KD Tripathi Essential of Medical Pharmacology. 8th edition -301-600 - 284 HORMO NES AND RELATED DRUGS Insulin receptor Glucose I ~-GNE proteins GTP

KD Tripathi Essential of Medical Pharmacology. 8th edition -301-600

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Unformatted text preview: 284 HORMO NES AND RELATED DRUGS Insulin receptor Glucose I ~--GNE proteins GTP ~--..... GDP GLUT4 - t ~- ~rt' ~ - GLUT4 ::?,:' ,§<. Pl3 kinase phosphorylation cascade Second messengers (PIP3 ) I Activation / Inhibition of Enzymes mRNA , . . . Cellular proliferation and differentiation Fig. 19.3: A model of insulin receptor and mediation of its metabolic and cellular actions T- Tyrosine residue; GLUT4-lnsulin dependent glucose transporter; IRS- Insulin receptor substrate proteins; PIP3- Phosphatidyl inositol trisphosphate; P l3 kinase-Phosphatidylinositol-3 kinase; GNE proteins-Guanine nucleotide exchange proteins; MAP kinase-Mitogen-activated protein kinase; T-PrK- Tyrosine protein kinase; Ras- Regulator of cell division and differentiation (protooncogene product). ca lled the rapid actions. Others involving D A mediated synthesis o f glucose transporte r and some enzymes of amino acid metabolism have a latency of few hours-the intermediate actions. In addition insulin exerts major long-term effects on multiplication and differe ntiation of many types of cells. Mechanism of action Insulin acts on specific rt!ceptors located on the cell membrane of practically every cell. but their density depends on the cell type: liver and fat cells arc very rich. The insulin receptor is a receptor tyrosine kinase ( RT K } which is a heterotetrameric glycoprotcin consisting of 2 extracellular a and 2 transmembrane f3 subunits linked together by disulfide bonds. It is oriented across the cell memhrane as a heterodimer (Fig. 19.3). The a subunits carry insul in binding sites, whi le the f3 subunits have tyrosine protein kinase activity. Binding of i nsul in LO Cl subunits induces aggregation and internalization of the receptor along with the bound insulin molecules. This activates tyrosine kinase acti vity of the subunits • pairs of f3 subunits phospho,y late e:-pose the catalytic tyro inc residues on each other • site to phosphorylate tyrosine residues of Insulin Receptor ubstrate proteins (I RS I. I RS2. etc) and other caveolar/ noncaveolar proteins. In tum, a cascade of phosphorylation and dephosphorylation reactions involving phosphatidyl inositol 3 kinase (Pl3 kinase) and other kinases is set into motion which amplifies the signal and results in stimulation or inhibition o f en7ymes involved in the rapid metabolic actions of insulin. Second messengers like phosphatidyl inosiLOI trisphosphate (PI P.) which arc generated through acti, ation of a specific Pl3-kinase also mt:diale the action of insulin on metabolic enLymes. Insulin stimulates glucose transport across cell membrane by ATP depende111 tra nslocation of gl ucose transporter INSULIN, ORAL ANTI DIABETIC DRUGS AND GLUCAGO N GLUT4 to the pla~ma membrane. The second messenger PIP, and certain tyrosine phosphorylated guanine nucleotide exchange proteins play crucial role in the insulin sensitive translocation of GLUT4 from cytosol to the plasma membrane, especially in skeletal muscle and adipose tissue. Over a period of time insulin also promotes expression of the genes directing synth~sis of GLUT4. Genes for a large number of enzymes and carriers arc regulated by insulin through Ras/Raf and MAP-Kinase as well as through the phosphorylation ca~cadc. Long-tem1 efTects of insulin are exe11ed by generation of transcription factors promoting proliferation and differentiation of specific cells. The internalized receptor-insu lin complex is either degraded intraccllularly or returned back to the surface from where the insulin is released extracellularly. The relative preponderance nf these two processes differs among differe11t tissues: maximum degradation occurs in liver. least in vascular e11dothelium. Fate of insulin Insulin i s d istri buted on l y extracellularly. It i s a peptide, and gets degraded in the g. i .t . if given o rall y. Injected in sul in or that rel eased from pancreas is m etabolized primarily in li ver and to a sma ller extent in kidn ey and muscles. early hal f o f the insu lin entering portal vei n from p ancr eas i s inactivated in the first passage th rough li ver. Thus, normally l iver i s exposed to a much higher concentration (4-8 fold) of i nsulin than are other tissues. As noted above, degradation of insul in after receptor m ediated internalization occurs to variable extents i n most target cells. During biotransformation the di sulfide bonds are reduced- A and B chains arc separated. T hese are further broken down to the constin1ent amino acids. The plasma t ½ of in su lin is 5- 9 min. Preparations of insulin The older commercial insulin preparations were produced from beef and pork pancreas. They contained - 1% ( I 0,000 ppm) of other proteins (proinsulin. other polypeptides, pancreatic proteins. insulin derivati,es. etc.) which were potentially antigenic. Such insulins are no longer produced and have been totally replaced by highly purified pork/beef insulins. recombinant human insulins and insulin analogues. Highly purified insulin preparations I n the 1970s improved purification teclrniques like gel fi l tration and ion-exc hange c hromatography wer e appli ed to produce 'sing l e peak ' and 'monocomponent (M C)' insu l ins w hich contain < IO ppm proinsul in. The MC insuli ns are more stable and cause less insulin resistance or injecti on si te lipodystrophy. T he immunogenicity of pork MC insulin is similar to that of recombinant human insulin. Table 19.1 : Types of 111suhn preparations and 111suhn analogues Type Appearance Onset (hr) Peak (hr) Duration (hr) Can be mixed with Insulin lispro Clear 0.2--0.3 1-1.5 3-5 Regular, NPH Insulin aspart Clear 0.2--0.3 1- 1.5 3-5 Regular, NPH Insulin glulisine Clear 0.2-0.4 1- 2 3-5 Regular, NPH Clear 0.5-1 2-3 6-8 All preparations (except insulin glargine/ detemir) Insulin zinc suspension or Lente• Cloudy 1- 2 8- 10 12-20 Regular Neutral protamine hagedorn (NPH) or isophane insulin Cloudy 1-2 8- 10 12- 20 Regular Insulin glargine Clear 2-4 24 None Insulin detemir Clear 1-4 20-24 None Rapid acting Short acting Regular (soluble) insulin Intermediate acting Long acting • Lente insulin is a 7:3 mixture of ultralente (crystalline) and semilente (amorphous) insulin zinc suspension. Ultralente (long-acting) and semilente (short-acting) are not separately marketed. The older protamine zinc insulin is also not marketed. 285 286 HORMONES AND RELATED DRUGS Types of insulin preparations Regular (soluble) insulin l t is a buffered neutral pH solution of unmodified insulin stabilized by a small amount of zi nc. At the concentration of the injectable solution, the insulin molecules self aggregate to form hexamers around the zinc ions. After s .c. injection, insulin monomers are released gradually by dilution, so that absorption occurs slowly. Peak action is produced only after 2- 3 hours and action continues upto 6-8 hours. The absorption pattern is also afTcctcd by dose; highe r doses act longer. When injected s.c. just before a meal, this pattern often creates a mismatch between the need and the availabi lity of insulin to result i11 early postprand ia l hyperglycaemia and late postprandial hypoglycaemia. Regular insulin is optimall y injected I hour before a meal. Regular insulin injected s.c. is also not suitable fo r providing a low constant basal level of action in the interdigestive period. However, the slow onset of action is not applicable to i.v. injection, because the insulin hexamer dissociates rapidl y to produce prompt action. Regular insulin is the only insulin used for i.v. inj ection. To ove rco me the above problems, so me long-acting ' modified' or ' retard ' preparations of insulin were soon developed. Recently, both rapidl y actin g as well as peakless a nd longacti ng insu lin analogues have become avai lab le. For obtaining retard preparations, insulin is rendered insoluble either by complexing it with protamine (a sma ll molec ul ar bas ic prote in) o r by precipitating it with excess zinc a nd increasing the particle size. Lente insulin (Insulin-zinc suspension): Two types of insul in-zinc suspensions have been produced. The one with large particles is crystalli ne and practically insoluble in water (ultra lente). It is long-acting. The other has smaller particles and is amorphous (semilente), is hort-acti ng. The ir 7:3 ratio mixture is called ' Lente insulin ' and is intermediate-acting. lsophane (Neutral Protamine Hagedorn or NPH) insulin: Protamine is added in a quantity just sufficient to complex all insulin molecules; nei ther insulin nor protamine is present in free form and pH is neutral. On s .c. injection, the complex di ssociates slowl y to yie ld an intermedi ate duration of action. However, the time course o f absorption a nd in tensity of action of NP H insulin is relative ly inconsistent. It is mostly combined with regular insulin (70:30 or 50:50) and injected s.c. twice daily before breakfast and before dinner (split-mixed regimen). I. 2. 3. 4. Highly purified (monocomponcnt) pork regular insulin: ACTRAPID MC. RAPIDICA 40 U/ml inj. High ly purified (MC) pork lentc insulin: LE TARD, M01\JOTARD MC, LENTINSULIN-HPI, ZlNULIN 40 U/ml Highly purified (MC) pork isophane ( PH) insulin: INSULATARD 40 U/ml inj. Mixture or highly purified pork regular insulin (30%) and isophanc insulin (70%): RAPIMIX, MIXTARD 40 U/ml inj. Human insulins In the 1980s, the human in ulin s ( ha ving the same am in o ac id sequence as human insulin) were produced by recomb ina nt DNA technology in Escherichia co/i- 'proinsulin recombinant bacterial' (prb) a nd in yeast- ' precursor yeast re combinant' (pyr), or by 'enzymati c modification o f porcine insulin ' (emp). I. 2. 3. 4. 5. 6. HUMA'\i ACTRAPID: Human regular insulin: 40 U1 ml, 100 U/ml, ACTRAPID IIM PENrIL 100 U/ml pen mj.• WOSU LI N-R 40 U/ml inj vial and JOO U/ ml pen injector canridge. HUMAN MONOTRAD. IIUMINSULIN-L: Human leme insulin; 40 U/ml, 100 Ulm!. IIUMA INSULATARD, IIUMINSULIN-N: Human 1mphane insulin 40 Ulm!. WOSULIN-"l 40 U/ml inj vial and 100 U/ml pen mjector canndgc. HU\,IA' ACTRAPHA E, II UM J. SULIN 30/70, II UMAN MIXTARD: lluman tol11hle insulin (30%) and iwphane insulin (70%), 40 U/ml. and 100 U/ml vials. WOSULIN 30nO: 40 U/ml vial and 100 U/ml cartridge. ACTRAPHANE HM PENFIL: Iluman soluble insulin 30% isophane insulin 70% 100 U/ml pen injector. INSUMA "I 50/ 50: Human soluble insulin 50% + i,uplwne insulin 50% 40 U/ml mj: II UMIJ\ SULIN 50:50. HUMAN MIXTARD 50: WOSuLIN 50/50 40 U/ml ,ial. 100 U/ml canndgc. In the USA pork and beef insulin s are no longer manufactured, but they a re still available in U.K., India and some European countries. In Britain now > 90% diabetics who use insulin IN SULIN, ORAL ANTI DIABETIC DRUGS AND GLUCAGON are taking human insulins or insuli n ana logues. In India a lso human insulins and analogues are commonly used, except for considerations of cost. Human insu lin is more water soluble as well as hydrophobic than porci ne or bovine insulin. It has a s lig ht ly more rapid s.c. absorption, earl ie r and more defined peak concen tration and slightl y shorter durati on of action. I luman insulin is a lso modi fied similarl y to produce isopha ne (NPll) and let11e prepara tions. Lente human insulin is no longer prepared in the USA. The allegation that human in, ulin produce; more l,ypog(1·cae111ic unawareness has not been substantiated. However, after prolonged treatment, irrespec1i,e of the type of insulin used, many diabetics develop relative hypoglycaemic unawareness/ change in hypoglycaemic symptoms, because of autonomic ncuropathy, changes in pcrception/a1111ude and other factors. Clinical superiority of human insulin over pork MC insulin has not been demonstrated. Though new patients may be started on human insulin,, the only indication for transfor from purified pork 10 human insulin is allergy to pork insulin. It is unwise lO transfer stabili7ed patients from one lo another species insulin without good reason. Insulin analogues Us ing recombinant DNA technology, ana logues of insulin have been prod uced which have modified p hannacok inetics on s.c. injectio n, but s imi lar p harmacodynamic effec ts and immunogenicity. Greater stability and consistency o f the preparations are the other advantages. Insulin lispro: Produced by reversi ng pro line and lysine at the carboxy term inus B 28 and B 29 posi tions, it fonns very weak hexamers that dissociate ra pidly after s.c. injecti on result ing in a quick and more de fined peak as well as sho rter duration of action. Individua l variability in absorption is minimized. Unlike regular insulin. it is best injected s.c. 0-20 min before a meal. A better control of meal-time glycaemia and a lower incide nce of la te post-prandia l hypoglycaem ia have been obtained. Usi ng a regimen of 2-3 dai ly meal-time insulin lispro injections, a slightl y greater reduction in HbA1c compared to regula r insulin has been reported. Fewer hypoglycaemic episodes occurred . HUM A LOG I00 U/ml, 3 ml cartndge. IO ml, ial. Insulin aspart: The proline at B 28 o f human insu lin is replaced by aspartic acid. T his change reduces the tendency for sel f-aggregation, and a time-action profi le s imilar to insulin lispro is obtained. It more closely mimics the physiological insu lin release pallern a fter a meal, with the same advantages as above. NOVOLOG, NOVORAPID 100 U/ml inj. Biphasic insulin aspart: The 70:30 mi xture of isopha ne complex or in sulin aspart w ith uneomplexed insulin aspart has the advantage of rapid a nd predictable onset a long w ith intermediate du ration of action. It is called 'biphasic insulin aspart', and can be injected twice dai ly j ust before each major meal. NOVO\IIX JO fLEXPEN 100 U/mL in J mL inj., also PENFIL injection. Insulin glu/tsine: Another rapidly actmg insulin analogue \\•ith lysine replacing asparaginc at B 23 and glutamie acid replacing lysine at O 29. Prop,:riie; and advantages are similar to insulin lispro. It has heen particularly used for continuous subcutaneous insulin infusion (CSII) by a pump. a!> Insulin glargine: This long-acting biosynth etic insulin has 2 additional arginine residues at the carboxy tem1inus of B cha in and glycine replaces asparagi ne at A 2 1. T his ana logue remains soluble at pH4 of the formulation. but precipitates a t neutral pH encountered o n s.e. injection. A depot is created from which monomeric insulin dissociates slowly to enter the circulation. Onset of action is delayed, but relatively low blood levels o f insu lin are main ta ined fo r upto 24 hours. A smooth 'peakless' effect is obtained. Thus, it is suitable fo r once da ily injection to provide background insulin action. Fasting and interdigestive blood glucose le vels are effective ly lowered irrespecti ve of time of the day when injected or the site of s.c. injection. It is mostly injected at bed time. Lower incidence o f night-time hypog lycaemic episodes compared to isophane insulin has been reported. However, it does not eono-o l meal-time g lycacm ia, for w h ich a rapid acting insuli n or an oral hypoglycaemic is used concurrently. Because of ac idic pH, it cannot be mixed with any other insulin preparation; must be injected separate ly. LANTUS OPTISET 100 U/ml in 5 ml vial and 3 ml prefilled pen injector. 287 288 HORMONES AN D RELATED DRUGS Insulin detemir Myristoyl (a fatty acid) radical is attached to the amino group of lysine at 829 of insulin chain. As a result, it binds to albumin after s.c. injection from which the free form becomes avai lab le slowly. A pattern of insulin action a lmost similar to that of insulin glargine is obtained, but twice daily dosing may be needed. LEVEM IR fLEXPEN 100 U/mL in 3 ml prefllled pen injector. Insulin degludec It is a new ultra long-acting ins ul in analogue with a flat p lasma glucose lowering effect lasting for ~ 40 hours, suitable for meeting basal ms11/i11 req11iremem in type I and type 2 diabetic patients. After single daily injection the day-to-day variability in response and risk of nocturnal hypoglycaemia are less than with insulin glargine. An alternate day regimen has also been tried, but may not be satisfactory. II has also been cofonnulated with rapid-acting insulin aspan. REACTIONS TO INSULIN 1. Hypoglycaemia This is the most frequent and potemially the most serious reaction. Hypog lycaem ic episodes are more common in patients of ' labile' di abetes in whom insulin requ irement fluctuates unpred ictably. Hypoglycaem ia can occur in any diabetic fo llowing inadvertent injection of large dose, by missing a meal after injection or by perfonning vigorous exercise. The symptoms can be divided into those due to counter-regulatory sympathetic stimul ation, viz. sweating, anx iety, palpitation, tremor; and those due to deprivation of the brain of its essential nutrient glucose (neuroglucopenic symptoms)dizziness, headache, behavioural changes, visual disturbances, hunger, fatigue, weakness, muscular incoordination and sometimes fall in BP. Generally, the reflex sympathetic symptoms occur, before the ne uroglucopenic, but the warn ing sympto ms of hypoglycaem ia d iffe r from patie nt to patient and a lso depend on the rate of fall in blood glucose level. Diabetic neuropathy can abolish the autonomic symptoms. Hypoglycaemic unawareness (loss of warning symptoms) tends to deve lop in patients who experience freque nt episodes of hypoglycaemia. Fina lly, when blood glucose fa ll further (to < 40 mg/ di) menta l confusion, abno rma l behaviour, se iz ures and coma occur. Irreversible neurological deficits are the sequelae of prolonged hypoglycaemia. Treatment Glucose (or g lucose yie lding carbohydrate, e.g. sugar) 15- 20 g orally reverses the symptoms rapidly in most cases. l f no improvement occurs, the sa me amount may be repeated after 15- 20 mi n. In severe cases 30- 50 ml of 50% glucose may be injected i.v. over 10 min. Glucagon 0.5- 1 mg i.v. or Adr 0.2 mg s.c. (less des irable) may be g iven as an expedient measure in patients who are not able to take s ugar orally and injectable glucose is not available. 2. Local reactions Swelling, crythema and stinging sometimes occur at the injected site, especially in the beginning. Lipodys1rophy o f the subcutaneous fat around the injection s ite occurred occasionally with the older pork/beef insulin preparations. This is rare with the newer preparations. 3. Allergy This is due to contaminating proteins, and is , ery rare with human/highly purified insulins. Un icaria, angioedema and anaphylaxis are the manifestations. 4. Edema Some patients develop shon-lived dependent edema (due to Na· retemion) when insulin therapy is staned. Drug interactions I. p adrenergic blockers prolong hypoglycaemia by inhibiting compensatory mechanisms o perating through p2 receptors (P 1 selective blockers are less liable). Warning signs of hypoglycaemia like palpitation, tremor and anxiety are masked. 2. Th iazides, furo se mid e , cort icostero id s, oral contracepti ves, salbutamol, ni fedi pine tend to raise blood sugar a nd red uce effectiveness of insulin. 3. Acute ingestion of a lcohol can precipitate hypoglycaemia by depleting hepatic glycogen. 4. Lithium, high dose aspi rin and theophyll ine may a lso accentuate hypoglycaemia by en hancing ins ulin secretion, as well as periphera l glucose uti lization. USES OF INSULIN Diabetes mellitus The purpose of therapy in diabetes mellitus is to restore metabolism to norma l, avoid symptoms due to hyperglycaemia and glucosuria, prevent short-term complications (infection, ketoacidosis, etc.) and long-term sequelae (cardiovascular, retinal. neurological, renal, etc.). 289 INSULIN, ORAL ANTI DIABETIC DRUGS AND GLU CAGO N The generally accepted criteria for adequate glycaemia control in an adult diabetic treated with insulin or oral antidiabetics are: • Fast ing (morning) blood glucose levels 90-130 mg/di • Blood glucose levels .:::150 mg/di 2 hours after meals • HbA1, levels < 7%. Insulin is effective in all forms of...
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