Clinical Drug Development

Pharmacology is the science of drugs. In the broad sense, it deals with the interaction of exogenously administered chemical molecules with living systems.

Drug therapy is a dynamic process. When a Drug product is administered, absorption usually proceeds over a finite time interval and distribution, metabolism and excretion of drug and its metabolite proceed conitusily at various rates. The relative rate of these ADME process determine the time course of the drug in the body most importantly at the receptor  sites that are responsible for the pharmacological action of drug .

The usual aim of the drug is to achieve and maintain effective concentrations of the drug at the receptor site .However the body is constantly trying to eliminate the drug and therefore it is necessary to  balance absorption against elimination to maintain the desired concentration. Often a receptor site is tucked away in the specific organ or tissue of the body, such as a central nervous system, and it is necessary to depend on the blood supply to distribute the drug from the site of administration, such as gastrointestinal tract, to the site of action.

For many drugs the locations for receptor site are unknown. Fortunately, body compartments are connected by the blood system , and distribution of dugs among the compartments usually occur much more rapidly than absorption and elimination of the drug .The net result is that the body behaves as a single homogenous compartment to many drugs , and the concentration of drugs in the blood directly reflects or is proportional to the concentration of the drug in all organs and tissues , Thus it may never be possible to isolate the receptor site and determine the concentration of the drug around it , but the concentration at the receptor site usually can be controlled if the blood concentration can be controlled

The objective of pharmacokinetics is to describe the time course of drug concentration in blood in mathematical terms so that

  1. The performance of pharmaceutical dosage forms can be evaluated in terms of rate and amount of drug they deliver to the blood
  1. The dosage regime of a drug can be adjusted to produce and maintain therapeutically effective blood concentrations with little or no toxicity

The elimination of drug from the body is written as:

[Drug in body]+ [Enzymes; membranes; PH; protein binding; etc] — metabolized or excreted drug.

AGONISTS:

A particularly important group of drug receptors consists of protein that normally serves as receptors for endogenously regulatory ligands (e.g., the hormones and neurotransmitters).Many drugs act on such physiological receptors and often are particularly selective because physiological receptors are speaclised to recognize and respond to individual signaling molecules with great selectivity. Drugs that bind to physiological receptors and mimic the regulatory effects, but their binding blocks the binding of the endogenously agonist.

ANTAGONIST:

When one drug decreses or inhibits the action of the another , they are said to be antagonist .Usually in an antagonist pair one drug is inactive as such but decrsees the effect of the another Depending of the antagonist involved , it may be classified as Physical : charcoal absorbs alkaloid and can prevent their absorption .  , chemical: drugs may react when mixed in the same syringe or infusion bottle .physiological/ functional: the two drugs act on different receptors or by different mechanism but have opposite overt effect on the same physiological function. In   short, such compounds with no stimulatory action of their own that still may produce useful effects by inhibiting the action of an agonist (egg. By competition for agonists binding sites) are termed antagonists. Agents that are only partly as effective as agonists, no matter the amount employed are termed as antagonist’s .Agents

That are only partly as effective as agonists no matter the amount employed are termed partial agonists, and those which stabilize the receptor in its inactive conformation are termed inverse antagonists.

RECEPTOR PHARMACOLOGY:

Receptor occupancy theory, in which it is assumed that response emanates from a receptor occupied be a drug, has its basis in the law of mass action, with modifying constant added to accommodate experimental findings.

Receptor theory was originated by Clark, who was first to apply mathematical rigor to the notions of drug action.Consedring the roles of the receptors in mediating the action of regulatory ligands acting on the cell , it is not surprising , that alteration in  receptors  and their immediate signaling effectors can be cause of disease. The loss of receptor, in a highly specialized signaling system may cause a relatively limited, if dramatic phenotypic disorder such as genetic deficiency disorder of the androgen receptor in the testicular feminization syndrome .Deficiencies in more widely used signaling system have a brooder effects, as are seen in myastina gravis, and some form of insulin resistant diabetes mellitus., which result from autoimmune depletion of nicotinic cholinergic receptors or insulin receptors.

PHARMACO-DYNAMICS:

Pharmacodynamics is the study of drug effects, and the attempt to elucidate the complete action – effect sequence and the dose effect relation. Modification of the effects of one drug by another drug and by other factors is also part and parcel of pharmacodynamics.

The basic types of drug action can be broadly classified as

Stimulation

Depression

Irritation

Replacement

Cytotoxic action

FACTORS MODYFING DRUG ACTION:

  1. Age
  2. Body size
  3. Sex
  4. Species and race
  5. Genetics
  6. Route and administration
  7. Environmental factors and time of administration
  8. Pathological States
  9. Psychological factor

 

Absorption is the movement of drug from its site of administration into the Circulation .Not only the fraction of the administered dose that gets absorbed , but also the rate of absorption is important .Expect when given iv, the drug has to cross biological membranes; absorption is governed by the above desired principles. Other factors affecting absorption are:  Aqueous solubility, Concentration, Area of absorbing Surface.

Blood flow of the area ,  Like increased  blood flows  hastens drug absorption  just as wind  hastens drying of clothes , and yes , of course another factor to draw your  attention is  Route of administration. Drugs are most often introduced into the body by the oral route of administration. In fact, the vast majority of drug dosage, forms is designed for oral ingestion, primarily for ease of administration. It should be recognized, however that this route may result in insufficient and erratic drug therapy.

DRUG METABOLISUM:

The ability of humans to metabolize and clear drugs is a natural process that involves the same  enzymatic pathways and transport systems that are utilized for normal metabolism of dietary constituents .Humans come into contact with scores of xenobiotics (substances foreign to the body ) through the exposure to environmental contaminants as well as in our diets .Fortunately , humans have developed a means to readily eliminate xenobiotic in the diet is from plants that have many structurally diverse chemicals , some of which are associated with  pigment production and others are actually toxins  called phytoallexins that protect plants against  predators. A common example is poisonous mushrooms that may have many toxins that are lethal to mammals, including amanitin, gyromitrin, and many more. Animals must be able to metabolize and eliminate in order to consume vegetation.Whille humans can now choose their dietary source, a typical animal does not have its luxury and as a result is subject to its environment and the vegetation that exist in that environment .Thus the ability to metabolize unusual chemicals in plants and other food sources is critical for survival.

Drugs are considered xenobiotic and most are extensively metabolized in humans. It is worth nothing that many drugs are derived from chemicals found in plants some of which had been used in Chinese’s herbal medicines for thousands of years.

Medicinal chemistry:

It is chemistry based and most important disciple.  There are various aspects of it.

Drugs are good, bad or ugly. Ultimate goal is the compound is biological active. Nonselective is bad drug and half life is less than 5 min, and of course expensive to make.

Acidity and basicity:

It is measured by pka .this is the ability of a group to dissociate. Acidity and basicity is important for all absorption and for binding for salt bridges.

TOLISS FREE:

Prof  Hay toliss, a German chemist , 60 years before developed and idea , he took the compound and noted its activity , and took its analogue and noted its activity that we could predict what he was going to have next. He devised this cascade; an aromatic ring or benzene ring with a proton on each position, and then a compound will have a certain activity. Make a compound with chorine in 4 positions. Measure the activity, if still more active, make a compound with 2 chlorine, if still more active change the positions of cl or o .So toliss work is based on a actual measurement of the relative lipocidity and acidity of the functional group . In short found most active compound.

BIOISOTERES:

So when placing chlorine by sulphur or vise versa or any compound to see which is highly reactive is called bioisoteres. It is of 2 types. Template and pharmacorphoric.

The latter group changing will have same biological or pharmacological properties. whereas as template as same type of size or oreitation.Replacing H with F is very interesting . F single have no much effect. “NITRO GROUP” is usually bad drug in compound. Has very significallty effect upon electrostatic group. They are generally toxic too.

Lipinski rule:

Worked in a pharmaceutical industry, not very late, just 15 years back, looked at oral drugs for disease… came up with some rules in which 90 percetage drugs fitted in it , with aspect to functional group , molecular weight and lipophilicity .lipophitcity means  how much it is in   octanol and water .

Value normal is 0 – 4.5. In actual between 0 to 3.

Molecular weight 200 -500.

Hydrogen bonding donated H can be bond to receptor site.

Hydrogen accepted.

We wish to have rigid molecule not a floppy one.

POTENCY:

Electrostatic profile is accountable.  .Potency is more properly related to the concentration of the drug in plasma to approximate more closely the situation in isolated systems in vitro. However if drug is to be administered by transdermal absorption, a highly potent drug is required because the capacity of the skin

SELECTIVITY:

It is increased affinity for a receptor shape than other. In short best “fit”.

METABOLISM:

How the drug process in broken down. Loss of activity.  Could be simple oxidation. Also to increase half life. At times body has to metabolize the substance till it becomes active, popularly called as protrobing .compound should not be very liphophilic.so that it can work more on its site of action. First big issue goes through liver.

FORMULATION:

Depends how to administer. Allow to dissolve well through the system.

Oily formulation for topical adminstartion to aid absorption. Skin has an oily layer.

Drug has to be stable.

TOXICITY:

Avoid groups, or selenium like products which cause toxicity .Acute toxicity tests are usually carried out in the rat, mouse, cat and dog. Deliberate overdosing usually “washes out” metabolism difference between species. In dogs it is common to give an IV dose five times that intended for humans. In rats it is included to 10 times. Irritation studies are done in rabbits.Sympots may be from simple headache to congenital defects .There are metal groups, like selenium, which could be toxic.

BIOAVAILABILLITY:

Bioavailbility refers to the rate and extent of absorption of a drug froma dosage form as determined by its concentration-time curve in blood or by excretion in urine. It is a measure of the fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form .Bioavailability of the drug injected i.v is  100 %, but it is frequently lower after oral ingestion because

  1. A Drug will be incompletely absorbed.
  2. The absorbed drug may undergo first pass metabolism in intestinal wall/liver

Or be excreted in bile, incomplete bioavailability after subcutaneous or intramuscular injection is less common, but may occur due to local binding of drug .Oral formulation of a drug from different manufactures or different batches from the same manufacturers may have the same amount of drug but may not yield same blood levels – biological equivalent .Before the drug is administered orally in the solid cant dosage form can be absorbed , it must break in the individual particles of the active drug .Tablets and particles may contain a number of other materials – diluents , stabilizing agents , binders , lubricants , etc. The rate of dissolution is governed by the inherent solubility, particle size, crystal form and physical properties of drug. Differences in bioavailability May arise due to disintegration and dissolution rates.

NOVELTY:

Product has to outstand in the market. Protect .In many ways we will not have same product as some one else .Have to get something unique and better.

All will work together to work as a best product.

Small impurity in the test substance will lead to reactive component. Very keen to use stable product.

We are looking for a single molecule, from the synthesis of the product. It involves number of different steps like, Crude chromatography, crystallization, distillation… Some times some compound will cure the disease but it is still not proven at the earlier stage of its development, that it would be very efficient to cure a disease. Particularly important in disease where parasite were involved.

Story goes back years; Development of Histamine antagonist for curing ulceration in stomach .Gastric acid is released by action of gastrin, acetacholine, histamine in 1964, this was known. Actetacholine is a small molecule, and it interfaces with so many sites of receptor, so stay away from it. We now wanted to find something to block this acid?? Anti histamines actually were many available in market. Antihistamine actually doesn’t block the release of acid.H1 AND H2 are name of these receptors. It is a hetracycline compound.

If you we look at these measures it helps us to see at its efficacy for clinical studies. Theses drugs are, they interfaced with the biological pathway. At the molecular level , drugs

Understanding the process of drug development, and realizing the type and limitations of data that support the efficacy and safety of the marketed product are necessary in estimating the risk to benefit the ratio of a new drug .By the time an investigational new drug application has been initiated and the drug reaches the stage of testing in humans, its pharmacodynamic, pharmacokinetic and toxic properties have been evaluated in vivo, in several species of animals in accordance with regulations and guideline  published by Food drug agency .Although the value of many requirements for preclinical testing is self evident such as those that screen for direct toxicity to organs and characterize to dose related effects , the value to other is still a controversial issue , particularly due to unknown interspecies variation in the effects of drugs.

Author Name:

DR.Prabhjyot Rihal

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