Every drugs has unique characteristics
The pharmacokinetic and pharmacodynamic parameters of each drug is unique. One drug may be well absorbed, another drug may be partially absorbed, and some drugs are not absorbed at all. One drug may produce a response, whereas another drug does not. These variations are due to particular features such as: molecular weight and size, stereoisomer, structure-activity relationship, ionization constant, partition coefficient, dosage form, salt preparation, affinity to bind with plasma proteins, receptors, and potency.
In this article, we will discuss the first four characteristics:
- Molecular weight and size
- Structure-activity relationship
- Ionization constant
Molecular weight and size
Molecular weight of a drug is one of the factors responsible to penetrate the biological barrier.
The majority of drugs have molecular weight with 100 to 1000. The drug with relatively low molecular weight (between 100 to 150) crosses through very small pores of epithelial lining of the body surface, cornea, gut and urinary bladder very easily. For example, ethanol (46) or nitrous oxide (44) can easily pass through the epithelial surface.
Insulin (about 5,800), dextran (40,000), and steroids are the examples of high molecular weight substances and these drugs can not easily pass through the epithelial lining. The drugs with molecular weight less than 600 enters from the mother's blood to fetal circulation via placenta.
Most of the drug molecules are of small size (5-10 Å long). The change in the size of drug particle (griseofulvin, digoxin, phenacetin) influences its absorption from the gastrointestinal tract. For example, micro-sized griseofulvin is absorbed twice as well as the normal particle. In addition, ultramicrosized particle is absorbed twice as well as the micro-sized particle. In general, the smaller the particle size of the drug, the greater is the absorption. Another drug tolbutamide can be formulated with a particle size that dissolves slowly, thus the gradual release of the drug in the gut is maintained for a longer period.
Many synthetically manufactured compounds exist in different stereoisomeric forms. Geometric (or cis/trans) isomers and diastereoisomers are both chemically and pharmacologically distinct. They are readily separable and are treated as different compounds in drug development program.
Mirror image enantiomers [(+) or (-) form], in contrast, differ only physically in their optical properties (rotation) and, except in a biological system (or chiral environment) in which only one of the enantiomers is recognized, which is chemically identical to the biological system. Until recently, it was impractical to separate optical enantiomers on a commercial scale. Such compounds were consequently developed for therapeutic uses as 1:1 racemates without studying or characterizing the properties of each enantiomer, even though it was recognized that the two quantities might have different pharmacokinetic properties and qualitatively or quantitatively different pharmacological or toxicological effects.
In instances in which two components of a racemate have been studied separately, differences in pharmacokinetic and pharmacodynamic properties have frequently been found. Differences in therapeutic effects are unpredictable. Sometimes they are negligible; isometric one of the enantiomers is biologically inactive (as in case with propranolol); sometimes two have different pharmacological properties [(+) sotalol is anti-dysarrythmic, while (-) sotalol is a beta-adrenoceptor antagonist]; and most importantly in a clinical context, one enantiomer may be toxic within therapeutic dosage range (as in the case of thaliodamide, levamisole, and carnitine). The (-) adrenaline possess greater potency than the (+) form of adrenaline. The structure is the same but the only difference is at the location of OH group at beta carbon position. The OH of (-) adrenaline lying downwards interacts with receptor site of the enzyme and as a result this stereoisomeric form is more potent (10 times) than the (+) form of the drug. Chloramphenicol - possessing 2 asymmetric carbon atoms - has 4 stereoisomers but only the D(-) threochloramphenicol has antibacterial activity.
The (+) amphetamine is 3 to 4 times more potent than the (-) form in excitation of the CNS. The (-) dobutamine is a potent agonist of the alpha-adrenoceptor. On the other hand, (+) dobutamine is a potent alpha 1-adrenoceptor antagonist that blocks the effect of (-) dobutamine.
Estrogenic activity; 10 times more active than cis form
( - )
( - )
( + )
( - )
The study of the variation of drug effects in relation to its chemical structure is termed structure-activity relationship. The new drug thus produced has the advantages over the previous ones in various aspects of pharmacokinetic and pharmacodynamic.
The absorption of a drug can be altered by changing the structure of that drug molecule. For example, only 30% of chlortetracycline is absorbed from the gastrointestinal tract. But catalytic removal of chlorine from chlortetracycline gives tetracycline, about 60-80 % of which is absorbed after oral administration.
The structure of a drug molecule influences its biotransformation caused by enzymes. For example, acetylcholine is rapidly metabolized by an enzyme cholinesterase. An addition of a methyl group to the carbon adjacent to the ester oxygen (in case of methacholine) causes hydrolysis at a considerably slower rate. The substitution of an amine group at the terminal of acetylcholine (in case of carbachol) makes the drug resistant to hydrolysis by cholinesterase.
Catechol-O-methyl transferase (COMT) is specific for catechol ring. The sympathomimetic drug will not be metabolized by COMT if the drug is devoid of hydroxy group at either 3 or 4 position of the benzene ring (eg, ephedrine, amphetamine). So half life of the drug will be longer. The effectiveness and duration of action are enhanced. The presence of a methyl group at the alpha carbon of the side chain reduces metabolism of sympathomimetic drug by monoamine oxidase (MAO).
Directly or indirectly acting nature of a sympathomimetic drug on adrenoceptor depends on the structure of drug molecule. The substitution at the 3 and 4 positions of the benzene ring by hydroxy or methoxy (-OCH3) group and a hydroxy group at the beta-carbon group causes the drug to act directly on adrenergic receptors. Adrenaline is a directly acting sympathomimetic drug. Drugs that have only one substitution or no substitution at these positions will be indirectly acting drugs. Amphetamine is an example of the latter group.
Most of the chemically important beta-adrenergic receptor antagonists have an oxymethylene bridge (O-CH) between the aromatic nucleus and the ethanolamine side chain. This oxymethylene bridge attached to the benzene ring converts the drug into an antagonist.
pH of Body Fluids:
6.20 - 7.20
7.30 - 7.35
5.00 - 7.00
7.35 - 7.45
1.00 - 3.00
4.00 - 6.80
4.60 - 8.00
3.40 - 4.20
Ionization constant (pKa)
Most of the drugs are organic compounds. Unlike inorganic compounds the organic drugs are not completely ionized in fluid. These are weak acids or bases. For example, hydrochloric acid is a strong acid as because it is completely dissociated into hydrogen ion (H+) and chloride ion (CL+)
H+ + Cl- ↔ HCL (a strong acid)
Whereas a fraction of an acidic drug is present in undissociated form (HA) and ionized form (both A- and H+)
HA ↔ H+ + A- (H+ is the cation and A- is the anion)
B + H+ ↔ BH+ (B is the nonionized base)
Here ↔ arrow indicates reversibility of the process.
The acidic drugs are ampicillin, disodium cromoglycate, frusemide, phenobarbitone, and sulfonamides. The basic drugs are allopurinol, amphetamine, chlorpromazine, imipramine, morphine, and propranolol. Ethanol is an example of a neutral drug. The extent to which a drug molecule in solution behaves as an acid or base depends not only on its own nature, but also on the local hydrogen ion concentration.
The concentration of hydrogen ion in different body fluids varies. For example, the pH of plasma ranges from 7.35 to 7.45. But the fluid in gastrointestinal tract have a wider range of pH. Within the stomach it is from 1.0 to 3.0. The pH of the intestinal fluid is alkaline. On the other hand, the pH of urine is in between 4.6 to 8. It can be readily appreciated that the degree of ionization of a given compound may vary considerably at different biologic barriers or at a particular barrier under different conditions of pH.
The Ka of a molecule is a measure of its strength as an acid. The pKa is the negative logarithm of the Ka (just like pH). The pKa of a drug is the pH at which the concentration of ionized and nonionized forms are equal. The word a of pKa comes from the term acid. Here, the law of mass action can be applicable and it should be possible to change the fraction of ionized or nonionized materials present in solution by changing the hydrogen ion concentration. According to the law of mass action, when a chemical reaction reaches equilibrium at a constant temperature, the product of the active masses on one side of the chemical equation, when divided by the product of the active masses on the other side of the equation, is a
constant regardless of the amount of each substance present at the beginning of
the action. Thus for an acid:
[ H+ ] X [ A ] / [ HA ] = K, a dissociation constant; where [ ] stands for concentration
For a base:
[ BH- ] / [ B ] X [ H+ ] = a constant
The Henderson-Hasselbalch equation stated for acidic drug:
log HA / A = log [ Non-ionized form ] / [ Anionic form ] = pKa - pH
From the above equation, the following form may be used:
pKa - pH = log [ Non-ionized form ] / [ Anionic form ]
Multiplying both sides by -1, we get:
-pKa + pH = -log [ Non-ionized form ] / [ Anionic form ]
pH = pKa + log [ Anionic form ] / [ Non-ionized form ]
pH = pKa + log [ A- ] / [ HA ]
When [ A- ]= [ HA ], then pH = pKa
For a weak base,
pH = pKa + log [ B ] / [ BH+ ]
Thus, the higher the pH (i.e.more alkaline solution) the higher is the ionization, and conversely, the higher the pKa the lower is the tendency to ionize. We can easily calculate the proportion of nonionized molecule by the pH value of the medium and pKa of the drug. Now the question is how will you calculate the percentage of nonionized and ionized fraction of drug when the pKa of a drug and pH of the surrounding fluid are known.
lonization of an acidic or basic drug can be calculated using the following formula:
% Ionized drug = 100 / 1 + 10 (pKa - pH) (for an acidic drug)
% Ionized drug = 100 / 1 + 10 (pH - pKa) (for a basic drug)
lonization constant affects the extent of absorption, excretion, and nature of distribution. For example, ephedrine has a pKa value of 9.6. ln gastric pH, most of ephidrine is in ionized form. So, the extent of absorption from the stomach is negligible. On the other hand, the amount of non-ionized form of aspirin (pKa is 3.5) is increased and readily absorbed from the stomach. The percentage of non-ionized form of aspirin is decreased with increasing the pH of surrounding fluid. Streptomycin is fully ionized and is not absorbed from the gastrointestinal tract.
pKa of some Acidic drugs:
pKa of some Basic drugs:
More Characteristics of Drugs
The second article in this series will discuss the remaining characteristics of drugs, including partition coefficient, dosage form, salt preparation, affinity to bind with plasma proteins, receptors, and potency: Characteristics of Drugs: Part 2
© 2013 Oyon B