times daily and proportionately less for children.

• Dosing in adults is now recommended not to exceed 4 g/d, in most cases.

2. KETOROLAC

• Ketorolac is an NSAID promoted for systemic use mainly as a short-term analgesic (not longer than 1 week), not as an anti- inflammatory drug (although it has typical NSAID properties)

• The drug is an effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain.

• It is most often given intramuscularly or intravenously, but an oral formulation is

3. TRAMADOL

• Tramadol is a centrally acting synthetic analgesic, structurally related to opioids

• Since naloxone, an opioid receptor blocker, only inhibits, 30% of the analgesic effect of tramadol, the mechanism of action of this drug must involve both non-opioid and opioid receptors.

• Tramadol does not have significant anti- inflammatory effects

• The drug may exert part of its analgesic effect by enhancing 5- hydroxytryptamine (5-HT) release and inhibiting the reuptake of norepinephrine and 5-HT

DRUGS USED IN GOUT

• Gout is a metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage.

• Gout is usually associated with a high serum uric acid level (hyperuricemia), a poorly soluble substance that is the major end product of purine metabolism

• In most mammals, uricase converts uric acid to the more soluble allantoin; this enzyme is absent in humans.

• The treatment of gout aims to relieve acute gouty attacks and prevent recurrent gouty episodes and urate lithiasis.

1. Colchicine

• Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale

• MOA: Colchicine produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis

• It also inhibits the formation of leukotriene B4 and IL-1?.

2. NSAIDs USED IN GOUT

• Indomethacin is commonly used in the initial treatment of gout as a replacement for colchicine. For acute gout, 50 mg is given three times daily; when a response occurs, the dosage is reduced to 25 mg three times daily for 5–7 days.

• All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes

• Probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks

• Lesinurad (RDEA594) is a promising new uricosuric agent that is currently in phase 3 trials

• With the ensuing increase in uric acid excretion, a predisposition to the formation of renal stones is augmented rather than decreased; therefore, the urine volume should be maintained at a high level, and at least early in treatment, the urine pH should be kept above 6.0 by the administration of alkali

• Uricosuric therapy should be initiated in gouty patients with underexcretion of uric acid when allopurinol or febuxostat is contraindicated or when tophi are present. Therapy should not be started until 2–3 weeks after an acute attack.

• The preferred and standard-of-care therapy for gout during the period between acute episodes is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase.

• Like uric acid, allopurinol is metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.

• When initiating allopurinol, colchicine or NSAID should be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL and they should be continued for 6 months or longer. Thereafter, colchicine or the NSAID can be cautiously stopped while continuing allopurinol therapy.

5. FEBUXOSTAT

• Febuxostat is a non-purine xanthine oxidase inhibitor that was approved by the FDA in 2009.

6. PEGLOTICASE

• Pegloticase is the newest urate-lowering therapy to be approved for the treatment of refractory chronic gout.

• Pegloticase is a recombinant mammalian uricase that is covalently attached to methoxy polyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic response

• Urate oxidase enzyme, absent in humans and some higher primates, converts uric acid to allantoin (This product is highly soluble and can be easily eliminated by the kidney.)

7. GLUCOCORTICOIDS

• Corticosteroids are sometimes used in the treatment of severe symptomatic gout, by intra- articular, systemic, or subcutaneous routes, depending on the degree of pain and inflammation.

• The most commonly used oral corticosteroid is prednisone.

• The recommended oral dose is 30–50 mg/d for 1–2 days, tapered over 7– 10 days. Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcinolone acetonide can be given if the patient is unable to take oral medications.

8. INTERLEUKIN-1 INHIBITORS

• Drugs targeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept, are used for the treatment of gout

ORAL ANTIDIABETIC AGENTS

DRUGS THAT PRIMARILY STIMULATE INSULIN RELEASE BY BINDING TO THE SULFONYLUREA RECEPTOR

SULFONYLUREAS

• increase insulin release from the pancreas

• bind to a 140-kDa high- affinity sulfonylurea receptor that is associated with a beta-cell inward rectifier ATP- sensitive potassium channel

• Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization.

• Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin

Efficacy & Safety of the Sulfonylureas

• Sulfonylureas are metabolized by the liver

• The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile.

• The second-generation sulfonylureas have greater affinity for their receptor compared with the first- generation agents.

• The correspondingly lower effective doses and plasma levels of the second-generation drugs therefore lower the risk of drug-drug interactions based on competition for plasma binding sites or hepatic enzyme action.

FIRST-GENERATION SULFONYLUREAS

• Tolbutamide is well absorbed but rapidly metabolized in the liver.

• Its duration of effect is relatively short (6–10 hours), with an elimination half-life of 4–5 hours, and it is best administered in divided doses (eg, 500 mg before each meal).

• Some patients only need one or two tablets daily.

• The maximum dosage is 3000 mg daily.

• Because of its short half-life and inactivation by the liver, it is relatively safe in the elderly and in patients with renal impairment

• Chlorpropamide has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity;

• approximately 20–30% is excreted unchanged in the urine.

• The average maintenance dosage is 250 mg daily, given as a single dose in the morning.

• Prolonged hypoglycemic reactions are more common in elderly patients, and the drug is contraindicated in this group.

• Other adverse effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and hyponatremia due to its effect on vasopressin secretion and action

• Tolazamide is comparable to chlorpropamide in potency but has a shorter duration of action.

• more slowly absorbed than the other sulfonylureas, and its effect on blood glucose does not appear for several hours

• Its half-life is about 7 hours.

• Tolazamide is metabolized to several compounds that retain hypoglycemic effects.

• If more than 500 mg/d are required, the dosage should be divided and given twice daily.

SECOND-GENERATION SULFONYLUREAS

• Glyburide, glipizide, gliclazide, and glimepiride are 100–200 times more potent than tolbutamide

• They should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.

• Glyburide is metabolized in the liver into products with very low hypoglycemic activity.

• The usual starting dosage is 2.5 mg/d or less, and the average maintenance dosage is 5–10 mg/d given as a single morning dose; maintenance dosages higher than 20 mg/d are not recommended.

• A formulation of “micronized” glyburide (Glynase PresTab) is available in a variety of tablet sizes.

• Glyburide has few adverse effects other than its potential for causing hypoglycemia

• Glyburide is contraindicated in the presence of hepatic impairment and in patients with renal insufficiency.

• Glipizide has the shortest half-life (2–4 hours) of the more potent agents.

• For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast because absorption is delayed when the drug is taken with food.

• The recommended starting dosage is 5 mg/d, with up to 15 mg/d given as a single dose.

• When higher daily dosages are required, they should be divided and given before meals

• At least 90% of glipizide is metabolized in the liver to inactive products, and the remainder is excreted unchanged in the urine

• Glipizide therapy is therefore contraindicated in patients with significant hepatic impairment.

• Because of its lower potency and shorter duration for action, it is preferable to glyburide in the elderly and for those patients with renal impairment

• Glimepiride is approved for once-daily use as monotherapy or in combination with insulin.

• Glimepiride achieves blood glucose lowering with the lowest dosage of any sulfonylurea compound.

• A single daily dose of 1 mg has been shown to be effective, and the recommended maximal daily dosage is 8 mg.

• Glimepiride’s half-life under multidose conditions is 5–9 hours.

• It is completely metabolized by the liver to metabolites with weak or no activity

• Gliclazide (not available in the United States) has a half-life of 10 hours.

• The recommended starting dosage is 40–80 mg daily with a maximum dosage of 320 mg daily.

• Higher dosages are usually divided and given twice a day.

• It is completely metabolized by the liver to inactive metabolites.

MEGLITINIDE ANALOGS

• Repaglinide is the first member of the meglitinide group of insulin secretagogues.

• These drugs modulate beta-cell insulin release by regulating potassium efflux through the potassium channels previously discussed.

• Repaglinide has a fast onset of action, with a peak concentration and peak effect within approximately 1 hour after ingestion, but the duration of action is 4–7 hours.

• It is cleared by hepatic CYP3A4 with a plasma half- life of 1 hour.

• Because of its rapid onset, repaglinide is indicated for use in controlling postprandial glucose excursions.

• The drug should be taken just before each meal in doses of 0.25–4 mg (maximum 16 mg/d);

• Hypoglycemia is a risk if the meal is delayed or skipped or contains inadequate carbohydrate.

• It can be used in patients with renal impairment and in the elderly.

• Repaglinide is approved as monotherapy or in combination with biguanides.

• There is no sulfur in its structure, so repaglinide may be used in type 2 diabetics with sulfur or sulfonylurea allergy

• Mitiglinide (not available in the United States) is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects.

• It has been approved for use in Japan.

d-PHENYLALANINE DERIVATIVE

• Nateglinide, a d-phenylalanine derivative, stimulates rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K+ channel.

• It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour.

• The overall duration of action is about 4 hours.

• It is taken before the meal and reduces the postprandial rise in blood glucose levels. It is available as 60- and 120-mg tablets.

• efficacious when given alone or in combination with non-secretagogue oral agents (such as metformin).

• Hypoglycemia is the main adverse effect.

• It can be used in patients with renal impairment and in the elderly.

DRUGS THAT PRIMARILY LOWER GLUCOSE LEVELS BY THEIR ACTIONS ON THE LIVER, MUSCLE, & ADIPOSE TISSUE

BIGUANIDES

• Metformin is the only biguanide currently available in the United States.

• Phenformin (an older biguanide) was discontinued in the United States because of its association with lactic acidosis.

• primary effect is to activate the enzyme AMP- activated protein kinase and reduce hepatic glucose production.

• Patients with type 2 diabetes have considerably less fasting hyperglycemia as well as lower postprandial hyperglycemia after administration of biguanides

• “euglycemic” agents.

• Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound.

• drug may impair the hepatic metabolism of lactic acid.

• In patients with renal insufficiency, the biguanide accumulates and thereby increases the risk of lactic acidosis, which appears to be a dose-related complication

Clinical Use

• Biguanides are recommended as first- line therapy for type 2 diabetes.

• Because metformin is an insulin-sparing agent and does not increase body weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such persons.

• indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate

• is useful in the prevention of type 2 diabetes (is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese persons with impaired glucose tolerance and fasting hyperglycemia)

• Common schedules would be 500 mg once or twice daily increased to 1000 mg twice daily.

• The maximal dosage is 850 mg three times a day.

Toxicities

• The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), occurring in up to 20% of patients.

• They are dose related, tend to occur at the onset of therapy, and are often transient.

• However, metformin may have to be discontinued in 3–5% of patients because of persistent diarrhea.

• Metformin interferes with the calcium- dependent absorption of vitamin B12–intrinsic factor complex in the terminal ileum, and vitamin B12 deficiency can occur after many years of metformin use.

• Periodic screening for vitamin B12 deficiency should be considered, especially in patients with peripheral neuropathy or macrocytic anemia

• Increased intake of calcium may prevent the metformin-induced B12 malabsorption.

• Lactic acidosis can sometimes occur with metformin therapy.

• It is more likely to occur in conditions of tissue hypoxia when there is increased production of lactic acid and in renal failure when there is decreased clearance of metformin.

• contraindicated in patients with associated risk factors (kidney, liver, or cardiorespiratory insufficiency; alcoholism)

• Acute kidney failure can occur rarely in certain patients receiving radiocontrast agents

THIAZOLIDINEDIONES

• Thiazolidinediones act to decrease insulin resistance.

• They are ligands of peroxisome proliferator- activated receptor gamma (PPAR-?)

• These PPAR receptors are found in muscle, fat, and liver.

• PPAR-? receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation

• increased insulin sensitivity in adipose tissue, liver, and skeletal muscle

• troglitazone, was withdrawn from the market because of hepatic toxicity

• Pioglitazone has some PPAR-? as well as PPAR-? activity.

• It is absorbed within 2 hours of ingestion; although food may delay uptake, total bioavailability is not affected.

• Absorption is decreased with concomitant use of bile acid sequestrants.

• Pioglitazone is metabolized by CYP2C8 and CYP3A4 to active metabolites

• Pioglitazone may be taken once daily; the usual starting dosage is 15–30 mg/d, and the maximum is 45 mg/d.

• Pioglitazone is approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the treatment of type 2 diabetes.

• Rosiglitazone is rapidly absorbed and highly protein bound.

• It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser extent by CYP2C9.

• It is administered once or twice daily; 2–8 mg is the usual total dosage.

• Rosiglitazone is approved for use in type 2 diabetes as monotherapy, in double combination therapy with a biguanide or sulfonylurea, or in quadruple combination with a biguanide, sulfonylurea, and insulin

• The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia.

• clinical trials with rosiglitazone suggested that this drug increased the risk of angina pectoris or myocardial infarction.

• Fluid retention occurs in about 3–4 % patients on thiazolidinedione monotherapy and occurs more frequently (10–15%) in patients on concomitant insulin therapy.

• Heart failure can occur, and the drugs are contraindicated in patients with New York Heart Association class III and IV cardiac status

• Macular edema, Loss of bone mineral density and increased atypical extremity bone fractures in women (due to decreased osteoblast formation), anemia, Weight gain occurs, especially when used in combination with a sulfonylurea or insulin, bladder tumors were observed in male rats on pioglitazone

• Troglitazone, the first medication in this class, was withdrawn because of cases of fatal liver failure.

• Although rosiglitazone and pioglitazone have not been reported to cause liver injury, the drugs are not recommended for use in patients with active liver disease or pretreatment elevation of alanine aminotransferase (ALT) 2.5 times greater than normal.

• Liver function tests should be performed prior to initiation of treatment and periodically thereafter.

DRUGS THAT AFFECT ABSORPTION

OF GLUCOSE

• The a-glucosidase inhibitors competitively inhibit the intestinal ?-glucosidase enzymes and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides.

• Acarbose and miglitol are available in the United States. Voglibose is available in Japan, Korea, and India.

• Acarbose and miglitol are potent inhibitors of glucoamylase, ?-amylase, and sucrase but have less effect on isomaltase and hardly any on trehalase and lactase

• Miglitol is not metabolized and is cleared by the kidney. It should not be used in renal failure.

• Prominent adverse effects of ?-glucosidase inhibitors include flatulence, diarrhea, and abdominal pain and result from the appearance of undigested carbohydrate in the colon that is then fermented into short- chain fatty acids, releasing gas

• These adverse effects tend to diminish with ongoing use because chronic exposure to carbohydrate induces the expression of ?- glucosidase in the jejunum and ileum, increasing distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon.

• Although not a problem with monotherapy or combination therapy with a biguanide, hypoglycemia may occur with concurrent sulfonylurea treatment.

• Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked.

• An increase in hepatic aminotransferases has been noted in clinical trials with acarbose, especially with dosages greater than 300 mg/d. The abnormalities

DRUGS THAT MIMIC INCRETIN EFFECT OR PROLONG INCRETIN ACTION

• An oral glucose load provokes a higher insulin response compared with an equivalent dose of glucose given intravenously.

• This is because the oral glucose causes a release of gut hormones (“incretins”), principally GLP-1 and glucose-dependent insulinotropic peptide (GIP), that amplify the glucose-induced insulin secretion.

• When GLP-1 is infused in patients with type 2 diabetes, it stimulates insulin release and lowers glucose levels.

• The GLP-1 effect is glucose dependent in that the insulin release is more pronounced when glucose levels are elevated but less so when glucose levels are normal

• GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and by other enzymes such as endopeptidase 24.11 and is also cleared by the kidney.

• The native peptide therefore cannot be used therapeutically.

• One approach to this problem has been to develop metabolically stable analogs or derivatives of GLP-1 that are not subject to the same enzymatic degradation or renal clearance.

• Four such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide and dulaglutide are available for clinical use

• The other approach has been to develop inhibitors of DPP-4 and prolong the action of endogenously released GLP-1 and GIP.

• Four oral DPP-4 inhibitors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are available in the United States.

• An additional inhibitor, vildagliptin, is available in Europe.

SODIUM-GLUCOSE

CO-TRANSPORTER 2 (SGLT2) INHIBITORS

• Glucose is freely filtered by the renal glomeruli and is reabsorbed in the proximal tubules by the action of sodium-glucose transporters (SGLTs).

• Sodium-glucose transporter 2 (SGLT2) accounts for 90% of glucose reabsorption, and its inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes

• The SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, all oral medications, are approved for clinical use

OTHER HYPOGLYCEMIC DRUGS

• Pramlintide is an islet amyloid polypeptide (IAPP, amylin) analog.

• IAPP is a 37-amino-acid peptide present in insulin secretory granules and secreted with insulin.

• At pharmacologic doses, IAPP reduces glucagon secretion, slows gastric emptying by a vagally mediated mechanism, and centrally decreases appetite.

• Pramlintide is an IAPP analog with substitutions of proline at positions 25, 28, and 29.

• These modifications make pramlintide soluble, non-self aggregating, and suitable for pharmacologic use.

• Pramlintide is approved for use in insulin-treated type 1 and type 2 patients who are unable to achieve their target postprandial blood glucose levels.

• Pramlintide is injected immediately before eating; dosages range from 15 to 60 mcg subcutaneously for type 1 patients and from 60 to 120 mcg for type 2 patients

• Pramlintide should always be injected by itself using a separate syringe; it cannot be mixed with insulin.

• The major adverse effects of pramlintide are hypoglycemia and gastrointestinal symptoms, including nausea, vomiting, and anorexia

• Colesevelam (bile acid sequestrant and cholesterol- lowering drug) and bromocriptine (dopamine agonist) have very modest efficacy in lowering glucose levels, and their use for this purpose is questionable.