Pharm 100 - Lesson A.3
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The term ‘potency’ refers only to the amount of drug that must be given to obtain a particularresponse. When we say that Drug A is more potent than Drug B, it simply means that one needs to takeless of Drug A to achieve the same effect that is obtained from Drug B
The ‘efficacy’ of a drug is a very important characteristic of a drug. Thisterm tells us what the maximum effect is that is obtainable with a given drug. For example, morphine hasgreater efficacy that aspirin in the relief of pain. Aspirin is only effective in relieving mild to moderatepain, while morphine is able to relieve pain of nearly all intensities
the injury of one kind of living matter without harmingsome other kind. There is a widespread need for agents, known as pesticides, that will kill fungi, weeds,and insect pests without harming plant growth.
Selective Toxicity by Accumulation
One way of achieving selective toxicity is to have an agent which will be selectively accumulated bythe species to be destroyed. An example of a selectively toxic agent working by this means is 10%sulphuric acid which has been used as a weed spray. The exterior of weeds is rough and wax free and theacid is accumulated by the weeds. On the other hand, the exterior of cereal grass is smooth and waxy andthe acid runs off the cereal grass. For this reason, 10% sulphuric acid is toxic to the weeds but exerts nodeleterious effect on the cereal grass.
multidrug resistance proteins
- The first, Pglycoprotein, was identified by Dr. Victor Ling in Toronto in 1976.
- The second, the multidrug resistanceprotein (MRP), was discovered by Dr. Susan Cole and Dr. Roger Deeley in 1992, at Queen’s University.
Paul Ehrlich, the father of chemotherapy, was born in Germany in 1854. He had noted that some dyes stained certain body tissues and not others. For example, the dye methylene blue stained nervous tissue preferentially. He reasoned that he should be able to design chemicals thatwould specifically stain parasites. He realized that the staining of the parasite would be equivalent to the strong binding of the chemical to the parasite. He appreciated that the combination of chemicals with the parasite would be insufficient to kill the parasite. However, he reasoned that if he could attach a toxic grouping to the chemical he would be able to design a substance that would specifically kill the parasite. He reasoned that the specifically-designed chemical would only bind to the parasite and not the humancells. Thus, human cells would be immune to the toxic agent attached to the binding group.
He had noted that some dyes stained certain body tissues and not others. For example, the dye methyleneblue stained nervous tissue preferentially. He reasoned that he should be able to design chemicals thatwould specifically stain parasites. He realized that the staining of the parasite would be equivalent to thestrong binding of the chemical to the parasite. He appreciated that the combination of chemicals with theparasite would be insufficient to kill the parasite. However, he reasoned that if he could attach a toxicgrouping to the chemical he would be able to design a substance that would specifically kill the parasite. He reasoned that the specifically-designed chemical would only bind to the parasite and not the humancells. Thus, human cells would be immune to the toxic agent attached to the binding group.
Ehrlich utilized arsenic as his toxic grouping and synthesized many derivatives of this compound. These arsenic compoundswere tested for their ability to cure syphilis in rabbits. After many failures, Ehrlich found the 606th compound that he tested was able to kill the syphilis organism in rabbits and was safe to use in man. Hecalled this compound Salvarsan which means “to save health”. At the beginning of the 20th century,most hospital beds in London were occupied by patients with syphilis. By 1920, several years after theintroduction of Salvarsan, such patients were rarely seen on the wards. Instead they were treated on anout-patient basis in special clinics.
success in scientific research
(1) Geld (money); (2) Geduld (patience);(3) Geschick (cleverness); (4) Gluck (luck).
Sulfonamides - Prontosil
In 1935, Domagk, working at the Bayer factory in Germany, studied the effects of a large number of chemical compounds against a bacterium known as streptococcus in mice. When thestreptococcus organism was injected into mice, the mice would usually die within a few days. Domagk injected numerous chemicals into mice together with streptococcus to see if any of these drugs could save the mice from the action of this bacterium. By this means, he discoveredthe drug Prontosil which was able to harm the streptococcus without harming the mouse. Between theyears 1932-1935, 71% of patients having streptococcus in their blood, died. However, after 1935 with the introduction of Prontosil, very few patients died from this cause. Prontosil was found to be inactivea gainst the streptococcus in the test tube. The reason for this was that Prontosil is split in the liver to give sulfanilamide which is the active principle.
How is it that sulfanilamide is selectively toxic?
both microbes and the host cells require a substance called ‘folic acid’ for growth. Folic acidis available in the body and crosses into the host’s cells which are then able to use the folic acid. Folicacid is, however, unable to enter microbes. The microbes must, therefore, have some device for makingfolic acid if they are to continue to grow. They do this by taking up a compound called paraaminobenzoic acid (PABA) which is then used for the manufacture of folic acid. Sulfanilamide closely resembles PABA in structure. The microbe cannot distinguish between sulfanilamide and PABA and is fooled into trying to use sulfanilamide instead of PABA. An analogy to this state of affairs, is that PABAcan be considered the key for the lock. Sulfanilamide closely resembles the key, gets into the lock and blocks the lock so that PABA (the key) cannot get into and open the lock. For this reason, folic acid is not made by the microbes and they cannot continue to grow. The body’s defence mechanism, namely the immune system, is then able to overpower the bacteria. Since the host cell uses preformed folic acid, it does not require PABA and is therefore not affected by the PABA antagonist, sulfanilamide.
Once the mechanism of action of sulfanilamide was understood, scientists wondered whether theycould not extend this idea to develop other antibacterial agents. They said “Let us study the chemicalreactions going on in microbes and in human cells to see if we can find differences between them”. Itwas thought that if differences could be found, then chemicals could be designed to interfere with areaction going on specifically in the microbe.Studies of this type have been extremely fruitful and led to the development of several drugs for thetreatment of viral diseases, including the HIV virus. Dr. Elion (a woman scientist) and Dr. Hitchingsreceived the Nobel Prize several years ago for research of this type which led to a variety of useful drugs. Their research was conducted over many years at the Burroughs-Welcome laboratories in the UnitedStates
Design of Anticancer Drugs
- Cancer cells were intensively studied to see if there were any differences betweenthe chemistry of cancerous and normal cells. It was hoped that if differences could be found then agentscould be designed to inhibit chemical reactions that were specific to cancer cells. Unfortunately, cancer cells are very similar in their chemistry to normal cells. However, several important chemical differenceshave been found. The amino acid asparagine is required by all cells for protein synthesis. Certain cancer cells cannot synthesize this amino acid and require asparagine from the blood. An enzyme, called asparaginase, can by used to reduce asparagine levels in the blood, this results in an inhibition of protein synthesis in cancer cells deficient in asparagine. This drug can be used to treat childhood acute leukaemia
- The most important difference between cancer cells and normal cells is that cancer cells divide continuously, whereas most normal cells are in a non-dividing state. For this process of cell division, DNA synthesis is required such that the two resulting daughter cells each contain sufficient DNA. Chemicals have been designed which are closely related to the building blocks of DNA. Thesechemicals prevent DNA formation and by this means inhibit the division of cancer cells. Unfortunately,not all the cells in the human body are in a dormant state. For example, the cells of the bone marrow,those lining the intestinal tract and cells of the hair roots divide continuously. For this reason, toxicity with these anticancer drugs is inevitable.
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