Incompatibilities in Pharmaceuticals

Therapeutic Incompatibilities

Therapeutic incompatibility refers to changes in responses or clinical effects of one or more drugs in a patient after administration.
- Can arise from drug-drug, drug-additive, or drug-food interactions.
- Also known as in-vivo incompatibility.
- More common with lipophilic drugs.
Pharmacological incompatibilities occur when a combination of substances leads to a decrease or loss of therapeutic effect or increases toxicity or adverse side effects.
- Pharmacological action can manifest as synergism or antagonism.
- Antagonism:
  - Lobelin and morphine: Lobelin excites respiratory centers, while morphine depresses them.
  - Strychnine and chloral hydrate: Strychnine excites the motor division of the nervous system, and chloral hydrate suppresses and paralyzes it.
  - $K^+$ and $Ca^{++}$ ions: $K^+$ ions inhibit cardiac activity, slow down glucose allocation by the kidneys, stimulate smooth muscle. $Ca^{++}$ ions increase cardiac activity, increase glucose secretion, and relax smooth muscle.
- Sinergoantagonism (Partial Antagonism):
  - Medicinal substances are synergistic in some effects and antagonistic in others.
  - Example: Streptomycin and ascorbic acid in treating acute pneumonia reduces antibiotic toxicity and improves X-ray, lab, and clinical parameters.
  - Similar results are seen when combining antituberculous medicines with pyridine-containing vitamins like nicotinic acid and pyridoxine.

Mechanisms of Therapeutic Incompatibility

Divided into two groups:
- Pharmacokinetics: The effect of a drug on another concerning absorption, distribution, metabolism, and excretion.
- Pharmacodynamics: Related to the pharmacological activity of interacting drugs, such as synergism, antagonism, altered cellular transport, or effects on the receptor site.
Pharmacokinetic Interactions:
- Altered GIT absorption
  - Altered pH
  - Altered bacterial flora
  - Formation of drug chelates or complexes
  - Drug-induced mucosal damage and altered GIT motility

Causes for Therapeutic Incompatibilities

Adverse reactions: Unwanted direct toxic effect.
Allergic reactions: Undesirable immune reaction.
Blood Dyscrasia: Drug-induced blood disorder.
Chemical carcinogenesis.
Chemical mutagenesis.
Contraindication.
Drug dependence (drug addiction).
Drug resistance.
Drug tolerance.
Extension effects.
Hyper-sensitivity.
Idiosyncrasy.

Types of Therapeutic Incompatibilities

(a) OVERDOSE
- Excessive single dose.
- Excessive daily dose: Dose and frequency must be checked by consulting physician.
- Synergism by drugs prescribed: E.g., Epinephrine and cocaine, Codeine and aspirin, Bromides and Barbiturates, Sulphonamides and penicillin.
- Cumulative effect: Overdoses of external medication may occur. E.g., Not more than 1% Phenol is used on the cutaneous membrane.
- Writing error: Misplacing of decimal point.
(b) UNDER DOSE
- Due to antagonistic combination: E.g., Stimulants and Sedatives (Depressants), Demulcent, and irritants.
- Prescription – Writing error: Misplacing of decimal point.
(c) PRESCRIPTION WRITING ERROR
- Wrong drug is prescribed: E.g., Mercuric chloride instead of Mercurious chloride, Barium sulfide instead of Barium sulfate.
(d) CONTRAINDICATED DRUGS
- Barbiturate, Morphine in Asthma: Extreme caution is necessary with severe respiratory depression and asthma exacerbation cases since morphine can further decrease the respiratory drive.
- Corticosteroids in peptic ulcers: Both gastric mucus production and gastric bicarbonate secretion are impaired by steroid administration, which results in a weakening of gastric mucosal defenses.
- Epinephrine in Hypertension: Through the direct action of epinephrine-greater probability of acute hypertensive crisis (dangerously high blood pressure), angina pectoris and myocardial infarction, as well as cardiac arrhythmias.
(e) ERROR OF DIAGNOSIS
- If a patient truly having a heart attack is told their pain is from acid indigestion.
(f) IMPROPER (OR) INCORRECT STORAGE
- Being exposed to extremes in temperature, humidity, smoke, fumes, pressure, or radiation due to a natural disaster, fire, accident, or equipment failure.
- CORRECTION: Consult the physician.

Incompatibilities of Medicinal Substances in Powders (Examples)

Analgin with Acetylsalicylic acid, sodium salicylate: Dampening.
Ascorbic acid with Hexamethylenetetramine, dimedrol, iron lactate, calcium gluconate, nicotinic acid, caffeine sodium benzoate, sodium bicarbonate, sodium nitrite, sodium phosphate, proserin: Dampening, yellowing.
Pancreatin with Oxidizers: Inactivation of pancreatin, oxidation, inactivation.
Atropine sulfate with Adsorbents (activated charcoal, clay minerals, vegetable powders, etc.): Adsorption.
Calcium gluconate with Ascorbic acid: Dampening.
Camphor with Anestesin, acetylsalicylic acid, menthol, sodium salicylate, sodium phosphate, resorcinol, phenyl salicylate, phenol: Creation of eutectics.
Iodine with Strong oxidizing agents: Decomposition; with Amidopyrin: Melting the mixture.
Novocain with Silver nitrate: Mutual decomposition.
Papaverine hydrochloride with Adsorbents: Adsorption.
Potassium acetate with Hexamethylenetetramine, acetylsalicylic acid: Dampening.
Potassium permanganate with Inorganic reducing agents (sodium thiosulfate, bivalent iron salts, sodium nitrate, iron recovered, sulfur, sulfides): Decomposition with explosion.
Salicylic acid with Antipyrine, bromcamphor, menthol, sodium salicylate, sodium tetraborate, sodium phosphate, pyrogalol, resorcinol, lead acetate, thymol, phenyl salicylate, phenol: Loss of fluidity.

Incompatibility of Vitamins

Vitamins exhibit high reactivity both with each other and with other medicines (pharmacological incompatibilities).
For fat-soluble vitamins, consider their light oxygen oxidation with oxygen.
Water-soluble vitamins:
- $B_1$ (thiamine chloride and bromide) are destroyed in alkalis and neutral solutions and inactivated under the influence of oxidizing agents and reducing agents.
- Riboflavin ( $B_2$ ) in a neutral medium is a weak oxidant and a potent reducing agent.
  - When heated solution of riboflavin (at pH 7.2-7.9) for an hour its activity decreases by 50 %.
  - It is the most stable in solutions at pH 5.0.
  - In aqueous solutions (especially in light) accelerates the oxidation of ascorbic and folic acid, thiamine.

Vitamins	Cause of incompatibility
$B_1$	$B<em>6$ , $B</em>{12}$ (when injected in one syringe) Decomposition of two vitamins; an increase in the allergenic effect of vitamin $b_1$
$B_2$	$B<em>{12}$ Destruction of vitamin $B</em>2$ by cobalt ions
$B_2$	$B_1$ Oxidation of thiamine
$B_6$	$B<em>{12}$ Destruction of vitamin $B</em>6$
$B_{12}$	E, $B_{15}$ (folic acid) Destruction due to pH difference
PP	$B_{12}$ Destruction of vitamin PP (vitamin B-3 include nicotinamide, nicotinic acid, and vitamin PP, because it prevents pellagra.)
С	$B<em>{12}$ , $B</em>{15}$ (folic acid), Е Destruction due to pH difference
Р	$B_{12}$ Destruction of vitamin P ( Flavonoids) by cobalt ions
А	D Mutual weakening of the action
D	Е Oxidation of vitamin E
А	К, Е, С, D Violation of the exchange of vitamins
$B_1$	РР, $B<em>6$ , $B</em>2$ , С Violation of the exchange of vitamins
С	РР, $B<em>2$ , $B</em>6$ , $B_{12}$ Inactivation of vitamin РР
$B<em>1$ , $B</em>2$ , , $B<em>5$ , $B</em>6$	Violation of the exchange of vitamins
$B_{12}$	$B<em>1$ , $B</em>2$ , $B_6$ , folic acid Violation of the exchange of vitamins

Common Incompatibilities

Acetate – with…
- Acids: Acetic Acid liberates.
- Ferric Salts: Red coloration.
- Quinine Sulphate: Quinine Acetate precipitates out.
- Spirit of Nitrous Ether: Effervescences due to ethyl nitrite.
Acids – with…
- Alkaline preparation
- Acacia Arabic: Acid liberate.
- Liq. Adrenaline: Adrenaline HCl ↑Oxidised.
- Hypo sulhitis: Sulphur liberates.
- Iodides: $I_2$ liberates.
- Glycosides: Glycosides ppt out.
- Salts of org. Acid: Benzoic acid or salicylic acid ppt out.

*List of Alkaline Preparations: Spt. Aromatic Ammonia – Ammoniate Tincture, Lime Water - Alkali substances

Alkaloidal – with salts
- Alkali: Result in the precipitation of Alkaloids
- Iodides and Bromides
- Tannic Acids
- Mercuric Chloride
- Meyer’s reagent
Alcohol – with
- Chloral Hydrate: Oily drops of Chloral alcoholate formed
- Acids: Esters and ethers formed
- Gums: Insoluble
- Oxidizing Agents: Aldehyde and acids formed
Alkalies – with
- Acidic preparation
- Alkaloidal Salts: Alkaloidal base - Precipitate out
- Iron salts – ppt out
- Fixed oil – soap formed
Alum – with
- Alcohol: Alum ppt out
- Pb. acetate: Lead sulfate ppt out
- Tartaric acid: Cream of tartar ppt out
- Tannic acid: precipitation
- Alkalies: Alum ppt out
Chlorates – with
- Reducing agent: Explosion
- HCl: $Cl_2$ - liberated
Aspirin – with
- Hexamine: Ppt formed
- Alkalies: Acetates and salicylate formed
- Water: Salicylic acid ppt out
- KI: $I_2$ liberated
- Quinine $SO_4$ : Salicylic acid ppt out
- Morphine and codeine: Poisonous compound formed
Digitalis – with
- Iron: Black color
- Cinchona preparation: Tannin ppt out
- Pb acetate: Lead tannate ppt out
Ferrous salts – with
- Alkalies: Ppt out
- Potassium chlorate: Chlorine liberates
- Tannic acid: Blue- black ppt out
Ferric salts – with
- Gum: precipitation
- Acetate: blood red coloration
- Phenol: Violet color
- Adrenaline: oxidation
- Alkalies: oxidation
- Benzoates: Buff colored ppt
- KI: $I_2$ liberaed
- Tannin: Black iron tannate
- Essential oils: Change in color
- Salicylate: Purple ferric salicylate ppt
Bismuth salicylate- with
- Carbonate: effervescence
- Ferric salt: Violet coloration
Bismuth subnitrate- with
- Carbonate effervescence
- Glycerin: Nitroglycerin produced
Caffeine citrate- with
- Benzoates: Benzoic acid precipitates
  - Salicylates: Salcylic acid precipitates
- KI: $I_2$ liberated
Camphor – with
- Chloral hydrate: Liquefaction (Eutectic)
- Menthol
- Phenol
- Thymol
- Salol
Borax - with
- Acacia: coagulation
- Acids: Boric acid precipitates
- Alkaloids: Alkaline base precipitates
- Alum: Pasty mass formed
- $HgCl_2$ : Red HgO formed
- $ZnSO<em>4$ : $ZnBO</em>3$ precipitates
Benzoates - with
- Mineral acid: Benzoic acid precipitates out
- Alkaloids: Alkaline base precipitates
- Caffeine citrate: Benzoic acid precipitates out
- Ferric salt: Red ferric benzoates precipitates
- Salt of Pb, Hg, Ag: precipitation

Responsibility of a Pharmacist and Ways to Complete Incompatibilities in Prescriptions

A medicine in which physical or chemical changes are possible cannot be released (USP Pharmacists’ Pharmacopeia 2008).
When preparing medicines, a pharmacist should apply all necessary measures to prevent or eliminate ingredient incompatibility.
For a qualitative solution, a pharmacist must constantly study reference literature and manufacturers' information on the properties of medicines to predict possible interactions.
There is no universal way to overcome incompatibilities in medicines; a pharmacist can find ways to solve the problem based on knowledge of the components' physical and chemical properties. For example:
- Drying of crystalline hydrates is recommended for preparing powders to remove crystalline water.
- Fractional mixing is recommended to reduce contact between ingredients in dosage forms.
- Introduction of auxiliary substances - moisture regulators is recommended for the adsorption of moisture in mixtures where chemical interaction of the components is possible. The quantity and type of regulator are selected experimentally, considering ingredient compatibility.
  *To overcome incompatibilities, the following methods can also be used, but such changes should be necessarily agreed with the doctor who prescribed the prescription.
- Replacement of medicinal substances and change of solvent. Reasonable is the replacement of the following substances: potassium bromide – sodium bromide, codeine – codeine phosphate, sodium caffeine benzoate – caffeine, sodium tetraborate – boric acid, euphylline – theophylline. If medicinal substances are insoluble in the prescribed solvents, partial or total replacement of the solvent is possible
- Replacement of the dosage form. A mixture of camphor with phenyl salicylate or chloral hydrate is not compatible in powders, but are compatible in the pills and in the liquid form – dental drops.
- Isolation of one of the components of the medicine. In the implementation of this method, it is prohibited to release poisonous, narcotic and strong effective medicinal substances out of the composition of the medicine. Isolation of one of the components of the prescription is also recommended when combined in one form of alkaloids, enzymes, antibiotics, glycosides or other medicinal substances with adsorbents. If it is necessary to introduce a form-forming component, then another filler, for example, sugar, sodium bicarbonate, is used. In each of the last three cases, you need to get a new prescription from a doctor.