Amir Motamedi Week 1-2

Amir Motamedi Week 1-2 - TA: Amir Motamedi Email:...

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Unformatted text preview: TA: Amir Motamedi Email: [email protected] TA: Amir Motamedi Email: [email protected] Slide 2|1: Pharmacogenetics: Pharmacogenetics examines the effects of genetic factors to variations in the drug response. Ex: I. Asian flush: •Happens due to accumulation of acetaldehyde (toxic). •Normally: Alcohol ----(Alcohol Dehydrogenase)---> Aldehyde --(Aldehyde Dehydrogenase) ---> carboxylic acid •Three mutations can happen for enzymes involved in alcohol metabolism: 1. Alcohol Dehydrogenase mutation --> becomes Less active --> slow conversion of EtOH to acetaldehyde --> accumulation of EtOH You fell drunk but not sick. 2. Alcohol Dehydrogenase mutation --> becomes more active --> rapid conversion of EtOH to acetaldehyde --> accumulation of acetaldehyde (toxic) 3. Acetalaldehyde Dehydrogenase mutation – becomes less active--> slow conversion of acetaldehyde to acetic acid --> accumulation of acetaldehyde directly and accumulation of EtOH indirectly You feel drunk and sick II. Codeine resistance: Not from lecture •Codeine is weak pain killer. •Morphine is strong pain killer. •Normally: Codeine (precursor drug) ----( gets metabolized by P450 enzyme) --> Morphine •Mutation can cause some people to have less active form of P450 enzyme --> Less metabolism of codeine to morphine --> Codeine remains unchanged. TA: Amir Motamedi Email: [email protected] Slide 3|1: Drugs: •Drugs are divided into three major groups. 1. Prophylactic: Refer to the drug or procedure aimed to prevent disease. Ex: vaccines and vitamins and supplements. 2. Palliative: Refer to the drug or procedure aimed to relieve symptoms. The vast majority of the drugs in the market belong to this group. Ex: Drug that reduce high blood pressure. The drug relieve the symptoms for a while but the symptoms comes back and more drug is needed to be used. 3. Therapeutic: Refer to a drug or procedure aimed to cure disease. Ex: antibiotics, cancer drugs. After the drug is used, the disease is cured and does not come back. Relatively small number of drugs in the market belong to this group. Some drugs can be categorized in two different category. Ex: Antihypertensive medication are both : 1. Prophylactic (prevent heart disease such as heart failure and stroke), 2. Palliative (reducing high blood pressure which is by itself a disease that has been caused due to a number of factors). TA: Amir Motamedi Email: [email protected] Slide 3|1: Effective dose (ED50): Effective dose is the concentration of drug at which 50% of the patients show a predefined response. Ex: ED50 is the dose by which 50% of the patients show drop in blood pressure. This is not the dose by which blood pressure (effect) drop by 50%. LD50 is the dose of drug by which 50% of the patient die. Efficacy: Efficacy is the inherent capability of a drug to produce desirable effect. Ex: different drugs have the same efficacy as long as they have the same effect (the extent of the effect (relative effectiveness) is not presented by efficacy). Ex: Codeine and morphine have same efficacy as pain killer. Potency: Compare the relative effectiveness of drugs to produce desirable effects Ex: Both Aspirin and Ibuprophine have the same efficacy as anti-inflammatory drugs but we need more aspirin than Ibuprophine to reach the same desirable effect. (Ibuprophine have higher potency). Sample Question: compare efficacy and potency? Same efficacy, and lower potency for B TA: Amir Motamedi Email: [email protected] Slide 5&6&7|1: Opium Pain killer Foxglove Also known as digitalis. Used to treat heart failure (cardiac insufficiency). Narrow therapeutic index. Homeopathy: Using a chemical which produced same symptoms as the dieses at high dose, can cure the disease at low dose. The remedy is extract from plants, animal and mineral. Postulate: The higher the dilution the more powerful the drug. Isolation, purification and chemical characterization of the active compound: 1. Allowed administration of a controlled dose 2. Allowed administration of the active component of herbal mixtures to be given alone. Some extract have more than one active compound which dependant on their nature can have good or toxic effect. EX: Castor bean contains castor oil ( has therapeutic effect as laxative) and ricin (has toxic effect). 3. Allowed definition of mechanism of action, leading to synthesis of improved agents Greater selectivity, Greater potency, Altered duration of action Ex: morphine is used as a pain killer and an anti-diarrhea agent and cough suppressant. Chemical modification of basic morphine structure allows to separate these three function. Slide 8&9&10|1: TA: Amir Motamedi Email: [email protected] Aspirin: Salicin (active ingredient) --> salicylic acid (tough on stomach) --> acetyl salicylic acid (A.K.A. Aspirin) Antimicrobial: 1. Sulfonamide : Sulfanilamide 2. Arsenic compounds : Arsephenamine= Salvarsan 3. Penicillins New drug Discovery: 1. Analogues to existing drugs 2. Finding new application for existing drugs: 3. Drug screening: 4. Rational drug design Know these: Sulfanilamide 1. Antimicrobial 2. Thiazide diuretics 3. Sulfonylurea hypoglycemics Aspirin 1. Anti- aggregatory --> Cardioprotective 2. Pain killer 3. Anti-inflammatory Slide 19&21&22|1: TA: Amir Motamedi Email: [email protected] Testing for toxicities including: 1. Teratogenicity Birth defect or malformation Only related to the fetus 2. Mutagenicity Cancer, and altering genetic information 3. Reproductive toxicity Related to the reproductive system of parents. All medicines must have evidence of efficacy, except for: 1. Dietary supplements 2. Pure soap Example of dietary supplements: Leptoprin contains, Ephiderine: synthetic adrenaline, band from dietary supplements, increase metabolism (thus good for weight loss), however heart rate and blood pressure goes up. Caffeine: Diuretic, just temporary weight lost Kelp : Source of iodine --> increase production of thyroid hormone --> increase basal metabolism. However, this excess iodine which does not change the thyroid production. Calcium: Might potentially have weight loss effect Slide 24+sommary of few slides|1: Establishing safety and efficacy: TA: Amir Motamedi Email: [email protected] •Preclinical study is done in either cell line or animal model. It is not performed in human. The purpose is to establish a pharmacological profile. (pharmacokinetics + toxicity) •Phase 1 is performed in healthy human with the intention of study (pharmacokinetics + toxicity) Pharmacokinetics of drugs: Disposition, metabolism, elimination of drug Thus, helps to figure out dose and route of administration of drug. Both phase 2 and 3 are performed in patients (human) with the intention of finding efficacy. Phase 3 focuses on placebo effect, and side effects. Side effects: Type A: Predictable Type B: Unpredictable Phase 4: Post marketing Surveillance Ongoing monitoring of drug safety under actual conditions of use in large numbers of patients. (Pharmacovigilance) Slide 24+sommary of few slides|1 : TA: Amir Motamedi Email: [email protected] Sample Question: Which phases of the licensing process are aimed to establish the efficacy of a new drug candidate in humans: 1. Preclinical studies 2. Phase I Answer is C and D 3. Phase II 4. Phase III 5. Post-marketing surveillance Sample Question: To which category do beta-1 receptor blockers as antihypertensive drugs belong? 1. Palliative 2. Therapeutic Answer is A and C 3. Prophylactic 4. None of the above What was the goal of the Orphan Drug Act of 1983? Answer: To promote the development of drugs that affect less than 200,000 people in the US TA: Amir Motamedi Email: [email protected] End Of Lecture 1 TA: Amir Motamedi Email: [email protected] Slide 1-7|2: TA: Amir Motamedi Email: [email protected] Oral Drug Administration: 1) Pills 2)Tablets 3)Sublingual Tablet 4)Coated Tablets (CT) 5) Capsules 6) Matrix Tablets(MT) 7)Solutions Function of Coat: 1) Facilitate swallowing 2) Cover bad taste 3)Protect active ingredient (Main Function) Orally administered drugs should pass the highly acidic environment of stomach. Some active ingredient are denatured in acidic environment, thus they need to be protected. Function of Matrix Tablets: Extended or targeted (intestinal) release Usually: (This is not a rule) •The coating around entire drug alters the location of release of drug. •The coating around the particles (pellets) alters the rate of release. Slide 8|2: Topical (Percutaneous) drugs: TA: Amir Motamedi Email: [email protected] •Remember: Skin is composed of many layers of lipid bilayer (lipophilic environment). Thus strongly passes lipophilic substances. •Remember: Movement of molecules from one environment to another is a function of: 1. Membrane permeability: In this case, skin is mostly permeable to Lipophilic (hydrophobic) molecules. Thus Lipophilic molecule gets absorbed readily. Hydrophilic molecule are not absorbed readily. 2. Driving force: In this case, depends of the solubility of molecule in each environment. •The inside environment is always constant. •We can only change outside environment to alter absorption. Lipophilic molecule is more soluble in Lipophilic environment --> tend to stay outside. Lipophilic molecule is less soluble in hydrophilic environment --> does not tend to stay outside. Slide 10-13|2: Topical (Percutaneous) Drug Administration: 1. Ointment and Lipophilic Cream 2. Paste 3. Lotion and Hydrophilic Cream 4. Gels 5. Transdermal Drug Delivery Systems =“Patches” 6. Eye Drops 7. Sterile; Isotonic; pH-neutral 8. Nose Drops/Nasal Sprays 9. Viscous Solutions 10. Pulmonary Formulations 11. Suppositories •Liner - Protects the patch during storage. The liner is removed prior to use. •Drug - Drug solution in direct contact with release liner •Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin •Membrane - Controls the release of the drug from the reservoir and multi-layer patches •Backing - Protects the patch from the outer environment TA: Amir Motamedi Email: [email protected] TA: Amir Motamedi Email: [email protected] Slide 14&15|2: Parenteral Drug Administration: Sterile: no live pathogen Pyrogen free: no live or dead bacteria in the drug. 1. Ampules 2. Single and Multi-dose Vials 3. Cartridge ampules 4. Infusions Advantages: – 100% “Absorption” – Drug enters general circulation without hepatic passage --> No first-pass hepatic elimination – Better bioavailability of hydrophilic drugs •Intravenous (i.v.): Fastest (infusions; cardio-vascular drugs) •Intramuscular (i.m.): Medium (anti-inflammatory; antibiotics) •Subcutaneous (s.c.): Slowest (vaccines; insulin; depot contraceptives) Note : all of the above result in 100% absorption, but the rate of absorption of each on is different. Sample Question: Which pharmacokinetic process is known as “First Pass Elimination”? Answer: Drugs taken up in the intestine first reach the liver via the hepatic vein, and are therefore subject to hepatic metabolism prior to entering the general circulation. Sample Question: What is bioavailability? Answer: Bioavailability is a measure of how much of an administered drug is absorbed into the bloodstream, actually reaching the intended site of action in the body. (defined as percentage of the drug that is detected in the systemic circulation after administration) Question: What is the route of insulin administration and why? Answer: Subcutaneous. This is because we want to have insulin released in the blood stream at constant rate over a long period of time so it would keep the blood sugar at constant level. Slide 16&17&18|2: TA: Amir Motamedi Email: [email protected] Overview of Pharmacokinetics: •Route of administration: Oral, Topical (including rectal and vaginal), Pulmonal (inhalation) , Parenteral (i.v., i.m., s.c., i.t.) •Absorption and distribution: No matter what the route of administration is, the absorbed drug ends up in the plasma (blood stream). Absorption and distribution requires passage through two barriers: 1. Epithelium: external absorption barrier in contact with outside environment. Tightly connected to each other by Zonulae occludens (tight junction). • 2. Endothelium: Internal blood tissue barrier. These are cells that line interior wall of blood vessel. Drug can pass this barrier mostly in capillary bed. Different permeability at different tissue, which provide the tissue with different • level of protection: Following are very important Cardiac muscle: high endo- and transcytotic activity Endocrine glands, gut: Fenestrations with diaphragms. (passage of small molecules) Liver: Large fenestration without diaphragms -> drugs exchange freely. Why Large fenestration? Liver is main detoxifying organ in body which requires toxic material to enter it for detoxification. Disadvantage: liver is the least protected organ. CNS, Placenta: Transcellular diffusion of drug of specific physicochemistry. Endothelia lack pores and little trans- cytotic activity Advantage: Most protected organ Disadvantage: Not all drugs targeted for the brain can pass the bloodbrain barrier. Slide 16&17&18|2: Overview of Pharmacokinetics (Cont.): TA: Amir Motamedi Email: [email protected] •Metabolism: Metabolism is a process through which drugs gets converted into a form so they can be eliminated from body. (If the elimination is through urine, metabolism coverts drug into hydrophilic form). Liver is principal site of drug metabolism. Not all drugs need to get metabolized, meaning that some drugs can be eliminated from body in there original form. -Usually these drugs are expelled through milk, sweat glands, and expired air. EX: lipophilic sex steroid through sweat gland and inhalation anesthetics diffuse out of blood stream into air in lungs and gets expelled from body. Note: Metabolites are the product of metabolism of the drug. (drug is no longer in original form). •Elimination: Most prominent route of elimination: (Kidney -->Urine) < (Gut --> Faeces) << (Breast& sweat glands -->Milk & sweat) ~ (Lungs --> Expired air) TA: Amir Motamedi Email: [email protected] Slide 16|2: •Pathway of oral Administration of drug, also known as First Pass Effect: Intestinal metabolism absorption of drug through guts (Intestine) --> hepatic portal system (blood stream which goes to liver) --> liver (site of drugs metabolism) --> Three things might happen: 1. Drug cannot get metabolized (neither in liver nor in any other part of body) and the original form of drug cannot be eliminated from body (lipophilic drug, more on this later) --> drug keep circulating in the blood stream and cannot be eliminated. 2. Metabolized drug or drug in original form gets released into blood stream --> kidney --> Urine. (default pathway of all orally absorbed drugs). 3. Entrohepatic circulation: Some of the Metabolites or drug in original form gets incorporated into the bile (bile is made in the liver) --> bile is released in the intestine by liver --> bile containing drug gets reabsorbed in the intestine --> hepatic portal system... Question: Which route(s) of drug administration lacks "First Pass Elimination"? Answer: Any route in which abortion through gut is not part of the pathway. Ex: Percutaneous (including rectal and vaginal), Parenteral (I.V., I.M., S.C.), Pulmonal (inhalation). TA: Amir Motamedi Email: [email protected] Slide 19|2: Movement of drug through membrane: 1. Passive diffusion: •Remember: Movement of molecules from one environment to another is a function of: 1. Membrane permeability: In this case, membrane is permeable to Lipophilic (hydrophobic) molecules which means drugs in uncharged (unionized) form. Majority of Drugs are weak acids and bases. Blood has a slightly basic pH, and Urine has a slightly acidic pH. Weak acids are uncharged in acidic (Low) pH --> membrane permeability. They become charged (ionized) in basic (high) pH --> no permeability. Weak bases are uncharged in basic pH --> membrane permeability. They become charged in acidic pH --> no membrane permeability. 2. Driving force: In this case, depends of the concentration of molecule in each side of the membrane. The higher the difference between concentration molecule on each side of • membrane, the higher driving force towards the side with lower concentration •Remember: The ionized and non-ionized form of one drug are not considered as the same molecule. Once drug is ionized, the concentration of drug (non-ionized form) is actually reduced. Case study: A drug that is weak base travels in blood in non-ionized form and reaches kidney. Drug is: 1. High in concentration in blood & low in concentration in urine Driving force towards urine is high. 2. Non-ionized has lipid solubility (membrane permeability) Due to 1 and 2 drug crosses the membrane into the urine (one might • think that steady state will reach after a while by increasing the concentration of drug in the urine), however acidic environment of urine ionizes the drug into a different molecule (ionized form of drug) the concentration of drug on urine side still stay low driving force stays high. Additionally, ionized drug on the urine side does not have membrane permeability to cross over into the blood gets expelled Slide 19|2: TA: Amir Motamedi Email: [email protected] Movement of drug through membrane (Cont): Effect of broccoli on drug elimination: •This is an example of Drug food interaction (more on this later): •Broccoli increase pH of urine to alkaline (basic pH, 7-8). •Case study: A weak basic drug reaches kidney and passes the membrane into urine which now has a high pH. Thus, drug does not get ionized concentration of drug on the urine side will increase (also the membrane is permeable to non-ionized form of drug on the urine side) driving force keeps decreasing as the concentration of drug on urine side increase Concentration of drug on urine side become equivalent to concentration drug on blood side driving force =0 steady state reaches drug does not get excreted into the urine (or excretion is very slow) drug elimination occurs very slowly half life of drug increase (more on half life later). •Diet that is more on plant side than grain side cause urine to be more basic. •Diet that is more on protein causes more acidification of urine. •Metabolic syndrome can also change pH of urine. 2. 3. Active transport: Drug uses transport mechanism that are in the body to transport some molecule that are required by body. Receptor mediated Endocytosis: drug binds a cell surface receptor and the complex of drug and receptor gets internalized to form endosomal vesicle. • This mechanism is used to transport toxic molecule into the cell. It is used for cancer therapy in the way that if there is a unique cell surface receptor on the surface of a cancer cell, you make an antibody for the receptor and complex the antibody with a toxic molecule. Thus antibody binds the receptor, and the complex gets internalized the toxic conjugated with the antibody will kill the cancer cell. TA: Amir Motamedi Email: [email protected] Slide 21&23|2: •Bioavailability is a measure of how much of an administered drug is absorbed into the bloodstream, actually reaching the intended site of action in the body (functionally available) = the AUC of the (orally) administered drug divided by the AUC of the intravenously administered drug. During administration, drug is being absorbed and eliminated at the same time. Once administration is complete, the curve reaches its peak and starts dropping. At this point drug is only being eliminated from body. •Volume of distribution: •Is not a real volume. It is a theoretical volume. •Drugs have different affinity for proteins in the blood. Once drug binds the plasma protein, it is no longer available to perform its activity. •What we measure and mean by drug concentration of plasma is the concentration of free drug in the plasma. •Formula: Vd = Amount of drug administered [mg]/ plasma concentration of drug [mg/ml] •Example: •A 70Kg patient has approximately 2.8L plasma volume available for drug. If this person take 100mg of a drug: If all drug stay in the plasma: plasma Concentration of drug is 100mg/2.8L Thus volume of distribution= 100mg / (100mg/2.8L) = 2.8L = 2.8L If 90% of drug gets bound to plasma protein--> only 10% of drug in plasma: Plasma concentration drug is 0.1(100mg)/2.8L Thus volume of distribution = 100mg/ (0.1(100mg)/2.8L) = 28L This is the same as saying we have 100mg of drug in 28L Remember: amount of binding of drug molecules to plasma protein alters half life of drug. TA: Amir Motamedi Email: [email protected] Slide 24& 25|2: • Rate of elimination: •Both filtration (kidney) and metabolism (liver) follow first-order kinetics meaning that rate of elimination depends in plasma concentration of drug. •There are only three drugs that have zero-order elimination (independent of concentration drug in the plasma). •Clearance is the volume of plasma cleared of all drug per unit of time. •Drug has a plasma concentration. The rate at which this concentration of drug is being eliminated from body is considered as clearance. Slide 26&27|2: TA: Amir Motamedi Email: [email protected] •Half life is the time required for the concentration of a drug to fall by 50% •Only drug that follow first order kinetics have constant half life. •Remember: In order to calculate these values, we experimentally measure Vd and half life. •Steady state concentration is the plasma concentration of drug at which amount of drug administered per time unit equals the amount eliminated per time unit. •Remember: the way you administer the drug does not change the steady state concentration. •Remember: you cannot calculate Css at any time. You have to wait until you reach steady state, then you measure infusion rate and clearance, and then you calculate Css. TA: Amir Motamedi Email: [email protected] Slide 28|2: •In order for the drug to have an effect in the body, it need to reach a specific plasma concentration. Loading dose is used to reach this specific concentration. •Once we reach desired drug concentration in the plasma, we need to maintain this concentration to maintain the effect. Thus we use maintenance dose. •Possible effects of drug protein binding: 1. Drug with high protein binding stays in body for longer period of time --> longer half life. 2. Effects of drug-drug interaction: •Drug A and B both bind to a protein. We first administer drug A which first bind two this specific protein. Then we administer drug B, which wants to binds to protein, but it cannot since the site of binding is occupied by drug A. Thus one or both of the following happens: I. Drug B reaches toxic concentration in plasma II. Drug B is eliminated faster than expected because of having higher concentration than what it is suppose to have. 3. Liver is site of albumin (plasma protein) synthesis. People with liver damage (or malnutrition) have less production of albumin --> less binding of drug to albumin --> higher concentration drug --> same effect that mentioned for drug B. Slide 33|2: TA: Amir Motamedi Email: [email protected] •Effective dose is the concentration of drug at which 50% of the patients show a predefined response. •LD50 is the dose of drug by which 50% of the patient die. End Of Lecture 2 ...
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This note was uploaded on 04/13/2010 for the course BIMM bimm 118 taught by Professor David during the Winter '09 term at UCSD.

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