Gastrointestinal agents

Gastrointestinal agents as per PCI syllabus for Diploma pharmacy PC-I subject

1. GASTROINTESTINAL A GENT By – Afroj shaikh . M.Pharm Institute of chemical technology

2. (GIT) consist of series of organs for the digestion of food; ingestion of food to the expulsion of waste as faeces. It starts from esophagus, oral or buccal cavity, stomach, the small intestines (consisting of duodenum, jejunum and ileum ) The large intestines (consisting of caecum, ascending, transverse and descending colons ) lastly rectum with exit anus. Each organ has definite functional role.

3. Gastro Intestinal (GI)Agents :- Drugs used in the treatment of GI disorders are known as GI Agents Classifications Acidifying Agents – Drugs which increase the gastric acidity are known as Acidifying Agents Eg : - Dil HCl 2 . Antacids – Drugs which neutralizes the excess of HCL secreted in the stomach. Eg :- Sodium Bicarbonate, Alumnium hydroxide gel, Calcium carbonate etc. 3. Protective & Adsorbents :- used in treatment of dirrhoae Eg :- Bismuth sub carbonate, Kaolin 4. Saline Cathartics :- are used to relieve constipation Sodium Potassium Tartrate , Magnesium Sulphate etc.

4. List Of GI disorders In event of impaired functions, the gastrointestinal ( GI) disturbances follows eg : A bsence or insufficient secretion of hydrochloric acid in stomach -leading to achlorhydria or hypochlorhydria . Excessive secretion of hydrochloric acid in stomach leading to hyperacidity, which causes ulcers inflammation Acute pain. Accumulation of toxins, gases, toxic substances etc; or insufficient absorption of fluids or electrolytes in the intestine stimulates intestine motility leading to diarrhea. Insufficient intestine motility leads to peristalsis leading to constipation.

5. Various inorganic GIT agents employed are:- Acidifiers or Acidifying Agents for acidity Antacids for hyperacidity Protectives for intestinal inflammation Adsorbents for intestinal toxins Cathartics for constipation .

6. Gastric acidifiers: Drugs uses to increase the acidity are known as Gastric acidifiers or acidifying agents. Some drugs are used to increase the Gastric HCl or some drugs to increase the metabolic acidosis. Eg :- HCl Normal HCL is secreted which helps in digestion of food & due to secretion of HCl the PH of stomach is acidic Stomach PH varies from 1 when stomach is empty & when food is ingested The gastric mucosa is made up with epithelial cells which secrets HCL & enzymes which are required for digestion. The HCL softens the fibrous food promotes formation of proteolytic enzyme pepsin from pepsinogen Kills the bacteria by food or drink.

7. Proteolytic activity of pepsin is based at PH 3-5. Due to some reason there is no secretion of HCl & it is called as Achlorhydria . Symptoms varies from patients to patients. 1)frequent bowel movement (mild diarrhea) 2) Epigastric pain.(upper middle portion of abdomen) 3) sensitivity to spicy food. two types of patients of Achlorhydria. Treatment :- counter effect the effect by using HCl .

8. Explain the term achlorhydria ? absence or insufficient secretion of hydrochloric acid in stomach -leading to achlorhydria Achlorhydria patients are of two kind 1 those who do not respond to histamine phosphate stimulation & remain free of gastric HCl . . 2.Those who respond to histamine phosphate stimulation for the release of HCl in the stomach. .

9. Monograph HCl DIL HCl used to treat achlorhydria Properties of HCl :- 1] It occurs as a colorless fuming liquid with pungent odour . 2] It is miscible with water, alcohol & has a specific gravity of 1.18 . Storage of HCl:- It is stored in glass-stoppered containers at a temperature not exceeding 30°C . Uses of HCl:- • Hydrochloric acid as such cannot be used as medicine . • The dilute hydrochloric acid is used as acidifying agent . • It is also used as a solvent in numerous industries . • Also used as laboratory reagent .

10. 2) ANTACID These are the agents that decrease gastric acidity by neutralizing HCL . Many used in the condition called hyperchlorhydria they give relief of pain due Hyperchlorhydria .(HCH) Effectiveness of antacids is measured in neutralizing capacity. In normal HCl is secreted by epithelial cell of gastric mucosa depending upon intake of food, The PH of stomach varies from 1-6 . Due to inflammation of gastric mucosa as in gastritis ,there results hypersecretionof HCL called as H.C.H . Prolong excessive secretion of HCl leads to peptic ulcer. Erosion of mucosal layer & various portion results in Esophageal ulcer, gastric ulcer, & duodenal ulcer.

11. Treatment:- Anticholergenic drugs, use of certain type of food, antacids 1)As antacids are alkaline in bases they neutralize the acidity occurred in H.C.H. 2) Production is continuous therefore use of antacid is required but antacid should act gradually without producing rebound acidity. 3) As antacids are used for longer periods they may produce side effects, 4) To produce good effects with lesser side effects should have following properties.

12. Ideal Characteristic of Antacid 1 . It should not be absorbable and cause systemic alkalosis 2. It should not be laxative or cause constipation 3. It should exert effect rapidly & over a long period of time 4. It should buffer in pH 4-6. 5. It should not produce large volume of gas 6. It should be palatable & inexpensive 7. It should probably inhibit pepsin

13. Antacids are of two types. l ) Systemic(absorbable) antacids: which are soluble readily absorbable and capable of producing systemic electrolytic alterations & alkalosis . E.g. sodium bicarbonate . 2) Non-systemic (non.absorbable) antacids :- which a not absorbed to a significant extent and thus do not exert an appreciable systemic effect.

14. This group is further sub-divided into following. Aluminum containing antacids : - e.g. aluminum hydroxide aluminum phosphate, dihydroxyaluminium, aminoacetate dihydroxyaluminium sodium carbonate, basic aluminium carbonate (gel). b ) Calcium containing antacids :- Eg. Calcium Carbonate tribasic calcium phosphate c) Magnesium containing antacids :-Eg . magnesium carbonate magnesium citrate, magnesium hydroxide, magnesium oxide magnesium phosphate , magnesium trisilicate

15. d) Combination antacid preparations :- e g Aluminum Hydroxide gel & Magnesium Hydroxide, Aluminum Hydroxide gel, Magnesium trisilicate , Magaldrate Simethicone (deforming agent) containing Antacids, Calcium carbonate containing antacid mixtures

16. Antacids :- SB, ALHG, ALP, CC, MG, MT , MO , COAP . A)SODIUM BICARBONATE. Chemical formula :-NaHCO 3 Mol wt :-84.01 Common name :-Baking Soda, Mitha Soda Synonym :-Sodium Hydrogen Carbonate . Preparation:- Industrial Scale:- prepared by Solvay process. Brine Sol ( NaCl ) is saturated with ammonia to remove impurities . Sol is filtered & passed through carbonating tower & allow to cool to enhance ppt. NaHCO 3 is less soluble in water below 15°C the ppt is filtered & dried

17. H 2 O + CO 2 H 2 C03 Water Carbonic acid NH3 + H 2 C03 NH 4 C03 Carbonic acid ammonium Carbonate NaCl + NH 4 C03 NaHCO3 + NH 4 Cl ammonium Carbonate Sodium biCarbonate

18. B) LAB SCALE :- prepared by passing through CO 2 gas through sol of NaOH . Sol is conc to obtain the product. 2NAOH + CO 2 Na 2 C03 + H 2 O 2Na 2 C03 + H 2 0 + CO 2 2NaHCO 3

19. Properties:- Colour:- White Nature:- Amorphus Taste:- Saline Solubility:- Soluble in water insoluble in alcohol. Incompatibility:- It inhibits the absorption of tetracycline from the gastrointestinal tract Storage: it should be stored in well-closed containers . USES:- Sodium bicarbonate was used as an antacid to reduce excessive acidity of gastric juice. sharp Increase in gastric pH 7 Neutralizes HCL but results in the production of CO 2 causing belching and flatulence, is not desirable .

20. 2 ) treatment of systemic acidosis. 3 ) It is used as electrolyte replenisher . 4 ) 5% solution of sodium bicarbonate is used as ear drops to an remove ear wax. 5) 3.5 % solution warm water is used as eye lotion. 6) Ingredients in Compound Sodium Bicarbonate . 7 ) It is also an ingredient in many effervescent antacid preparation. NOTE:-Cardio vascular patients or those on sodium restricted diet . advised to avoid this antacid . Usual dose :-300 mg to 2 g four times a day.

21. 2) ALUMINIUM Hydroxide Gel:-Al(OH) 3 Synonym:- Aluminium Hydroxide/Hydrate Powder Colour:- White Nature:- Amorphus Taste:- Tasteless Solubility:- Soluble in mineral acids insoluble in water alcohol Chemical:- When Heated To Redness (Ignited) it decomposes to water & Aluminium Oxide. Al(OH) 3 Al 2 O 3 +H 2 O It reacts readily with acids, such as HCl, forming water & aluminium salts. Al(OH) 3 + 3HCl AlCl 3 + 3H 2 O

22. Uses:- 1.As an Antacid( Above Reaction) Imp Note:-Acts as antacid not by neutralization but by physical adsorption of acid. When gel passes into the intestine the acid is released. 2. In treatment of Phosphate Urinary Calculi Al(OH)3 finally forms Aluminium phosphate in intestine, thereby reducing phosphate absorption. 3. Externally As mild astringent & desiccant. 4.Infrequently as protective in treatment of diarrhea & cholera. 5.Externally as dusting powder for desiccating foul wounds. 6. In Silicosis therapy, Given by inhalation.

23. Storage:- In Airtight container at temp not exceeding 25. °C but not to be freezed . Aqueous Suspension of Hydrated Aluminium containing aluminium carbonate and contains not less than 3.5% w/v and not more than 4,4% w/v of aluminium oxide (AI 2 3 ). sodium benzoate as preservative (antimicrobial agent), oil of Mentha as a flavoring agent and glycerin or sucrose as sweetening agent. Properties: White Viscous Suspension . Clear Liquids gets Separated when it is Kept Standing For some time.

24. Advantages 1)Non absorbale.no evolution of CO 2 2) This allows the gastric PH at just about the desires level. Disadvantage Loss of Antacid property on aging- Particularly with Dried Aluminium Hydroxide. 2) It also have adsorbent properties:-Caution should be exercised in co-administration with other drug simultaneously. Preparation:- A hot sol of potash alum is added slowly with constant stirring to a hot sol of sodium carbonate after complete removal of C02 , The precipitated aluminium hydroxide is filtered, washed thoroughly with hot water until it becomes free from sulphate ions . The precipitate may be suspended in the purified water to required strength of aluminium hydroxide gel.

25. Assay: - performed by gravimetric method as per IP. Procedure:- 1)Weigh about 5gm + add 10ml of HCL + 100ml water . 2)methyl orange is used as an indicator & sufficient amount of dil NH 3 sol is added to it. 3) End point:- distinct yellow color. 4) Heat to boil & filter wash with 2.5% w/w solution of ammonium nitrate until the ppt is free from Cl dry the ppt at 120°C & weigh it.

26. Aluminium Phosphate Synonym:- Dried Aluminium Phosphate Chemical formula :- AIPO 4 Physical properties Colour :- White Nature:- powder containing suitable freiable aggregate . Solubility:- Practically insoluble in water ethanol& Soluble in dil mineral acids. It also contain preservatives, flavoring & sweetening agent. Uses:- As an Antacid: on absorbable, useful where loss of phosphate may create problem to patient. ( Endogenous phosphates spared)

27. CALCIUM-CONTAINING ANTACIDS The calcium antacids are usually constipating & therefore supplied in combination with magnesium antacids. calcium carbonate & Tribasic calcium phosphate CALCIUM CARBONATE Chemical formula:- CaC03 Mol wt :- 100.09 Synonym:-Precipitated Chalk, Precipitated Calcium Carbonate . Preparation:- It is prepared by precipitation by mixing the boiling the solutions of Calcium chloride & sodium carbonate allowing the resulting precipitatio n subside on cooling . CaCl 2 + Na 2 C03 2NaCl + CaC03.

28. Chemical Properties Water Solubility increase in presence of CO 2 & ammonium salts due to formation of bicarbonate & free calcium ion respectively. CaCO 3 + H2CO 3 Ca(HCO 3 ) 2 CaCO 3 + 2NH4 Ca +2NH 3 + H 2 O + CO 2 Calcium Carbonate Neutralizes acid by effervescence . Physical Properties Colour :- White microcrystalline powder. Odour :- odourless , Nature:- Amorphus Taste:- tasteless Solubility:-insoluble in water alcohol .

29. USES:- As an Antacid. It neutralizes gastric acid& forms CaCl2 Which gets converted in calcium salt which is insoluble & tends to be constipating It is used as an dentifrice because of its mild abrasive action . Disadvantage: - The Ca 2 + ions can be either absorbed systemically or precipitated as calcium phosphate salt in the intestine or as insoluble calcium soaps (formed from the glycerides resulting from the hydrolysis of digested food containing oils and fats). Burnett syndrome (commonly known as milk-alkali syndrome), characterised by an acute alkalosis, hypercalcaemia , hyperphosphatemia, renal failure and azotemia. Though insoluble can cause systemic alkalosis .

30. This syndrome is often is misunderstood as hyperparathyroidism . On account of calcium's constipating effect, calcium antacids are preferred in combination with magnesium antacid which have cathartic action. However, they should not be used in patients with hypertension, renal insufficiency, a history of urinary calculi, gastrointestinal hemorrhage or dehydration an electrolyte imbalance due to excessive loss of fluids and electrolytes consequent to diarrhea, vomiting or aspiration of gastric contents Usual dose 1 g, 4 to 6 times a day . Usual dose range 1 to 10 g

31. M AGNESIUM CONTAINING ANTACIDS magnesium salts e.g. magnesium carbonate magnesium citrate, magnesium oxide, magnesium phosphate and magnesium trisilicate are common antacids. Magnesium antacids are practically insoluble in water, but dissolve slowly in acidic media due to neutralization reaction Except magnesium trisilicate, they all act in the same manner. Mg 2+ ion is not readily absorbed from GIT because its absorption is retarded by alkaline media, thus, magnesium salts absorption takes place only in the acid medium of the duodenum. Due to the slow absorption of Mg+ ions, a saline laxative action occurs Most of the magnesium is excreted in the faeces as Insoluble magnesium salt.

32. A small amount of Mg 2+ ions are also absorbed which are excreted by the kidneys. On account of this, magnesium salts are not to be used in patients with renal insufficiency because magnesium retention leading to magnesium poisoning may occur. Magnesium antacids are practically insoluble in water, but dissolve slowly in acidic media due to neutralization reaction.

33. Magnesium carbonate It is a hydrated basic magnesium carbonate of varying composition. It exists in two forms viz. Heavy Magnesium Carbonate , and Light Magnesium Carbonate . Physical Properties Colour :- Light, White, friable mass or as a bulky white Odour :- Odourless , Taste:- Tasteless Solubility :- Insoluble in water alcohol but dissolves in dilute acids with effervescence

34. Usual dose range:-500 mg to 2 g four times daily. USES:- As an antacid Abrasive in tooth powder Magnesium carbonate also finds its use as saline cathartic when given in adequate dosage (8 g). also used as an abrasive in some tooth powders, as a cosmetic and as an ingredient in silver polishes. Storage:- In air tight container.

35. MAGNESIUM OXIDE Chemical formula :- MgO Synonym:- Magnesia Mol Wt :- 40.30 Properties : Magnesium oxide Occur in two different varieties commonly known as " light" magnesium oxide and " heavy " magnesium oxide . On exposure to air, it absorb carbon dioxide and forms basic carbonates, also absorbs moisture. Light magnesium oxide hydrates more easily than heavy Mg(OH)2 oxide and will dissolve readily in water & is clearly alkaline & phenolpthalein.carbon dioxide or acid. MgO + 2H 2 0 Mg(OH) 2 + H 2

36. Magnesium hydroxide so formed goes into the sol & reacts gastric HCl Mg(OH)2 Mg2+ + 20H - 2H 3 + 4 H 2 Mg(OH)2 + 2HCI MgCl 2 + H20 Storage:- It should be stored in airtight containers . Uses :- low dose works as an antacid and higher dose laxative . Usual dose an Antacid 250 mg 4 times daily; Laxative: 4 g. Usual dose range 250 mg to 4g daily. A mixture of magnesium oxide, tannic acid & charcoal is well know as universal antidote.

37. MAGNESIUM TRISILICATE Chemical Formula:- ( 2Mg0. 3Si0 2.xH 2 O) or ( MgSiO 3 ) 2 SiO 2 .xH 2 O Mol wt : Anhydrous 260.86 Physical Properties:- Colour :- White Odour :- Odourless Taste :- Tasteless Solubility:-Insoluble in water alcohol but readily decomposed by mineral acids with HCL forms Magnesium Chloride & gelatinous trisilic acid Storage :- It should be stored in airtight containers.

38. Magnesium trisilicate when treated with acid E.g.. HCl 'decomposes to form and gelatinous trisilicic acid. (MgSIO 3 ) 2 SiO2 . XH 2 O + 4HCl 2MgCl 2 +2H 2 Si0 3 + SiO 2 + X H2O Colloidal mixture (gelatinous) In the stomach, a similar reaction takes place with HCl & gelatinous mass is formed with gastric content which also works as protective & adsorbent 2. The colloidal silicate protects the ulcer from further acid & peptic attack and possibly adsorbs the pepsin.

39. Usual dose 1 g 4 times a day. Usual dose range 1 to 16 g a day. Magnesium trisilicate powder is an emulsifying agent for mineral, vegetable and animal oils when used in proper proportions.

40. Importance of combination preparations of antacid- No single antacid meets all requirements for ideal antacid hence Antacids are used in combination. Antacids are used in combination for following reasons- To balance constipating effect of Aluminum and Calcium containing antacids with laxative effect of Magnesium containing antacids. 2. Some antacids gives rapid action but for short duration while some antacids gives delayed action but for longer duration. So to get quick and longer duration of action antacids are used in combinations. 3. Few combination antacids contain Simethicone, Dimethicone as they are Antiflatulents or antifoaming agents and reflux suppressants like alginic acid .

41. Examples of Combined Antacids- Combination of Aluminium hydroxide gel and Magnesium hydroxide 2. Combination of Aluminium hydroxide gel and Magnesium trisilicate 3. Combination of Aluminium hydroxide gel and Calcium carbonate 4. Combination of Aluminium hydroxide gel, Calcium carbonate and Magnesium hydroxide 5. Sodium bicarbonate and alginic acid 6 . Simethicone containing antacids 7. Magaldrate - Mg(OH)2 & Al(OH)3 8. Aluminum hydroxide gel & kaolin combination etc.

42. Protective & adsorbents Def :- Inert sub Treat mild Diarrhea dysentery, GI disturbance associated with indigestion. Adsorbs gases toxins, bacteria. Protective layers on painful ulcers. Dysentery: - Frequent elimination of watery fluid with or without mucus/blood Causes:-Infection ( Amoeba) Diarrhea:- Frequent elimination of intestinal contents in form of watery fluids .Electrolyte imbalance Causes. Improper digestion bacterial infection improper digestion of food bacterial toxins chemical or poisonous drug. Action:- Bacteria, bacterial toxins stimulate flow of electrolyte into intestine causing watery stools.

43. Protective & Adsorbents- Adsorb bacteria & Bacterial toxins . They are adsorbents insoluble salts. therefore forms protective coating on mucosal membrane & provide mechanical protection . Note:- Antibacterial drug should be taken along with P & A if diarrhea is due to bacterial infection. P & A do not have antibacterial activity.

44. Three different classes namely. 1)Bismuth salts or Bismuth Containing Product:-. Bismuth Subnitrate , Bismuth Sub carbonate Milk of Bismuth, Bismuth subgallate , Bismuth Subsalicylate, Bismuth Ammonium citrate. 2)Activated Clays and other Adsorbents e.g. Light Kaolin 3)Activated Charcoal.

45. Bismuth Containing Products Oral Administration of bismuth-containing ' results in black stool due to the action of intestinal hydrogen sulphide to bismuth sulphide . Bismuth compounds to their toxicity coupled with discovery & availability of newer & more effective drugs the been gradually withdrawn from the medicinal practice .

46. BISMUTH SUBCARBONATE Chemical formula Approx . ( BiO ) 2 CO 3 ) 2 . H 2 O Synonym :- Basic Bismuth Carbonate Properties Colour :- white or pale-yellow Odour :- odourless Taste:- tasteless powder Storage:-light or well-closed light resistant containers. Solubility:- It is practically insoluble in water and in alcohol but dissolves completely in HCl and nitric acid with effervescence and forms corresponding salts.

47. Uses:- as mild antacid , protective, mild astringent, dusting powder and antiseptic. i t was earlier used internally in gastric disorders , ulcers, diarrhea, dysentery, ulcerative colitis etc. as protective. It is still used as topical protective in lotion and ointments. Note:- On account of systemic toxicity & availability of safer drugs it is deleted from pharmacopoeia.

48. ACTIVATED CLAYS AND OTHER ADSORBENTS This group is mostly composed of clays which have excellent adsorbent properties and most of them are used for that purpose industrially as well. They appear to have a definite clinical use, at least in mild diarrhea of short duration. Light Kaolin Chemical formula Approx :. Al 2 3 .2SiO 2 ·2H 2 O Properties colour:-white yellowish-white powder Nature:- unctous to touch Odour:- Clay like odour Taste:- clay like earthy Solubility:-insoluble in water, Dil acids, or in alkali hydrooxide .

49. Chemically it is inert , since it is insoluble in all the common solvents. Uses:- Kaolin is used internally for its adsorptive properties as well as its ability to coat irritated intestinal mucosa. Used in diarrhea, enteritis, colitis & dysentery caused by food or alkaloidal poisoning It helps in by absorbing gases, toxins & bacteria . Usual dose:-15 to 17 g in three divided doses Infants:-1g one to three times daily Children:-(1-5years) 2g one to three times daily. Externally as dusting powder, adsorbent in ulcers .

50. Cathartics • Def:_Drug that brings about defecation & relieves a person from individual from constipation. Constipation:- Inability to defecate intestinal contents for a period Causes:- Weakness of intestine, intestinal spasm, injury, use of certain drugs, dietary habits, emotional factors, less water/ fluid intake Purgatives:- Also cathartics, act similarly but mild in action. Laxatives:- Mild type of Purgative

51. Define Cathartics.(1Marks) Classify with examples.(3Marks) Ans .Cathartics are the agents that quicken & increase evacuation from bowels & also drugs used to relieve constipation. Classification: The cathartics can be considered under the following class, 1 .Mild purgatives or laxatives : It helps to promote defaecation causing minimum adverse effects. Drugs included in this group are: a)Bulk –producing drugs: Which promote evacuation by increasing the stools bulk-volume & water contents e.g. Isapgol , agar-agar, methycellulose , bran, psyllum seed, sodium carboxymethylcellulose & karaya gum. b) Stool softners (Emollient): Which penetrate ,lubricate & soften the stool e.g. D- octyl sodium sulphosuccinate , liquid paraffin.

52. 2.Strong Purgatives: It cause complete evacuation of the bowel & the bowel become inactive . There are two kinds of strong purgatives: a) Irritant or stimulant purgatives e.g. Phenolphthalein, senna glycosides ,aloe, cascara sagrada , Rhubarb extract, Podophyllin , castor oil, bisacodyl . b) Saline cathartics/Purgatives ( osmatic laxatives) these are further sub classified as under: i ) Sodium-containing products e.g. Sodium biphosphate , sodium phosphate, potassium sodiumTartrate ii) Magnesium-containing product e.g. magnesium hydroxide, magnesium citrate, Magnesium sulphate iii) Sulphur as cathartic iv) Non official cathartics e.g. sodium sulphate , potassium phosphate, potassium bitartrate,calomel.

53. Properties & uses of magnesium sulphate:- Chemical Formula:- MgSO 4 .7H 2 O Synonyms:- Epsom Salt, Mag Sulph • Properties : • It occurs as colorless crystals, with cool, saline and bitter taste . • It is freely soluble in water , sparingly soluble in alcohol and dissolves slowly in glycerin. • Uses : • Magnesium sulphate is given orally in dilute solutions as a cathartic & parenterals as an anticonvulsant. Given as enema Used in cholecystitis Ingredient of Mineral water

54. SODIUM POTASSIUM TARTRATE Synonym:- Potassium Sodium tartrate , Rochelle Salt , Seignette's Salt . Properties:- white colorless nature:- crystalline powder, odour :- odourless , Taste:-cooling saline taste and Solubility:-. It is freely soluble in water and practically insoluble in alcohol. and sodium carbonates.

55. Uses:- 1.It is a saline purgative; depending upon dose, its action ranges from mild laxative to active hydragogue. 2. Ingredient of compound Effervescent powder. 3.The tartrate anion has very poor intestinal permeability and causes a watery evacuation of bowel after 1 to 2 hours without producing irritation. 4. Also used as food additive.