Inorganic Substances as Pharmaceuticals and Medicinal Agents

Inorganic Substances as Pharmaceuticals and Medicinal Agents

Introduction

• Many pharmaceutical agents are organic compounds.
• Inorganic compounds also play important roles as therapeutics.
• They act as:
  • Body electrolytes
  • Antimicrobials
  • Gastrointestinal agents
  • Anticancer
  • Antiviral, etc.

Examples of Inorganic Compounds Used as Drugs and Diagnostic Agents (Table 1)

• The table lists various elements and compounds with their uses.
• Some examples include:
  • Silver sulphadiazine: Antibacterial
  • $Al(OH)_3$: Antacid
  • Salvarsan, Melarsen, Tryparsamide: Antimicrobial
  • Gold(I) thiolates, Auranofin, Gold(I) diphosphine complexes: Antitumour, Antiarthritic, Antiviral
  • Barium sulphate: X-ray contrast
  • Bismuth subsalicylate, colloidal bismuth citrate, ranitidine bismuth citrate: Antacid, antiulcer
  • Sodium bromide: Sedative
  • Chromium complexes: Antidiabetic
  • Copper histidine complex: Supplement for Menkes Disease treatment
  • Coenzyme B₁₂: Supplement
  • Sodium nitroprusside: Vasodilator
  • Fe(III) desferrioxamine chelates: Antimicrobial
  • Gd metallotexaphyrins: MRI contrast agent
  • Mercurochrome: Antiseptic
  • Sodium Hypochlorite: Antiseptic
  • Lutetium complexes: PDT
  • MgO: Antacid, laxative
  • Mn-SOD complexes: Superoxide scavengers
  • Gadolinium: MRI contrast agent
  • Cisplatin, carboplatin: Anticancer
  • Ru(III) complexes: Anticancer
  • Pentostam, N-methylglucamine antimonate: Antileishmanial
  • AL(OH)Si: Antidiarrhoeal
  • Tin(IV) ethyl etiopurpurin: PDT
  • $^{99}Tc(V)$ propyleneamine oxime: Diagnostic imaging
  • Titanocene dichloride, bis(β-diketonato) Ti(IV): Anticancer
  • bis(maltolato) oxovanadium(IV): Antidiabetic
  • bis(glycinato) oxovanadium (IV): Anti-HIV activity
  • bis(methylpicolinato oxovanadium (IV)
  • Polyoxometallates: Skin ointment
  • ZnO: Antiviral
  • Zn(II)bicyclam complexes: Supplement
  • Zinc citrate: Antiperspirant
  • Zn(IV) glycinato
  • Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one): Synthetic antioxidant
  • Phenylaminoalkyl selenide (4-hydroxy-α-methyl-phenyl-2-aminoethyl selenide): Anti-inflammatory neuroprotective agent
  • Selenazofurin: Antihypertensive
  • Selenotifen: Anti-allergic agent

Inorganic Ions as Body Electrolytes

• Electrolytes are compounds that produce ions.
• They play significant roles in the body by maintaining osmotic pressure in the cells.
• Approximately 60% of a typical male's body weight is water.
• Total body fluid is divided into:
  • Intracellular fluid: ~40% of body weight (total space within cells).
  • Extracellular fluid: ~20% of body weight.
• Extracellular spaces generally contain high concentrations of sodium, chloride, bicarbonate, and proteins, but are relatively lower in potassium, magnesium, and phosphate.

Body Fluid Distribution

• For a typical male weighing 70kg:
  • Intracellular Fluid: 28 L
  • Extracellular Fluid: 12 L

Ions Used in Replacement Therapy

• Chloride ion ($Cl^−$):
  • Major extracellular anion of the body fluid.
  • Responsible for maintaining osmotic balance with sodium.
• Sodium ion ($Na^+$):
  • Predominant cation in the extracellular fluid compartment.
  • Used as NaCl in the maintenance of isotonic solutions.
• Bicarbonate ion ($HCO_3^−$):
  • Second most predominant anion in the extracellular fluid compartment.
  • Serves as the body’s most important buffer.
• Phosphate ion ($PO_4^{2-}$
  • Main anion of the intracellular fluid compartment.
  • Many drugs in which the anion is the active ion are administered as phosphate salts.
• Potassium ion ($K^+$):
  • Cation present in the intracellular fluid.
  • Essential for growth, normal cell metabolism, and cardiac function.
  • Used as KCl.
• Calcium ion ($Ca^{2+}$):
  • Useful for normal muscle and nerve function.
  • Essential to blood clotting.
  • Used as calcium chloride for electrolyte replacement.
• Magnesium ion ($Mg^{2+}$):
  • Second most predominant intracellular cation.
  • Replaced through the use of magnesium chloride.

Fluid and Electrolyte Replenishers

• Multi-component solutions used to replenish fluids and electrolytes:
  • Darrow’s solution (Lactated potassium saline injection): Contains KCl (2.6g), NaCl (4.0g), and Sodium lactate ($NaC<em>3H</em>5O<em>3$) (5.9g) in 1 L of $H</em>2O$ for injection.
  • Ringer’s injection: NaCl (8.6g), KCl (0.3g), $CaCl<em>2 "." 2H</em>2O$ (0.33g) in 1 L of $H_2O$ for injection.
  • Lactated Ringer’s injection: NaCl (3.0g), Sodium lactate (3.1g), KCl (0.3g), $CaCl<em>2 "." 2H</em>2O$ (0.2g) in 1 L of water for injection.
  • Hartmann’s solution for injection (intravenous infusion): NaCl (6.0g), KCl (0.4g), $CaCl<em>2 "." 2H</em>2O$ (0.27g), lactic acid (2.4mL), NaOH (1.15g), and dilute HCl in 1 L of water for injection.

Oral Rehydration Therapy (ORT)

• ORT: Simple treatment for acute diarrhea-related dehydration.
• Contains a solution of salt and sugar (glucose, sucrose, citrates, or molasses).
• Example: WHO/UNICEF glucose-based oral rehydration therapy contains NaCl, anhydrous glucose, KCl, and Trisodium citrate dihydrate.

Electrolytes in Acid-Base Correction Therapy

• Normal function of physiological processes depends on maintaining appropriate acid-base balance.
• pH deviations can negatively affect pH-dependent enzymes, membrane transport proteins, and metabolic pathways.
  • Acidemia: Arterial pH lower than 7.35; causes disturbances including arterial vasodilation, insulin resistance, compromised immune function, and reduced neuronal excitability.
  • Alkalemia: Arterial pH greater than 7.45; causes disturbances including reduced myocardial blood flow and seizures.
• Maintaining controlled blood pH is crucial.

Examples of Electrolytes Used in Acid-Base Correction Therapy

• Infusion of sodium carbonate ($Na<em>2CO</em>3$) into cholera patients to compensate for loss of serum alkali in diarrhea. Also a component of buffers used as tablets or injections to combat hyperacidity and systemic acidosis.
• Sodium acetate
• Ammonium chloride: Used in the maintenance of acid-base equilibrium of the body.
• Sodium citrate: Used in chronic acidosis and as an anticoagulant for whole blood and in chelating serum calcium.
• Potassium citrate: Used as an alkalizer.
• Potassium bicarbonate (potassium hydrogen trioxocarbonate(IV))

Inorganic Compounds as Gastrointestinal Agents

• Gastrointestinal drugs can be classified into:
  • Products that alter gastric pH
  • Antacids
  • Adsorbents
  • Laxatives or Cathartics

Products Altering Gastric pH

• In cases of lack of hydrochloric acid in gastric secretion, the following can be given:
  • Glutamic acid hydrochloride
  • Glycine hydrochloride

Antacids

• Antacids are alkaline bases used to neutralize excess gastric hydrochloric acid, which may lead to ulcers. They also act as protectives for intestinal inflammation.
• Properties of antacids:
  • Should not be absorbable or cause systemic alkalosis.
  • Should not cause constipation or act as laxatives.
  • Should exert their effect rapidly and over a long period of time.
  • Should buffer in the pH 4-6 range.
• A combination of antacids is usually employed, as no single antacid satisfies all criteria.

Examples of Antacids

• Sodium bicarbonate BP:
  • Can cause systemic alkalosis due to its continued neutralizing effect.
• Aluminium salts:
  • Examples: \Al(OH)3 BP, Aluminium phosphate $(AlPO</em>4)$, aluminium glycinate.
  • Slow-acting antacids used in the treatment of peptic ulcers.
• Calcium salts:
  • Examples: $CaCO<em>3$ (Calcium trioxocarbonate (IV)), $Ca</em>3(PO<em>3)</em>2$ [Calcium tetraoxophosphate (V)].
  • Non-systemic antacids.
• Magnesium compounds:
  • Examples: magnesium carbonate BP, magnesium phosphate USP, Magnesium trisilicate BP, magnesium tetraoxophosphate (V).
• Bismuth salts:
  • Example: Bismuth subcarbonate $(Bi<em>2O</em>2(CO_3)$

Adsorbents for Intestinal Toxins

• Examples:
  • Kaolin (hydrated aluminium silicate powder) and activated charcoal.
  • Activated attapulgite BP $[Mg<em>5(SiO</em>{20})(OH)<em>2 "." 8H</em>2O]$
  • Bismuth subcarbonate, bismuth subgallate, and bismuth subnitrate.
• In acute diarrhea caused by bacterial toxins, chemical poisons, drugs, allergies, or disease, these adsorbents protect by adsorbing toxins or bacteria and providing a protective coating to the intestinal mucosa.

Laxatives or Cathartics

• Laxatives quicken and increase evacuation from the bowels, especially in cases of constipation.
• Examples of inorganic laxatives:
  • Saline laxatives: sodium sulphate BP ($Na<em>2SO</em>4$, also known as Glauber’s salt), Sodium hydrogen phosphate, potassium sodium tartrate USP, magnesium citrate USP, magnesium sulphate BP (Epsom salt, $MgSO_4$).

Inorganic Compounds as Pharmaceutical Aids

• Pharmaceutical aids are excipients and other substances required in the formulation of drugs into various dosage forms to provide suitable physical properties or to alter flavor/odor characteristics.

Examples of Pharmaceutical Aids

i. Solvents

• Water acts as a solvent for a wide variety of substances.
  • Types of water for pharmaceutical use:
    • Potable water
    • Purified water (soluble salts removed by distillation or deionization)
    • Water for injection

ii. Acids, Bases, and Buffers

• Acids:
  • HCl is used in pharmaceutical neutralization.
  • Many nitrogen-containing drugs are formulated as hydrochlorides to enhance aqueous solubility.
  • Boric acid is used in topical medications to maintain acidic pH.
• Bases:
  • Examples include sodium bicarbonate, NaOH, Sodium carbonate, KOH, $NH<em>4OH$, and $Ca(OH)</em>2$
• Buffers:
  • Used to maintain the pH of formulations to ensure chemical stability and solubility of a drug as well as patient comfort.
  • Examples: phosphate buffers and borate buffers (borates are not used in injectables due to their poisonous nature).

iii. Clarifiers and Filter Aids

• Clarifiers are added to remove unwanted solid particles such as suspensions.
• Purified talc and activated charcoal are used as filter aids and clarifiers.
• Activated charcoal BP is used for the adsorption of colored and odorous substances, acids, bases, and neutral salts.

IV. Suspending, Thickening, and Emulsifying Agents

• Bentonite (Hydrated aluminium silicate): Used as a thickening, suspending, gelling, and emulsifying agent. Used in calamine lotion.
• Aluminium magnesium silicate BP and aluminium glycinate BP: Used as suspending and thickening agents due to their good adsorbent and absorbent properties. Also used as emulsion stabilizers in pharmaceutical preparations for internal and external use.

V. Tablet Aids

• Include binders, diluents, disintegrants, and lubricants.
• Calcium sulphate BP (calcium tetraoxosulphate (VI)) and silicon (IV) oxide are used as tablet diluents.
• Calcium stearate, zinc stearate, magnesium stearate, aluminium monostearate, and purified talc are used as lubricants. They are non-toxic and have a greasy feel.

VI. Antioxidants

• Prevent oxidative decomposition of compounds (e.g., pharmaceutically active components).
• Antioxidants and their reaction products must be physiologically harmless.
• Examples:
  • Sulphur (IV) oxide: used in injectable preparations at concentrations as low as 0.1-1.0 %w/v.
  • Sodium hydrogen trioxosulphate (IV) (0.1%w/v sodium metasulphide BP): used in solutions of drugs containing phenolic or catechol nuclei to prevent their oxidation to quinones and similar substances (e.g., epinephrine, norepinephrine, ascorbic acid injection, penicillin suspension).
  • Thiosulphates and hypophosphorous acid and its salts: used as antioxidants in HI and FeI syrups, preventing the formation of iodine or oxidation of Fe(II) to Fe(III).
  • Nitrogen and sodium nitrite are also used as antioxidants.

VII. Glass

• Used in the storage and dispensing of most drug products.
• Four types of glass:
  • Highly resistant borosilicate glass
  • Treated soda-lime glass
  • Ordinary soda-lime glass
  • General-purpose soda-lime glass
• Amber-colored glasses are recommended for protection from light for light-sensitive products.

Inorganic Compounds as Topical Agents

• Substances used on the body surface.

Classes of Topical Agents

Protective Agents

• Applied to the skin to protect certain areas from irritation.
• Usually insoluble and chemically inert to limit absorption and interaction with tissues.
• Examples: talc, ZnO, calamine BP ($ZnCO<em>3$ with a small proportion of $Fe</em>2O_3$), simethicone (antifoaming agent used in ointments and creams as a water repellent and protective against irritation).

Antimicrobial and Astringent Compounds

• Antimicrobial substances may be antiseptic or germicidal agents that destroy or inhibit the growth of pathogenic microorganisms on living tissue.
• Examples: silver nitrate ($AgNO<em>3$), hydrogen peroxide ($H</em>2O<em>2$), and potassium tetraoxomanganate (VII) ($KMnO</em>4$).
• Other examples of disinfectants: sodium hypochlorite (NaOCl), halazone, and chloramine-T.
• Common household bleaching agent: 4.5%w/v solution of sodium hypochlorite (Dakin’s solution).
• Chloramine-T, dichloramine-T, and halazone are used as disinfectants and in the purification of water supplies; they slowly hydrolyze to release hypochlorous acid in water.

Classification of Antimicrobials Based on Mode of Action

Oxidizing Antimicrobials

• Examples: $H<em>2O</em>2$, metal peroxides (Na, Ba, and Zn peroxides).
• Liberate oxygen when in contact with tissue, mechanically cleansing wounds by dislodging fixed bacteria.
• Antibacterial action of permanganates depends on their ability to oxidize protein or other biogenetic substances.
• $KMnO_4$ is usually applied to the skin as a neutral aqueous solution.
• Antibacterial properties of some oxo-halogen anions (e.g., sodium and calcium hypochlorites) are due partly to the liberation of chlorine, which has an oxidizing action.

Protein-Precipitant Antimicrobials

• Interaction of proteins with metallic ions (Cu, Ag, Al) leads to protein precipitation.
• Soluble silver salts, such as silver nitrate (0.5-1.0%w/v) aqueous solution, are used for wet dressing on burned areas.
• Antimicrobial action of silver salt is based on the complex interaction between silver nitrate and protein in the wound tissue to form a heavy precipitate.
• Astringents are substances that, in very dilute solutions, provide a local surface protein-precipitant action on tissues, resulting in the formation of a superficial layer when applied to damaged skin or mucous membrane.

Uses of Astringents

• To stop bleeding from cuts by promoting coagulation of blood and constricting small capillaries.
• Restrict the supply of blood to the surfaces of mucous membranes to reduce inflammation.
• Remove unwanted tissue by direct action on the skin.
• Examples: salts of aluminum (aluminium chloride, aluminium sulphate, aluminium acetate, aluminium subacetate), copper sulphate USP ($CuSO<em>4 "." 5H</em>2O$), lead subacetate, zirconium carbonate, etc.

Other Dermatological Agents

• Sodium thiosulphate BP ($Na<em>2S</em>2O<em>3$), selenium sulphide BP ($SeS</em>2$).
• Used as antiparasitic agents (in scabies), as antifungal and as keratolytic agents.
• $Na<em>2S</em>2O_3$ is used topically to prevent ringworm.
• CdS (cadmium sulphide) and $SeS_2$ are used in the treatment of dandruff.

Inorganic Compounds in Dentistry

• Most toothpastes contain fluoride to combat the acidity of the oral cavity and prevent dental caries (tooth decay).
• Excessive fluoride can cause streaks on teeth and is poisonous when swallowed repeatedly.
• Used as components of dentifrices.
• Examples: insoluble sodium metaphosphate ($NaPO<em>3$), calcium hydrogen phosphate ($CaHPO</em>4$), calcium carbonate.
• Sensodyne for sensitive teeth contains sodium fluoride and 5% potassium nitrate to relieve painful sensitivity.
• These are called desensitizing agents. Other examples are potassium citrate, which blocks the mechanism of pain transmission between nerves.
• Plaque and tartar toothpastes contain tetrasodium pyrophosphate as an anti-tartar agent.
• Plaque hardens into tartar over time.

Inorganic Compounds in Complexation and Chelation

• The most stable complex ions are formed by the cations of the transition elements, particularly those of group VIII (e.g., Fe, Co, and Ni).
• Also, Group 1B (e.g., Cu and Ag), 2B (e.g., Zn, Cd, and Hg), 3A (e.g. Al), 6B (e.g. Cr) and 7B (e.g. Mn).
• They form complexes with molecular ligands involving the elements of group 5A (e.g., N), 6A (e.g., O and S).
• Coordination number: the maximum number of ligands that a metal ion can accommodate.
• Ligands can be unidentate, bidentate, or polydentate.

Types of Ligands

• Unidentate ligand: has only one non-bonded pair of electrons to donate to the metal ion (e.g., $NH<em>3, H</em>2O$).
• Bidentate ligands: can donate two non-bonded pairs of electrons (e.g., ethylenediamine $H<em>2NCH</em>2CH<em>2NH</em>2$).
• Polydentate ligands: form a ring structure when complexed with a metal ion; the ring structure is called a chelate, and the ligand used in the formation of the chelate is called a chelating agent (e.g., Ethylenediaminetetraacetic acid (EDTA)).

Application of Complexation and Chelation in Pharmacy

i. Qualitative Analysis

• Some metals form water-soluble chelates, which is utilized in the volumetric determination of such metals and their salts.
• EDTA is used as the disodium salt and forms complexes with many divalent and trivalent cations ($Ca^{2+}$, $Mg^{2+}$, $Zn^{2+}$, and $Fe^{3+}$).
• These metal salts can be determined quantitatively by complexometric titration using disodium edetate.
• EDTA can also be used to determine the hardness of water.

ii. Treatment of Heavy Metal Poisoning

• Some chelating agents selectively form soluble chelates with metal ions such as arsenic, copper, gold, iron, lead, mercury, and other heavy metals and promote the excretion of the metals from the body in a relatively non-toxic form.
• Examples:
  • EDTA forms complexes with calcium and helps lower blood calcium in hypercalcaemia.
  • Dimercaprol BP is used as an effective neutralizing agent for As, AU, Pb, and Hg and is used in the treatment of heavy metal poisoning.

iii. Promoting Urinary Excretion of Excess Copper

• D-penicillamine is used in promoting urinary excretion of excess copper since it is able to form stable complexes with copper and other metals such as Au, Fe, Pb and Hg.

Assignment

• Describe the application of inorganic compounds as the following:
  • Diagnostic agents
  • Emetics
  • Diuretics
  • Expectorants
  • Artificial atmosphere
• Give at least two examples of inorganic compounds used in each case.