Characteristics of drugs (Part 2)
The movement of a drug through biological membranes depends on the particular coefficient.
It may be expressed as lipid/water partition coefficient (as the main component of biological membrane is lipid and water is in the extracellular and intracellular space), chloroform/water partition coefficient, or blood/gas partition coefficient (considering the movement of drug from the lungs to blood and vice versa)
Lipid/water partition coefficient
Lipid/water partition coefficient means the relative solubility of a drug in lipid as compared to water. It can be measured as the ratio of the concentration of drug in two immiscible phases: lipid representing the membrane and the water representing the plasma.
Lipid/water partition coefficient (K) can be expressed as:
K= CO/ CW
Where CO is the total concentration of drug (both ionized and nonionized forms) in organic phase and CW is the total concentration of drugs in aqueous phase; o stands for organic and w for water.
Urea has low lipid/water partition coefficient of 0.0016 (1:6250). Inorganic ions are not soluble in lipid, so their lipid/water partition coefficient can be considered as near zero. The higher the lipid/water partition coefficient, the higher is the affinity for the cell membrane and the more rapidly the drug crosses the membrane. There is a linear relationship of partition coefficient of drug and drug absorption.
Phenobarbitone has high lipid/water partition coefficient of 5.9.
Thiopentone sodium has a chloroform/water partition coefficient of about 100, so it is highly soluble in lipid. The relatively high lipid solubility of thiopentone mainly reflects the presence of S = C moiety.
Hexamethonium has chloroform/water partition coefficient of zero. This drug is used for the treatment of hypertension and is administered only by injection as because it is not absorbed from the gastrointestinal tract.
Lipid/water partition coefficient of a drug can be changed. When the polarity of a drug is increased either by increasing its degree of ionization or by adding a carboxyl (-COOH), amino (-NH,) or hydroxyl (-OH) group to the drug molecule, then lipid/water partition coefficient of that drug will be decreased. On the other hand, when the polarity of a drug is decreased either by decreasing its degree of ionization or by adding phenyl -or butyl- group, the lipid/water partition coefficient will be increased. The addition of 2-hydroxyl groups in estrone results in a 45-fold decrease in lipid/water partition coefficient, so there is decreased in coefficient of estriol when compared to estrone.
Blood/gas partition coefficient
Blood/gas partition coefficient indicates the relative solubility or affinity of an anesthetic for blood compared to air. Blood/gas partition coefficient for nitrous oxide, halothane, and methoxyflurane are 0.47, 2.3, and 12.0 respectively. The value for nitrous oxide is very low which means that 1 volume of nitrous oxide will be dissolved in blood for every 2 volume in the alveolus. Its low solubility in blood causes rapid equilibrium with the brain and faster induction of anesthesia. On the other hand, ether has a high blood/gas partition coefficient, which means that 12 volume of it will be dissolved in blood for every volume in the alveolus. The high solubility of ether within the blood makes the induction and emergence slow. Only 20% of the equilibrium concentration occurs even after 40 minutes.
A cool video on drug dissolution and disintegration!
Pharmaceutical companies dispense a drug in a variety of formulations suitable for a single or multiple routes of administration.
Some antibiotics are available in tablet, capsule or suspension form for oral administration. So, it is the doctor who has to choose the formulation suitable for the patient. It is important because it influences the bioavailability of drug. For example, digoxin when injected intravenously, the bioavailability of that drug is 1.00. But when the same amount of the drug is administered into the body by oral route in tablet form, the bioavailability is about 0.62. On the other hand, the bioavailability of digoxin elixir administered orally is 0.80.
When tablet form of a drug is swallowed, it is necessary to disintegrate as well as to dissolve before absorption. But in case of capsule, there is no question of disintegration. Only dissolution is necessary. In case of suspension, there is no disintegration or dissolution. So, the rate of absorption is greater from suspension than from capsule or tablet.
What is bioavailability? What do you mean by disintegration or dissolution? These will be discussed later.
All drugs are not soluble in water. For example, streptomycin is water soluble whereas diazepam is lipid soluble (not water soluble).
The nature of solubility of a drug can be changed by adding salt. Theophylline alone is insoluble in water. But when ethylenediamine hydrochloride is added to theophylline the mixture is known as aminophylline. Aminophylline is water soluble. Water solubility makes the aminophylline suitable for intravenous administration.
In addition to aminophylline, there are several salt preparations of theophylline (choline theophylline, theophylline glycinate). 80% of the total weight of aminophylline is theophylline whereas 45% of the total weight of theophylline sodium glycinate is theophylline.
Another example is morphine. Morphine sulfate is preferred to morphine as because it is much more water soluble.
Methyldopa is poorly soluble in water and can only be administered orally. On the other hand, methydopate is the ethyl ester of methyldopa and is available as the hydrochloride salt. Methyldopate hydrochloride is soluble in water and is suitable for intravenous administration.
The reason for solubility of salt in water is that salt is ionic compound and that is why it is soluble in water.
Erythromycin base has a bitter taste. This bitter taste can be overcome by using erythromycin ethyl succinate.
Affinity to bind...
Usually a drug has the affinity to bind with food particle, other drugs, plasma protein, erythrocyte, specific receptor or tissue. The binding of a drug with its specific receptor usually produces response whereas the binding with plasma protein or tissue does not produce any response, instead acts as a storage site.
Affinity to bind with food particle or other drugs
Some drugs such as tetracycline, iron, calcium, aluminum hydroxide bind with food particle or other drugs. This binding alters the absorption of drug from the gastrointestinal tract. Thus, the drug that is taken orally in empty stomach shows better absorption. However, the absorption of griseofulvin is better with fatty diet.
Affinity to bind with plasma protein
After entering into the systemic circulation, most drugs bind to plasma proteins, mainly albumin. Each albumin molecule has more than one site to which a drug may bind. At pH 7.4, albumin has negative charge and has high capacity but low affinity for binding cationic drugs. Molecules of one drug may bind to more than one site on each albumin molecule and the differentiate may not have the same affinity for the drug molecule. While considering the binding of drug to plasma proteins, it is found that acidic drug principally binds to albumin while basic drug binds to α1-acid glycoprotein.
The affinity of a drug for plasma proteins may be altered in disease condition such as chronic renal failure. In this condition, the accumulated compounds that are not significantly removed from the body by dialysis displace acidic drugs from the albumin binding sites.
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Affinity to bind with specific receptor
Many drugs have the affinity to bind with their specific receptors. When a drug [D] binds with receptor [R], drug-receptor complex [DR] is formed.
The rate at which a drug molecule combines with its specific receptor is the association constant k1. Similarly, the rate at which the drug-receptor complex splits apart is the dissociation constant k2. The tendency of a drug to form a complex with receptor and subsequently maintain it is the affinity. It can be quantitatively expressed as k1 / k2.
The affinity of a drug to different subtypes of receptor varies. For example, prazosin has 1,000-fold greater affinity to α1-adrenergic receptor than that to α2-adrenergic receptor. On the other hand, propranolol has equal affinity for both β1and β2-adrenergic receptors.
Affinity to bind with tissue
Drugs from the systemic circulation will be distributed and accumulated into some tissues. Presence of some drugs in some tissues are due to their affinity to bind with those tissues. For example, tetracyclines are accumulated in the bones, chloroquine is accumulated in the retina, etc.
A symptom or disease can be treated by more than one drugs and so it is necessary to consider which one is more potent. The potent drug acts at a lower concentration and the log dose-response curve is shifted to the left. Several drugs such as morphine, pethidine, butorphanol, hydromorphone and fentanyl are used to relieve pain. If we consider the unit of morphine is 1, then butorphanol is 5 times potent than morphine. That is to relieve pain 10 mg of morphine is usually administered. To get the same analgesic effect, 2 mg of butorphanol is used. Pethidine is 10 times less potent than morphine. Intravenous injection of either noradrenaline or angiotensin II causes an increase in both systolic and diastolic blood pressure. Angiotensin II is 40 times potent than noradrenaline.
Potency is a comparative rather than an absolute expression of drug activity. It is in no way related to its value, efficacy or safety. The least potent drug among agents with similar effects may be no less effective than the most potent one as long as each agent is employed in its appropriate dosage.
That's all for today!
To read more interesting articles on pharmacology go to our main page! But before doing that make sure you answer the following questions to test yourself! To answer some of the questions below, you might have to read the first part of this article!
1. What are the important characteristics of a drug?
2. How does molecular weight of a drug affect its absorption as well as excretion? Give example.
3. What is racemic mixture? Give example.
4. Why tetracycline hydrochloride is considered as superior to chlortetracycline?
5. Why is hexamethonium administered parenterally for the control of hypertension?
6. What are the differences between the acetylcholine chloride and the methacholine chloride?
7. Describe the influence of pH on degree of ionization.
8. Write down the pH of any 4 different body fluids. How does it affect the absorption of drug? Give an example.
9. Why the pharmaceutical companies prepare the drug in a variety of formulations?
10. What is the difference between the aminophylline and theophylline? Which one is administered intravenously and why?
11. What are the types of drug receptor agonists? Give example of each.
12. Name the drugs that have both agonist and antagonist activity.
13. How can you quantitatively express the term affinity?
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