Introductory question
How much active ingredient is in a 10 mg cetirizine tablet?
- (a) 5 mg
- B) 7.5 mg
- C) 10 mg
The correct answer is a.
Image and mirror image
Many active pharmaceutical ingredients exist as racemates. They consist of two molecules that behave like an image and mirror image of each other. These are referred to as enantiomers. Enantiomers are characterized by the fact that they cannot be made to coincide. They resemble a pair of gloves – the left glove does not fit on the right hand. These properties are called chirality (“handedness”). Most of these molecules contain a chiral carbon atom. It is called chiral if it carries four different substituents. Depending on the configuration, a distinction is made between the and -enantiomer. Sulfur (S), phosphorus (P), and nitrogen (N) atoms can also be chiral (e.g., omeprazole, cyclophosphamide, methaqualone).
Biological activity
The prerequisite for a drug to have an effect is usually that the drug interacts with a molecular structure, called a drug target. For example, it must insert itself into the binding site of a receptor. The three-dimensional structure of the active ingredient and that of the binding site must fit together. Since the structures of the two enantiomers differ, under certain circumstances only one active ingredient can interact with the drug target – the other does not bind and therefore does not trigger a pharmacological effect. This is because chiral drugs encounter a chiral environment in the body. In practice, various scenarios exist:
- Both enantiomers are active
- Only one enantiomer is active
- One enantiomer is weaker active
- One enantiomer mediates undesirable effects
- Both enantiomers have a different effect (e.g., nebivolol, sotalol)
The active agent is referred to as , the inactive or weaker-acting is referred to as . However, the differences affect not only pharmacodynamics, but also pharmacokinetics (ADME), for example, metabolism and elimination.
Enantiomerically pure active ingredients
A distomer represents unnecessary ballast in a drug. Therefore, drugs are being developed that contain only the eutomer. For example, levocetirizine (Xyzal) is the active -enantiomer of cetirizine (Zyrtec). Both drugs are commercially available. Enantiomerically pure active ingredients are also marketed because the eutomer is patentable. This allows the patent protection of a drug to be extended.
Dose aspects
A film-coated tablet containing the racemate cetirizine contains 10 mg of active ingredient – whereas one containing the eutomer contains only 5 mg. This is logical, since there is 5 mg of “ballast” in the racemate. Both tablets therefore contain the same amount of levocetirizine (5 mg). The calculation is not always so simple, because a conversion from one enantiomer to the other can take place in the body. This has been described, for example, for ibuprofen and other NSAIDs as well as for thalidomide. This is called a chiral inversion. It can be uni- and bidirectional.
Examples
The following list shows some examples of active ingredients that exist as racemates. The eutomers, which are marketed, are indicated with an arrow:
- Alfuzosin
- Amlodipine
- Amphetamine dexamphetamine
- Atenolol
- Bupropion
- Cetirizine Levocetirizine
- Chloroquine
- Citalopram Escitalopram
- Donepezil
- Dopamine levodopa
- Doxylamine
- Ibuprofen dexibuprofen
- Indapamide
- Ketamine esketamine
- Ketoprofen Dexketoprofen
- Lorazepam
- Mefloquine
- Methadone levomethadone
- Metoprolol
- Nebivolol
- Omeprazole esomeprazole
- Oxazepam
- Pantoprazole
- Propranolol
- Salbutamol levosalbutamol
- Tramadol
- Verapamil
- Warfarin
- Zopiclon Eszopiclon
