Physicochemical Parameters That Influence The Drug Action
The ability of a chemical compound to show a pharmacologic /therapeutic effect is related to the influence of its various physical and chemical. Physical-chemical properties is alternative QSAR methods quantitative structure-activity relationships (QSARs) are derived with biological potency as dependent and physicochemical parameters as independent. These characterize hydrophobic, electronic and steric properties of drugs and are usually applied to characterize variations of substituents. It also refer to both physical and chemical properties of the drug molecule that may have an effect on its biological activity, partition coefficient, degree of ionization, surface activity, isosterism, intermolecular forces, oxidation-reduction potentials, interatomic distances between functional groups, stereochemistry. Drug molecules should have the required physicochemical properties to be accessible to active sites to have favorable drug. receptor interaction.
Physicochemical properties of drug is a key physicochemical property that plays a crucial role in determining ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the overall suitability of drug candidates. There is increasing evidence to suggest that control of physicochemical properties such as lipophilicity, within a defined optimal range, can improve compound quality and the likelihood of therapeutic success. If an organic drug molecule dissolves fully or partially in a nonaqueous or lipid solvent, the molecule is said to be lipophilic or to have lipophilic character.
If a compound is too lipophilic, it may be insoluble in aqueous media (e. g. gastrointestinal fluid or blood(, bind too strongly to plasma proteins and therefore the free blood concentration will be too low to produce the desired effect, distribute into lipid bilayersand be unable to reach the inside of the cell(can go to the other lipophilic sites in the body).
Haloperidol is an example of first generation typical antipsychotic used in the treatment of schizophrenia and Tourette syndrome. One of the tricks for sneaking a neurological drug past the blood-brain barrier is to make the molecule lipophilic. Although a greasy compound might slip into the brain easily, it can be tough to get a therapeutic amount of the drug to dissolve in the blood. Consequently, such drugs often are administered in high doses.
Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) for the short-term treatment of pain and fever in animals. In the United States and United Kingdom it is no longer approved for human use (except for ankylosing spondylitis, because no other treatment is available), as it can cause severe adverse effects such as suppression of white blood cell production and aplastic anemia. It is rapidly and completely absorbed from the GI tract or the rectum. More than 98% of the drug is bound to plasma proteins. In humans, phenylbutazone undergoes extensive biotransformation. Hydroxylation of the phenyl rings or the butyl side chain and glucuronidation are the most significant primary reactions. Active metabolites with long plasma half-lives are formed.
Ceftriaxone is, sold under the trade name Rocephin, is an antibiotic useful for the treatment of a number of bacterial infections. This includes middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle. Rapidly and completely absorbed following intramuscular administration Losartan, sold under the trade name Cozaar among others, is a medication mainly used to treat high blood pressure. Other uses include for diabetic kidney disease, heart failure, and left ventricular enlargement. is well absorbed following oral administration and undergoes significant first-pass metabolism to produce the 5-carboxylic acid metabolite, designated as EXP3174 Statins are a class of drugs often prescribed by doctors to help lower cholesterol levels in the blood. By lowering the levels, they help prevent heart attacks and stroks. Steric effect is the influence of the spatial configuration of reacting substances upon the rate, nature, and extent of reaction. The sizes and shapes of atoms and molecules, the electrical charge distribution, and the geometry of bond angles influence the courses of chemical reactions.
Bulky (large) substituent may shield and hinder the ideal interaction between drug and receptor alternatively may help to orientate a drug for maximum receptor binding, increasing activity. The word steric is derived from ‘stereos’ meaning space. Steric effect essentially arises because of the fact that each atom of molecule occupies some space. If two atoms are brought closer than their vanderwaal’s radii, their electron clouds repel each other. Thus such process in energetically unfavourable.
Electronics effects
The methyl group and, more generally all alkyl groups, are the only substituents acting by an inductive electron-donating effect. All the other groups are electron donors by mesomeric effects This means that the methyl and the alkyls are electron donors in any environment while a basic group, dimethylaminoethyl for example, will be a mesomeric donor in basic or neutral medium but will become strongly electron attracting by protonation in gastric medium (pH 2). The terms "resonance" and "induction" refer to the electronic effects that atoms or functional groups may have within a compound.
Inductive effect
The inductive effect affects the stability as well as acidity or basicity of a chemical species. Electronegative atoms draw electrons toward themselves, which can stabilize a conjugate base. Groups that have -I effect on a molecule decrease its electron density, making the molecule electron deficient and more acidic. Induction or the inductive effect of an atom or functional group is
- Function of that groups
- Electronegativity
- Bonding order and charge.
Resonance
Resonance may be defined as bonding or sharing of electrons between more than two atoms Typical covalent and ionic bonding involves sharing (covalent) or transferring (ionic) electron pairs between two atoms as shown in the examples of ethane and sodium chloride below. In these examples the bonding electrons are localized: Lipophilic drugs Acidic Basic. Greater water solubility can also result from a decrease of the crystal lattice energy, the methyl groups hindering the various intermolecular interactions (hydrogen bonds dipole-dipole bonds ).
In the antibacterial sulfonamide series, the substitution of the pyrimidine ring of sulfadiazine by one, then two, methyl groups causes an increase in solubility one would expect why the methyl substituted derivatives are less soluble. This for the double reason that they show increased lipophilicity and that they are less dissociated than the parent molecule. Indeed the inductive character of the methyl groups disfavors ionization and the non- ionized form of a molecule is always less soluble than the corresponding ionized form. Despite this unfavorable electronic effect, sulfamidine is approximately five times more soluble than sulfadiazine In conclusion, there are a lots of Physicochemical parameters that influence the drug action like lipophilicity, steric, electronic and crystal lattice cohesion and every property has its one effect in drug action either in passage in BBB or ability to absorbed and degree of ionization.
Knowledge of the physicochemical properties of potential chemical alternatives is a requirement of the alternatives assessment process for two reasons. First, the inherent hazard of a chemical, such as its capacity to interfere with normal biological processes, and its physical hazards and environmental fate (degradation, persistence) are determined by its intrinsic physicochemical properties and the system with which it is interacting. For organic and inorganic chemicals, these intrinsic properties are determined by molecular structure, while for materials, they are determined by composition, size, structure, and morphology. Second, physicochemical properties can be used to eliminate from consideration chemicals that are likely to exhibit particular physical or toxicological hazards. As important as these data are, obtaining them is relatively fast and inexpensive, and can be readily done at the initial stages of the alternatives assessment.
In summary, Structure Activity Relationship (SAR) is an approach attempts to identify the physio-chemical properties of a drug and to see whether any of these properties has an effect on the drug’s biological activity.
A lipophilic (hydrophobic) group consisting of a long carbon chain which has little affinity for aqueous solvents, only dissolve in oil-based substances, molecules are suitable for passive diffusion in cellular activities.
A hydrophilic (or lipophobic) group consisting of polar group such as COOH, OH, …which has high affinity for polar solvents, molecules get absorbed or dissolved in water, require facilitated diffusion.
The steric effect arises from the fact that the atoms composing molecules occupy some degree of space, and when atoms come too close together there is a rise in the energy of the molecule due to the atoms being forced to occupy the same physical space.
The electronic effects of various substituents affect drug’s ionization or polarity which may affect the easily passage through cell membranes. Or the strong interaction with the binding site.
