Another TCM doctor expelled from Health Bureau’s Healthcare Subsidy Scheme, due to accepting healthcare voucher to pay for ginseng and dried seafood products In the hope to partially lessen residents’ burden on medical expenditure, make good use of the medical resources available in community and promote the concept of family doctor, the government is subsidizing the local residents
Conversely, injection forms, though being painful and needing help of medical personnel for application, help to quickly achieve necessary concentration of preparation in blood amoxil online Antibiotic is usually chosen in an empiric way (at random). But when choosing one is obligatory guided by definite rules.
1.pdf1997 Pharmacology Semester 1 page 1 of 6 By Duy Thai: www.geocities.com/d.thai
Targets of drug action• Drugs which are developed can act on 4 types of proteins: • The reasons why proteins (and I will refer specifically to enzymes here) make good targets is because: • They have high structural specificity • Species differences in enzyme properties.
• Although the enzyme may have the same name and same function, there are slight chemical differences between species which is exploited by species specific drugs.
• Enzymes act as catalysts for reactions • Some enzymes work in cascade reactions.
• We must target the rate limiting enzyme because this enzyme limits the rate of all the other • Most enzymes have more than one isoform.
• The development of drugs which target specific isoforms can help in: Mechanisms by which drugs interact with an enzyme• Competitive inhibitors • Bind to the same binding site as the substrate.
• Does not bind to the same binding site as the substrate.
• Have high affinity to an enzyme and a slow off rate. The binding is non-covalent but because the affinity is so strong, they can be considered irreversible.
• Bind to the enzyme with strong covalent bonds • Does not participate in a reaction.
• Binds to the enzyme and increases its catalytic ability.
• Binds to a site different from the substrate binding site.
• Drugs can act as substrates, substituting for endogenous substrates with biological activity.
Types of enzymes targeted by drugs• Enzymes regulating cellular metabolism • Enzymes that pump ions (ion channel ATPases) • Enzymes involved in homeostatic regulation • Degradation or action of regulatory factors 1997 Pharmacology Semester 1 page 2 of 6 By Duy Thai: www.geocities.com/d.thai
Cholesterol synthesis and hypercholesterolaemia• Cholesterol synthesis occurs in all cells in the body, although the liver has a greater capacity to do this than other HMG CoA Reductase
• The cholesterol which is formed is used for a variety of things: • Constituent of cell membranes, making them fluid • HMG CoA reductase is the rate limiting enzyme of cholesterol synthesis.
• In people with hypercholesterolaemia, we inhibit this enzyme so that production of cholesterol ceases.
• These 2 drugs act globally (there is no need to be tissue specific) because we want to reduce cholesterol • The drugs have close structural resemblance to the substrate of this enzyme, namely HMG CoA.
• By binding to the same binding site on the enzyme, HMG CoA cannot move to the next step of • Treatment of a cholesterol synthesis inhibitor drug is not enough to reduce the hypercholesterolaemia. The drugs are usually used in conjunction with drugs which chelate bile salts.
• The bile salts are prevented from being absorbed and going back to the liver (enterohepatic circulation).
They thus remain in the gut to be excreted.
• Remember that bile salts are a major source of cholesterol in the body.
Antiviral drugs• The 2 antiviral drugs mentioned today are: • Both drugs show species selectivity. You cannot use one Acyclovir against HIV • They are administered in an inactive form and are activated in the body, either by human enzymes or viral • Thus, the drugs act as substrates for one set of enzymes and when activated, act as inhibitors to another set Pharmacology Semester 1 page 3 of 6 By Duy Thai: www.geocities.com/d.thai
• Acyclovir is an analogue of a guanine base • Zidovudine is an analogue of a thymidine base • Thus, you can predict that the drugs are involved in inhibiting nucleic acid synthesis by competing with the guanine • The active form is acyclovir triposphate (-P-P-P).
• The inactive Acyclovir is selectively activated by the viral kinase.
• Thus, if there were no herpes viral infection, acyclovir would not be activated because it needs specifically • Acyclovir -P-P-P inhibits the viral DNA polymerase by being a competitive inhibitor to the other DNA bases, • Here, we have species selectivity between the human and the virus.
• Both humans and virus have DNA polymerase.
• If acyclovir were to act on human DNA polymerase, this would be bad.
• Luckily, acyclovir is designed to be specific for the virus DNA polymerase, and so the human Zidovudine (AZT)• Targets HIV and other retroviruses.
• A retrovirus is a virus which contains a strand of RNA • The virus has a special enzyme, reverse transcriptase (humans do not have this enzyme) which allows the RNA to be “reverse transcribed” into DNA.
• The DNA is incorporated into host cell DNA.
• Whenever the host cell transcribes a section of DNA, the viral DNA is also transcribed along with it.
Transcription of the viral DNA produces viral RNA. Translation of the RNA produces viral proteinswhich are necessary for the virus’s viability.
1997 Pharmacology Semester 1 page 4 of 6 By Duy Thai: www.geocities.com/d.thai
• AZT is activated by human kinases. Hence it is activated everywhere in the body, even when there is no viral • However, if there is no viral infection, the active form of AZT has got nothing to do because it is species selective for • Humans do not have this enzyme, so AZT has nothing to bind to unless there is a viral infection by a retrovirus. Only retroviruses have reverse transcriptase.
• Notice how the drug is species selective between humans and other viruses.
• AZT inhibits reverse transcriptase by preventing the addition of nucleotide bases, particularly thymidine.
• What we have just seen in the 2 examples given are: • Competition for a natural substrates (the nucleotide bases) • Species selectivity between humans and virus, and between virus and virus • e.g. Acyclovir does not work in all cells of the body. It only works in virally infected cells because it required the viral kinase to activate it.
A recent breakthrough in the fight against HIV - Protease inhibitors• After the HIV has reverse transcribed its RNA into DNA, the DNA strand is incorporated into the host cell DNA.
• The viral DNA codes for polyproteins.
• 1 gene codes for several proteins strung together.
• Proteases are used to chop up this string of proteins so that individual proteins are produced.
• Human proteases chop up the polyproteins to produce coat proteins.
• Coat proteins are the proteins found on the surface of the virus • Viral proteases chop up the polyproteins to produce core proteins.
Pharmacology Semester 1 page 5 of 6 By Duy Thai: www.geocities.com/d.thai
• Core proteins are found inside the virus particle.
• Protease inhibitors are drugs which inhibit the protease enzyme.
• If we inhibit the human protease, the virus will lack surface proteins. However, the proteases in other, healthy cells are also inhibited, which is not a good thing.
• Drugs have been developed which specifically target the viral proteases. This prevents formation of the • The virus particle which is formed, thus has an intact surface coating but lacks core proteins, • An example of a protease inhibitor is Saquinavir • Saquinavir competitively inhibits the active site of the protease.
• It mimics the cleavage site of the viral polyprotein.
• Protease inhibitors are often used in conjunction with AZT because resistance can develop against the protease inhibitor (via mutations in the polyprotein).
Antibacterial drugs - Folic acid metabolism inhibitors• Folic acid is used in the synthesis of bases (e.g. guanine, thymidine, uracil, cytosine, adenine) of nucleotides which • The structure of folic acid is like so: • Mammalian cells cannot make folic acid. They obtain it from their diet.
• Hence, mammalian cells do have a folic acid transporter molecule.
• Bacteria do not have a folic acid transporter because they don’t need it.
• Bacteria have enzymes which are capable of making folic acid de novo.
• These enzymes are good targets for antibacterial drugs because the enzymes are only found in bacteria.
• An example of this type of drug is Sulphanilamide • It is an analogue of the pABA portion of folic acid.
• It competitively inhibits the enzyme by binding to the substrate binding site, thus preventing the actual pABA molecule to bind and form folic acid.
• Both these drugs do not prevent the synthesis of folic acid. Instead, they prevent the recycling of it.
• Both bacteria and humans have DFHR but the enzymes are slightly different structurally, therefore selective drugs can be developed to target either the human form or the bacterial form.
• Methotrexate and Trimethoprim are slightly different.
• They do not differ in mechanism of action. Instead, they differ in context of use.
1997 Pharmacology Semester 1 page 6 of 6 By Duy Thai: www.geocities.com/d.thai
• Trimethoprim is selective for the bacterial form of DHFR.
• Hence, it is used as an antibacterial drug • Methotrexate is mainly selective for the human form of DHFR • Methotrexate is used in chemotherapy to prevent the synthesis of nucleotides required for DNA synthesis in rapidly dividing mammalian cells (cells which are out of control).
• Digitoxin belongs to a family known as cardiac glycosides.
• It is used in cardiac failure to improve the cardiac output of the heart by increasing the force of contraction.
• It acts by inhibiting the Na+K+ATPase, particularly in cardiac muscle cells.
• In a cardiac myocyte, a low intracellular Na+ concentration allows Na+ to flow down its concentration gradient into the cell. This helps to remove a Ca2+ load in the cell.
• The Na+ enters the cell via a Na+ Ca2+ counter exchange.
• When the Na+ flows into the cell, its concentration is prevented from rising by its removal via a Na+ K+ ATPase which pumps Na+ out of the cell (against its concentration gradient) and K+ into the cell (alsoagainst its concentration gradient).
• Digitoxin binds to the Na+ K+ ATPase pump and shuts it.
• Digitoxin is acting as an allosteric enzyme inhibitor. It does not occupy the ATP binding site.
• If the pump is inactivated, the Na+ concentration in the cell will rise. An increase in intracellular Na+ concentration reduces the concentration gradient, and so less Na+ ions flow in.
• Less Na+ flowing in means less Ca2+ flowing out and so Ca2+ levels rise.
• The Ca2+ is sequestered by the sarcoplasmic reticulum • The next time there is a depolarisation, more Ca2+ can be released, resulting in a stronger force of Cardiac glycosides and heart failure• In heart failure, the heart is unable to deliver enough blood to match the body’s requirement.
• Increased peripheral resistance due to peripheral vascular disease • This increases the cardiac output, resulting in improved perfusion of peripheral tissues • It reduces the venous pressure (which is high in heart failure) by allowing more venous blood to go to the
A STUDY OF THE NEW AGRICULTURAL EDUCATION CURRICULUM Submmitted in partial fulfillments of the requirements for the degree of Doctor of Philosophy in Education University of Illinois at Urbana-Champaign, 1990 A STUDY OF THE NEW AGRICULTURAL EDUCATION CURRICULUM University of Illinois at Urbana- Champaign, 1990 The purposes of this study were to investigate how the new Kenyan agricultural ed