Basic Pharmcology and Pharmacokinetics
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By Prof Thomas Buckley School of Pharmacy University of Connecticut Written for Medic & Pharmacy Staff Training Mae Tao Clinic Tak, Thailand
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Basic Pharmcology and Pharmacokinetics
- 1. Introduction to Basic Pharmacology and Pharmacokinetics University of Connecticut School of Pharmacy
- 2. What do medications do? In general, medications may do the following: 1. Alter the activity of cells 2. Replace substances that are deficient or missing in the body 3. Neutralize substances that are excessive or doing harm to body 4. Destroy cells that harm the body
- 3. What do medications do? In general, medications do the following: • Alter the activity of cells • Replace substances that are deficient or missing in the body • Neutralize substances that are excessive or doing harm to body • Destroy cells that harm the body
- 4. Cells have specific functions Some cells in heart are responsible for keeping the heart beating at a certain rate Some cells in the liver break-down drugs and other chemicals Some cells in the pancreas release insulin, a hormone to control blood sugar Some cells in our stomach release acid to digest food Some cells in our guts absorb food, nutrients and drugs into the body Some cells in muscle controlling how the muscle contracts and relaxes
- 5. Lock and Key- Receptor Signaling
- 6. Agonist vs Antagonist Go and Do It! Stop! Don’t do it! Blocker
- 7. Medicines may alter cell functions • Digoxin affects the cells in heart that regulate the rate of heartbeat • Glibenclamide affects the cells in the pancreas to increase insulin release • Hydrochlorothiazide affects the cells in kidney to increase loss of water in urine
- 8. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells that harm the body
- 9. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells that harm the body
- 10. Deficiency could be Disease • Patients with Type 1 Diabetes don’t have cells that release insulin • Some diabetes patients may need to inject insulin to treat diabetes Drugs may replace the Deficiency
- 11. Deficiency could be Disease Low calcium in diet increases risk of osteoporosis, a condition of weak bones that break/fracture easily. Calcium supplement can keep bones strong to prevent fractures Drugs may replace the Deficiency
- 12. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells that harm the body
- 13. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells that harm the body
- 14. Drugs may neutralize After we eat, cells in our stomach release acid to digest the food. This acid does not bother us as long as it’s within the stomach. Sometimes when excess acid is released, it moves from its natural place in the stomach up into the food pipe. This causes a burning sensation around the chest. Antacids, like calcium carbonate, work by reacting with and neutralizing the excess acid.
- 15. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells that harm the body
- 16. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells or organisms that harm the body
- 17. Drugs may kill harmful cells or organisms • Mebendazole kills harmful worms or parasites that infect our guts (intestines) • Amoxycillin is a drug used to kill bacterial cells during certain bacterial infections • In cancer patients, chemotherapy drugs are used to kill tumor cells
- 18. Pharmacology – How do drugs work? • Altering the activity of cells • Replacing substances that are deficient or missing in the body or are needed in higher amount • Neutralizing substances that are excessive or doing harm to body • Destroying cells or organisms that harm the body
- 19. Pharmacokinetics The trick to right dose Too High or Supra-therapeutic dose Too Low or Sub-therapeutic dose Optimal dose Drug Concentration in Blood Time
- 23. Pharmacokinetics – How much drug is there? • Absorption • Distribution • Metabolism • Excretion
- 24. Absorption • Some medicines work from outside the body – Dettol or Povidone Iodine to clean a wound • Most medicines need to enter the body – Drug needs to overcome body’s barrier to entry eg. gut wall for an oral drug
- 25. Routes of Administration Most Common: • Oral (Tablet, Capsule, Liquid) • Injectable (IV/IM/SQ Injection) Less common: • Rectal (Suppository, Cream) • Inhaled (Inhaler) • Dermal (Cream, Ointment, Lotion) • Vaginal (Suppository, Cream) • Intra-nasal (Spray) • Ophthalmic/Ocular (Eye or Ear drops)
- 26. Oral Absorption
- 29. Food can affect absorption
- 30. Absorption through Latter Parts of Small Intestines & Large Intestines
- 31. Factors affecting Oral Absorption • Breaking-down and dissolution of drug particles • Digestive system’s movement and mixing of drug • Presence and type of food • Ability to pass through gut wall • Stability of drug to enzymes • Blood flow to the gut
- 32. Pharmacokinetics – How much drug is there? • Absorption • Distribution • Metabolism • Excretion
- 33. Distribution • Describes how the drug circulates in the blood to different parts of the body after absorption • Affects concentration of drug at the target organ Drug in Gut Drug in Blood Drug in Target Organ ABSORPTION DISTRIBUTION Drug
- 34. Factors Affecting Distribution • Flow of blood to the different organs • Drug’s tendency to bind to proteins in blood • Drug’s ability to cross the wall of blood vessel and/or other barriers and enter the target organ
- 35. Pharmacokinetics – How much drug is there? • Absorption • Distribution • Metabolism • Excretion
- 36. Metabolism • Better described as conversion or transformation of drugs – Generally converted to a more water-soluble form so it can be easily excreted in urine • Enzymes specialized to detoxify natural toxic compounds can also affect drugs • These enzymes are located primarily in LIVER but may also be found in other places like kidney, lungs or gut wall • Drugs may be converted to: – Less toxic or effective compounds – More toxic or effective compounds – Compounds with different type of effect or toxicity
- 37. Factors affecting Metabolism • Race – Different ethnicities have different metabolizing capabilities • Age – Reduced in elderly and children • Sex – Women are slower in metabolizing ethanol than men • Disease state – Patient’s condition of liver may affect metabolism • Other drugs – Some drugs, eg cimetidine, slow down the conversion process of some other drugs – Some drugs, eg carbamazepine, speed up the conversion process of other drugs • Food – May speed up or slow down metabolism
- 38. Pharmacokinetics – How much drug is there? • Absorption • Distribution • Metabolism • Excretion
- 39. Excretion • Process of eliminating or throwing out the drug (either actual or converted) from the body • Primarily happens through KIDNEY with urine but also through other organs – Feces (if poorly absorbed in gut or if diarrhea) – Lungs – Skin – Breastmilk in lactating women • Use caution with dose if patient’s kidney function is poor • Use caution if patient is breastfeeding
- 40. Drug Interactions • A drug’s effects is not solely determined by itself. Drugs interact with other things. • Drug interactions can increase or decrease the desired or undesired effects of drug • Three broad categories of drug interaction: – Drug-Drug • One drug’s effect changed by another drug • Eg. Increased/decreased metabolism in liver • May happen when two or more drugs are taken – Drug-Food • Drug’s effect changed by food • Eg. Decreased absorption by binding in the gut. – Drug-Condition • Drug’s effect changed by patient’s health condition • Eg. Harmful effects to a fetus when patient is pregnant
- 41. Effects of Drug Interaction • Four general types of interaction effects: – Additive (3+2=5) • Enalapril + Hydrochlorothiazide can lower blood pressure more than either drug alone – Synergistic (3+2= 50) • Paracetamol + Alcohol can increase risk of liver toxicity – Potentiation (0+2=20) • Metronidazole + Alcohol can cause serious side effects or sudden death • Enalapril + Pregnancy can cause injury or death of fetus – Antagonism (3+(-2)=1) • Doxycycline + Calcium/Milk taken together can decrease the absorption and therefore effectiveness of Doxycycline • Poison + Antidotes may cure the toxic effects of poison
Editor's Notes
- One very basic question to ask about medications is how do drugs treat diseases. There are several ways by which drugs work and some of them are very complex. But, very broadly speaking, we can summarize the activities of drugs in four general mechanisms. Drugs may work by following ways. They may: Alter the activity of cells Replace substances that are deficient or missing in the body Neutralize substances that are excessive or doing harm to body Destroy cells that harm the body
- We will take each of these mechanisms and try to understand them a bit more indepth by using examples. First comes, altering the activity of cells.
- Cells are the smallest functional unit in our body. They perform specific functions/tasks upon receiving specific instructions. For example there are cells in heart that are responsible for keeping the heart beating at a certain rate. There are cells in muscle that control how the muscle contracts and relaxes. There are cells in the stomach that release acid to digest food. There are cells in the liver breaking-down drugs and other chemicals. There are cells in the pancreas that release insulin, a hormone to control blood sugar. There are cells in the gut absorbing food, nutrients and drugs into the body.
- To receive these instructions, cells have receptors. These receptors are structures that respond to specific signals. To understand how specific they are, you may think of these receptors as locks and think of the signals as keys. Each lock will only allow certain keys to fit in. Just like that, each receptor has specific signals that it will respond to.
- Generally speaking, the signal can be of two types: An agonist or antagonist. Agonist tells the cell to do whatever task the cell does. The antagonist tells the cell to stop doing the task that a cell does. Let us go through an example to understand this better. Let’s say the blood pressure in a healthy person is just starting to go low. Then the cells in that person’s body that are responsible for raising blood pressure will get an “agonist” signal saying do what needs to be done to raise the blood pressure. Now if that person’s blood pressure was going too high, these cells will get an “antagonist” signal saying stop doing the things that raise blood pressure. Why is this important to understand? Because it helps us understand what’s happening in a sick patient. Many diseases happen because this signaling process is not working effectively. For example in patients with high blood pressure, their body is not being able to send those “antagonist” signal appropriately to keep the pressure within the normal range. We can then give those patients a medicine or a drug that will go to those specific receptors of cells and work as an antagonist to stop blood pressure from being too high.
- Digoxin is an example of drug that affects the heart cells responsible for the rate of heartbeat and it’s often used in Congestive Heart Failure. Glibenclamide affects the cells in pancreas to cause them to increase release of insulin and thus it is used in treatment of Diabetes. Hydrochlorothiazide affects the cells in kidney to increase loss of water in urine. This decreases blood volume and decreases blood pressure in patients with hypertension.
- So we have seen one of the major ways most drugs work and that is by changing the activity of cells to bring things to normal.
- Another way some drugs or medicines work is by replacing substances in our body that we don’t have or don’t have enough of.
- Deficiency of certain substances could be the main cause of certain disease. For example patients with Type 1 Diabetes don’t have the cells (in the pancreas) that release insulin. As a result, they are deficient of insulin and their blood sugar can sometimes be so high that they can die. Injected insulin is a life-saving medication for them to replace the missing insulin in their body.
- People who take low calcium in their diet have weaker bones that break/fracture easily, a condition known as osteoporosis. What food can we get calcium from??? (milk, oranges, soy milk, green vegetables, tofu, sunflower seeds – but hard to get enough if you are deficient)Providing them with calcium supplement is one of the major treatments of this condition.
- A third-way drugs can work is by neutralizing substances that are excessive or doing harm to body.
- After we eat, cells in our stomach release acid to digest the food. This acid does not bother us as long as it’s within the stomach. Sometimes when excess acid is released, especially after a spicy meal, the acid moves from its natural place in the stomach up into the food pipe. This causes a burning sensation around the chest. Antacids, like calcium carbonate, work by reacting with and neutralizing the excess acid.
- A fourth way drugs may work is by destroying cells that are harmful to the body. Drugs using this activity are useful in treating infections and cancer.
- Mebendazole kills harmful worms or parasites that infect our guts (intestines) Amoxycillin is a drug used to kill bacterial cells during certain bacterial infections In cancer patients, chemotherapy drugs are used to kill tumor cells
- That sums up the four general ways drugs may work to treat diseases. Any questions? A Game: 5 teams Write down which mechanism group these 6 medicines belong to… Furosemide, Atenolol Ferrous Sulphate (Iron Supplement), Vitamin C Erythromycin, Artesunate
- Now that we have better understanding of how drugs work in general, we may now switch our attention to how much drug is needed to make them do what we want them to do. In other words, what’s the right dose? We can even ask ourselves what does the term “right dose” mean? Here’s an easy answer to that question: A right dose is a dose that is neither too low that it doesn’t have any effect, nor too high that it becomes toxic. It is range in between.
- Every time we take a drug, the level of that drug in our blood goes up by a certain amount. Let’s represent that by using a line going up. With time, that level slowly falls down and let’s represent that by a line going down. Now we can take the drug again and take level back up again, which will consequently start falling again with time. Continuing this pattern of dosing we can continue to draw the lines as this patient keeps taking the medicine. As long as the lines representing the levels of drug are within the range of “right/optimal dose” we are fine.
- How would this pattern look like if this patient was taking too high a dose of this same drug? Sooner or later, it will reach that toxic level.
- How would this pattern look like if this patient was taking too low a dose of this same drug? It will never reach the range of “right dose” and we will never get the effects we are looking for. Now the next question becomes what causes these levels or lines to rise and fall the way they do?
- To understand how drug levels are determined, we need to understand four process that most drugs go through when we take them. They are: Absorption Distribution Metabolism Excretion. We will go through each of them with more detail.
- Some medicines work from outside patient’s body. For example, Dettol or Povidone Iodine to clean a wound. But most medicines need to enter the body. Our body has natural barriers to not allow everything enter inside it. For example not everything we ingest by mouth can cross the walls of our gut to enter our body, but instead will be excreted in feces. Drugs similarly, in order to enter the body, need to overcome certain barriers.
- What are some ways drugs may enter our body? Most commonly they enter our body by mouth or orally. Tablets, capsules or liquids are examples. Another very common way is by injection and there are different types of injections. There are also other less common ways to give drugs to our body. These include: Rectal (Suppository, Cream) Inhaled (Inhaler) Dermal (Cream, Ointment, Lotion) Vaginal (Suppository, Cream) Intra-nasal (Spray) Ophthalmic/Ocular (Eye or Ear drops) For the purposes of understanding absorption, we will go through oral drugs and see what happens to them after we take them.
- To understand absorption of drugs that are taken by mouth, we need to familiarize ourselves with the digestive system. The digestive system starts at the mouth. The mouth is connected to the stomach by a food pipe or esophagus. After stomach, comes the small intestine, then the large intestines and then the anus.
- After a drug is taken by mouth, it travels through the food pipe or esophagus and reaches the stomach. After reaching the stomach, the drug is exposed to heavy mixing and acidic environment. This causes the drug to break down and dissolve. Drugs that are broken down and dissolved, are better candidates for absorption than the drugs that don’t break. Drugs which are acidic in nature, get absorbed in the stomach and reach the blood. Drugs which are not acidic in nature, move on to the small intestine.
- Drugs are then absorbed at the first part of small intestines and through the “portal vein” travel to the liver. Some drugs are immediately broken down or metabolized by the liver. This is referred to as the “first-pass metabolism.” Drugs which are not broken down immediately then enter the body’s blood circulation.
- All drugs in the small intestine may not be absorbed. One thing that may affect some drugs is the presence of food in the intestine. Food may bind to certain drugs and prevent them from crossing the gut wall.
- Drugs which are not absorbed in the first part small intestine, may get absorbed in the latter parts or in large intestine. Otherwise they are excreted with feces.
- So from going through the journey of oral drugs through our guts, we can identify following factors that may affect their absorption: Breaking-down and dissolution of drug particles Digestive system’s movement and mixing of drug; if the drug moves too fast than it may not have enough time to get absorbed Presence and type of food Ability to pass through gut wall Stability of drug to enzymes (eg in liver) Blood flow to the gut which is understandable because if there’s little blood flow around the stomach or intestines than there is little opportunity for the drug to get into the blood stream.
- The process of distribution describes how the drug circulates in the blood to different parts of the body after absorption. A drug after it is swallowed, enters the gut. From their it enters the blood. From the blood the drug reaches it’s target organ or it’s site of action. Just like absorption helps us understand how much of the drug will go from the gut to the blood, distribution helps us understand how much of the drug in blood will to the target. There is less and less amount of drug left as it travels to the target.
- Similar factors that affect the absorption of drug also affect the distribution of the drug. Blood flow to each organ is different and therefore the exposure to organs to different drugs is different. Some organs which have high blood flow, eg the heart and the liver are easily exposed to drugs. Others with less blood flow are not as easy. Just like if drugs are bound to food, they don’t get absorbed into blood, drugs that bind to protein in blood don’t reach the target site of action and are, therefore, not able to exert any effect. A drug that can easily cross the wall of blood vessel, will be able to easily reach it’s site of action. Depending on the site of action, certain drugs may also have to cross other barriers.
- Metabolism is better described as conversion or transformation of drugs. Drugs are generally converted to a more water-soluble form so it can be easily excreted in urine. Our body has it’s own natural ways of getting rid of certain toxic chemicals. We have enzymes or special proteins that allow easy conversion of toxic compounds to non-toxic compounds. Drugs can get caught up in these enzymes too. These enzymes are located primarily in LIVER but may also be found in other places like kidney, lungs or gut wall. Drugs, going through these enzymes can get converted to Less toxic or effective compounds More toxic or effective compounds Compounds with different type of effect or toxicity.
- The factors that affect metabolism include: Race: Different ethnicities have different metabolizing capabilities Age: metabolism is reduced/slowed down in elderly and children Sex: Women are slower in metabolizing ethanol than men Disease state: Patient’s condition of liver may affect metabolism Other drugs Some drugs, eg cimetidine, slow down the conversion process of some other drugs Some drugs, eg carbamazepine, speed up the conversion process of other drugs Food: May speed up or slow down metabolism
- Excretion is the process of eliminating or throwing out the drug (either actual or converted) from the body. Just like LIVER was the body’s main organ of metabolism, KIDNEY is the body’s main organ of excretion. But drugs may also be excreted in other ways such as feces, which is increased if the drug is poorly absorbed in gut or if patient has diarrhea. Drugs are also excreted via lungs, skin and breast milk and this becomes particularly important in lactating women when we need to consider the safety of the baby. Since Kidney is the main organ of excretion, in patient’s with reduced kidney function, we need to exercise caution is dosing drugs. Caution should also be used in prescribing drugs to a mother who is nursing.
- SHOW DRUGS.COM EXAMPLE!!! Assignment – to please put your stock in A-Z order by next Thursday.. We will come and check them. It is easy to do and doesn’t take long, will save you time and mistakes. The best stock will get a price!! A drug’s effect is never solely dependent upon itself. Drugs interact with other things and these interactions can increase/decrease the desired or undesired effects of drugs. Desired effects are effects we want to see. Undesired effects are side effects or adverse effects of the drugs and are unwanted. There are three broad categories of drug interaction. They are: Drug-Drug, Drug-Food and Drug-Condition. Drug-Drug Interaction occurs when one drug’s effect is changed by another drug. This can happen when two or more drugs are taken together. As we have seen previously, drugs can increase or decrease the metabolism of other drugs and thus effect their activity. Drug-Food Interaction occurs when drugs effect is changed by food for example by binding in the gut and not allowing proper absorption. Drug-Condition Interaction refers to the specific effects of drug that may be more pronounced in certain patient conditions. It also refers to certain effects of drugs that are only considered in certain types of patients. For example, a drug that can harm a fetus is of concern if the patient is pregnant.
- The effects of drug interactions can be generally of four types. They can be additive which is most common. It means two things combined will have a higher effect than either thing alone. Enalapril and Hydrochlorothiazide together can lower blood pressure more than either drug alone. Depending on the patient, this added effect may or may not be desirable. For someone whose blood pressure is out of control after taking one, adding a second drug may be beneficial. The second type of effect is synergistic. This happens when two things together cause an effect that is more than what is expected by adding the two together. It’s almost like adding 3 and 2 but the effect is equal to 50 instead of 5. Prolonged high dose paracetamol with alcohol intake triggers such an effect of liver toxicity. The third type of effect is potentiation. This happens when a certain drug gives a certain effect only during interaction. Metronidazole, for example, a relatively safe drug, can cause serious life-threatening side effects when taken with alcohol. Enalapril can cause injury or death of fetus if taken during pregnancy. The fourth type of effect is antagonism. This occurs when two things oppose each other and lead to a decreased effect. Doxycycline when taken with calcium or milk is poorly absorbed and therefore is less effective. Another example is the use of antidotes to oppose the effects of poisons.