Pharmacology Mid Material Lecture 1 PDF

Pharmacology Mid Material – Lecture 1 Introduction to Pharmacology lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  Pharmacology Pharmakon = Drug; Logos = Science Pharmacology can be defined a...

Pharmacology Mid Material – Lecture 1 Introduction to Pharmacology lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  Pharmacology Pharmakon = Drug; Logos = Science Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. Drug A term of varied usage. Medicine: any substance with the potential to prevent or cure disease or enhance physical or mental welfare. – We talk about the drugs in general, about the outcomes of the drug Pharmacology: any chemical agent that alters the biochemical or physiological processes of tissues or organisms (a substance that is listed in the pharmacopeia). – It’s more specific, we talk about the process of the drug. Pharmacopeia A book describing drugs, chemicals, and medicinal preparations: issued by an officially recognized authority and serving as a standard. It contains: Information about the drugs, descriptions, how to use, how to prepare, main reasons for use. E.g. British pharmacopeia (BP) and United state pharmacopeia (USP). 2|Page  Margin of error = 5% for paracetamol Major objective of drug treatment To have a drug at the site of action in a proper concentration that is good enough to reverse a defect without producing side or toxic effects. We should give the drug in the right way so it reaches the site of the action and at the appropriate concentrations. Not supra-therapeutic that leads to toxicity. Not sub-therapeutic that doesn’t give the action required. Drug classification 1. Drug source. 2. The need for prescription. 3. Therapeutic use. 4. Pharmacological category. 5. Physiological system targeted by the drugs. 6. Chemical nature. 7. Drugs to treat common vs. rare diseases. 3|Page  1. Drug Source A. Natural: Plants (atropine, digoxin), Animals (insulin), Human (growth hormone), Microorganisms (Penicillin, streptomycin and many other antibiotics) B. Minerals: Liquid paraffin, magnesium sulfate, magnesium trisilicate, kaolin, etc. C. Genetic engineering: Human insulin, human growth hormone etc. D. Semisynthetic: (human insulin) E. Synthetic: (agonists; antagonists) most common, and now used widely more than those of other sources. 2. The need for prescription A. Prescription drugs: Are used under only medical supervision and dispensed by an order of medical practitioner only. – Any drug that has a potential for abuse, EX: Antibiotics, their misuse (overuse) leads to increase bacterial or antibiotic resistance. B. OTC (Over the Counter) drugs: Can be sold over the counter without prescription – Drugs that have little potential of abuse. – It differs among different countries. 3. Therapeutic use A. Anti-hypertensive drugs: Atenolol, Furosemide, Amlodipine, Ramipril (Same therapeutic use, but different physiological activity). B. Anti-microbial drugs: Amoxicillin, Ciprofloxacin, sulfamethoxazole C. Anesthetics: Ketamine, isoflurane, xylazine D. hypoglycemic drugs: Insulin, Metformin, Linagliptin, Pioglitazone E. Anticoagulants: Warfarin, Heparin, Rivaroxaban 4|Page  4. pharmacological action This should be precise. Atenolol: Beta blocker (BB) Furosemide: Loop diuretic Amlodipine: Calcium channel blocker (CCB) Ramipril: Angiotensin converting enzyme inhibitor (ACEI) 5. Physiological systems targeted by the drug Drugs acting on respiratory system: Selective beta-2 adrenergic receptors agonists (Albuterol) – Bronchodilator for Asthma. Drugs acting on gastrointestinal tract: Proton pumps inhibitors (omeprazole) 6. Chemical Nature Common chemical groups or structures can be used to classify drugs that have similarity in their pharmacological profile. Ex: Alprazolam, which is an oral benzodiazepine. They have the same nucleus but different side chains. 6. Drugs to treat common vs. rare diseases A. Essential Medicines, as defined by the WHO are those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford. – Ex: Antibiotics and pain killers. – Used because of frequent exposure to infections. – For common disease that have high frequency and vast majority of population get advantage from them (Wider availability). 5|Page B. Orphan Drugs: These are drugs or biological products for diagnosis/treatment/prevention of a rare disease or condition, or a more common disease (endemic only in resource poor countries) for which there is no reasonable expectation that the cost of developing and marketing it will be recovered from the sales of that drug. E.g. sodium nitrite (cystic fibrosis), fomepizole (antidote for methanol poisoning), liposomal amphotericin B (pulmonary fungal infection) and many more. Main branches of pharmacology Pharmacokinetics Pharmacogenomics Pharmacodynamics Chemotherapy Toxicology Pharmacognosy Pharmacotherapy Pharmacoeconomics Clinical pharmacology Pharmacoepidemiology Pharmacogenetics Branches of pharmacology usually answer all of the following questions: How much of a drug to give? Dose How frequent a drug should be given? Related to the biological half- life (t1/2) When to give it? Before or after meals; at bed time, PRN... How to give it? Route of administration - The dosage regimen definition is "Decision of drug administration regarding formulation, route of administration, drug dose, dosing interval and treatment duration." 6|Page  Pharmacokinetics The branch of pharmacology concerned with the movement of drugs within the body. Deals with ADME process i.e. what the body does to the drug Pharmacodynamics The branch of pharmacology concerned with the effects of drugs and the mechanism of their action Drug’s plasma concentration, its response and duration of action i.e. What the drug does to the body and how. Toxicology The branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems. Pharmacotherapy It is the clinical application of pharmacodynamics and pharmacokinetics for treatment Clinical pharmacology Medical discipline which combines pharmacological and clinical expertise with the ultimate goal of improving efficacy and safety in the clinical use of drugs. Pharmacogenetics and pharmacogenomics pharmacogenetics usually refers to how variation in one single gene influences the response to a single drug. Pharmacogenomics is a broader term, which studies how all of the genes (the genome) can influence responses to drugs. The distinction however, is arbitrary and both terms can be used interchangeably 7|Page  Chemotherapy The treatment of disease by means of chemicals that have a specific toxic effect upon the disease producing microorganisms or that selectively destroy cancerous tissue We usually use the word Chemotherapy referring to cancer, while it actually refers to any drug that has toxicity (Chemically) on microorganisms (Antibiotics) or on cells like cancer cells. Pharmacognosy The study about the physical, chemical, biochemical, and biological implications of natural products for medicinal or health benefit purposes. Pharmacoeconomics The branch of economics that uses cost-benefit, cost-effectiveness, cost-minimization, cost-of-illness and cost-utility analyses to compare pharmaceutical products and treatment strategies. Pharmacoepidemiology The study of the utilization and effects of drugs in large numbers of people; it provides an estimate of the probability of beneficial effects of a drug in a population and the probability of adverse effects. It can be called a bridge science spanning both clinical pharmacology and epidemiology. 8|Page  Dosage forms It is the physical form of drug product that is suitable for administration to man. It contains specified dose or amount of drug in a specified quantity or unit of the formulation. A. Solid B. Semi-solid C. Liquid D. Gas Solid Tablets Capsules Powder The capsule may contain powder or small particles but the whole thing with its shell is called a capsule. Powder can be used topically it can be also reconstituted and then injected into the blood, also some kinds of drugs are not stable in the liquid form so we store it in the powder (solid & dry) form till the using time (we reconstitute it). A tablet may contain a very small amount from the drug substance itself (like 10 micrograms) and another suitable substance to make it a bit bigger and swallowable. It (The tablet) might be coated (ex. With sugar) in a shell to give it a colour or taste or to make it slowly absorbed so it won't be completely broken down at one place (high does at that place only), And it can be uncoated. 9|Page  Semi-solid Creams Ointments Paste Gel Suppositories 1. Creams are more aqueous and watery (easily dissolved in water when washing it )while ointments are more oily in nature which gives it a relatively longer contact time, so we give it when the injured area is more exposed also ointments have a moisturizing like function so for example when a dryness in the skin leads to an infection ,ointments are a very good option to treat both dryness and the infection itself. 2. Pastes are similar to creams but highly concentrated and they are relatively thick in nature so it's less spreadable (Can't diffuse easily). 3. Eye Gels have longer contact time than eye drops. 4. Suppositories are semi solid because they dissolve very easily when in contact with the body (at body temp). In cases of skin pigmentation (skin discoloration); the medications used are relatively of strong effect on skin that is why it is preferable to give pastes in such cases so that we prevent the diffusion of these medications to other areas of skin. 10 | P a g e  Liquid Monophasic Syrup Solution Biphasic Suspension Emulsion Monophasic drugs are completely dissolved in the solution (Once looking to bottle you see no particles in it). Syrups are more sugary than solutions and it also have longer contact time (i.e., cough medicines are usually syrups). Biphasic drug; it is seen in one of the two ways: 1.Solid suspended in liquid solution 2. liquid suspended in liquid solution. Gas Inhalers 11 | P a g e  Routes of administration In order for the drugs to exert their effect, they should reach to the site of action or receptor to produce the effect. This is a complex process This involves the release of the drug from the dosage form, absorption, distribution, metabolism and elimination (pharmacokinetics will be discussed in details later) Routes of administration (the way in which the drug is taken) depends on: 1. The properties of the drug itself and the route of absorption (ex. Some drugs are degraded completely in the GI system so it doesn't reach the blood so it can't be taken orally), so is to ensure that the drug reach the site of action in order to produce the desirable effects 2. It depends also on the patient: – kids can't swallow tablets. – Stroke patients usually have what is called Dysphagia (difficulty in swallowing). Main routes of administrations 1. Buccal and Sublingual 2. Oral 3. Inhalational 4. Parenteral 5. Topical 6. Rectal 7. Transdermal (Patches). 12 | P a g e  Buccal and sublingual Buccal: between the inner cheeks and the gums. Sublingual: under the tongue. Solid (tablet) or liquid (spray) dosage form They are systemic drugs, once the drug is absorbed it reaches (enter) systemic circulation directly. Drug absorbed from the buccal cavity (highly vascular) and the presence of saliva fasten the dissolution in case of tablet dosage form, so that the absorption rate is relatively fast. Advantages: 1. Quick onset of action 2. Avoid first pass effect 3. Can be used for unconscious patients Oral Used for local or systematic effect Solid or liquid dosage forms Drug absorbed from the GI tract Most common Advantages: A. Simplest rout B. Self-administration Disadvantages: A. Slow onset of action B. Absorption issues C. Drug destruction by GIT enzymes D. First pass effect E. Food-drug interaction F. Unsuitable for unconscious or vomiting patients 13 | P a g e  Inhalational Used for local (predominantly) or systematic effects Solid (powder), liquid or gas dosage forms Mostly used for respiratory conditions such as asthma inhalation is usually used locally to treat diseases, most commonly asthma and COPD (that we’ll know more about when we study the respiratory system). inhalers could also be used to give systematic effects; the drug gets absorbed through the lung to the blood circulation and then moves with the blood to the sites of action. because the effects of it is usually local and inhaled directly to the lung, it doesn’t go through the GI tract, so it doesn’t undergo destruction or liver metabolism, and so the dosage of the drug that we need is less when used locally to give the same effect. we can avoid systematic side effects in inhalation and that’s due to it not going through the circulation and not reaching the blood and different tissues. (as opposed to oral) Its effect is instant, for an example: When asthma patients have difficulty in breathing and they take the inhaler Ventolin (trade name for albuterol or salbutamol) the bronchi dilate instantly and breathing goes back to normal, that is due to the fact that it didn’t need the process to through the blood and reach the target, it instantly reached the site of action (the lung). 14 | P a g e  Advantages: A. Smaller dose than oral route B. is used to give the same effect C. Lower incidence of side effects D. Rapid onset of action Disadvantages: A. Local side effects (inhaled corticosteroids) In chronic diseases such as Asthma and COPD, the patient uses inhalers for a long period of time to control their diseases, and because asthma inhalers are corticosteroids & usually having steroids in them, after using them for some time steroids accumulate in the oral cavity resulting in local fungal infection. As a doctor, you should be advising your patients using any inhaler with cortisone in it to rinse their mouth after using the inhaler to prevent that infection. B. Not easy to use in children Explaining it to a child is hard because of its complicated instruction. Parenteral Drugs are given by a rout out of the alimentary canal most commonly by injections A. Intradermal is superficial injection and it is used for diagnostic tests for allergy and vaccines B. Subcutaneous injection used for drugs that cannot be given orally. It gives quick onset and prolonged action (insulin) C. Intramuscular used for solutions (aqueous and oil) and for suspensions. D. Intravenous injection used for aqueous solutions only (antibiotics and parenteral products). E. Intraarticular injection used in arthritis patients to administer corticosteroids. 15 | P a g e 1. Immunologists use intradermal injection to know what is causing a patient allergy and that is through giving them allergens usually in the back in small doses to know exactly what is causing the allergic reaction. 2. Subcutaneous injection (slightly deeper) is given in the fatty tissue, it solves the issue of some drugs (when given by oral administration) being unstable in the GI tract because some of them break down in the GI therefore it won’t be useful, giving it in this way gives a fast effect while still sustaining the release; solving another problem because the sudden release of some drugs to the blood (insulin in this case) can be harmful and lead to hypoglycemia (can cause coma) The subcutaneous injection effects are important (rapid onset of action & sustained release) 3. Intramuscular injection (IM) features: a. we can give bigger doses of the drug in this way. (e.g. 3-5 mL injections cannot be given intradermally or subcutaneously) b. it can be a either an aqueous drug (water-soluble) or it can be oily (lipid- soluble). c. we can give Biphasic liquids (suspensions with solid particles) through this injection. Meanwhile giving it in the vein (IV) can cause some issues like blood clots. 4. Intravenous injection (IV) can be given in huge amounts to patients (in liters; such as in Parenteral Nutrition) as long as it is an aqueous solution otherwise it will cause clotting. 5. Intraarticular injection is given in the joints to avoid systemic side effects that would be caused by cortisone or other components. Topical Can be cream, ointment, gel, paste or lotion for external use. Easy to use It is usually for local use. 16 | P a g e  Rectal Used for local or systematic effect Rectal = suppositories. Solid, liquid or semi-solid dosage forms Drug absorbed from the rectum (3 veins) High bioavailability (but not 100%) Advantages: A. Can be used for vomiting of unconscious patients, children, elderly or mentally disturbed and patients with dysphagia B. Can be used for local action (laxatives) Disadvantages: A. Less convenient than oral rout B. Lower patient acceptability o Rectal effect can be: local (e.g. enemas are used for constipation/to give a laxative effect) systemic (e.g. paracetamol for children if they can’t take it orally due to vomiting) fast absorption due to 3 rectal veins; Two of the three veins in the rectum are directly in contact with the systemic circulation and the third one is in contact with the portal vein (to the liver); therefore 2/3 of the drug are directly absorbed and 1/3 is metabolized, that’s why it has high bioavailability (but not 100%). Transdermal Applied to the skin and deliver a controlled dose of a drug over a specified period of time to produce systemic effect (nicotine patches). =>Most important transdermal use are the nicotine patches helping smokers to quit smoking by giving them controlled amounts of nicotine that diffuse from the patch through the skin to the blood circulation(systemic); sustained release, replaced each day. 17 | P a g e  Test Yourself Overdose midterm selected questions: 1. What is the 'Orphan drug'? a) Drug with cheap price b) Drugs used to prevent & treat rare diseases. c) Work on orphan receptors d) More than one answer is correct Correct answer: B Vagus midterm selected questions: 2. A 35-year-old patient came to your clinic suffering from psoriasis. after looking into his case, you decided that giving local Dithranol will be the best strategy for treatment of this patient. if you know that Dithranol is a corrosive drug that local irritation when applied to the skin, which one of the following dosage forms would be the best for this drug administration to minimize this side effect on the intact skin? Answer: Dithranol paste 18 | P a g e  Pharmacology Mid Material – Lecture 2 Drug discovery and development lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  Drugs from bench to bedside Discovery Development Pharmacovigilance Before the release After the release Drug discovery Drug discovery is the process through which potential new medicines are identified. It involves a wide range of scientific disciplines, including biology, chemistry and pharmacology. For example: the discovery of the factor that induced Mydriasis from the plant Atropa Belladonna by isolating & analysing different chemicals of that plant. Drug Development The process of developing a new drug that effectively targets a specific weakness in a cell. This process involves specific pre-clinical development and testing, followed by trials in humans to determine the efficacy of the drug. The trial starts on: 1-cells and tissues(preclinical) 2- animals like rats (preclinical) 3-on humans(clinical), and after it passed all of these stages we can get to marketing. The development of new drugs is very complex, costly and risky. Complex because we have multivariant stages. Costly; a company can spend millions over the development of one drug Risky if we don’t know much about the medicine, it can present a risk on the patients’/healthy volunteers’ life. 2|Page  Pharmacovigilance The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems This stage happens after the release of the drug to the market; the company keeps on tracing the rare drug’s side effects that shows after a big number of people use it. Will be discussed later during the semester. Investigational Drug Success Discovery/Screening: 5000-10,000 Enter Preclinical Testing: 250 Enter Clinical Testing: 5 Approved by Regulatory Bodies: 1 Elimination for drugs before entering the preclinical testing trials due to reasons for example: finding a reactive group in a drug that may cause toxicity, or due to its large size that may stop it from being absorbed Drugs may cause test-animals’ death, toxicity, undesirable side effects, or have less-than-expected efficacy in the preclinical testing trials, so only a small number successfully passes to the Clinical testing trials (trial on Humans). Reductine is a drug used for weight reduction, before it was released it passed all the trials and was approved to be released to the market, but then they discovered it had lethal side-effects & caused a stroke to the patients and therefore the benefit wasn’t worth the risk so it was pulled out of the market. 3|Page  Drug Discovery & Development 1. Starts with prediction=an idea & hypothesis Awareness of the beneficial effects of plants and animal products (natural sources) Chemical identification of a wide variety of natural mediators and the possibility of modifying them chemically Avoid chemicals with highly reactive groups (toxic) 2. Design and synthesis of useful drugs or substances through simple techniques or with the help of advanced technology. ▪ Plant → fractionation, chromatographic experiments → identification of the active ingredients → isolation → purification → good drug (recently most drugs of plant source could be synthesized). ▪ Animal → isolation of a substance (insulin) Simple peptides → a.a sequencing machine Complex proteins → recombinant DNA technology ▪ Receptology studies: Allowed synthesis of huge number of agonists and antagonists Rational drug design This implies the ability to predict the chemical structure of drug molecule on basis of 3-dimensional structure of its receptor, employing at present suitable computer programs. Only few drugs in clinical use at present were developed in this rational way. Most drugs were in the past developed through random testing of chemicals, or modified molecules of known drugs that are known to have some other pharmacological effect. However, as more would become known about detailed structure of receptors, rational drug design with aid of computers will become more feasible. 4|Page  Facts about development of drugs Enormous and increasing costs, with estimates from $150 million to $900 million, are involved in the research and development of a single new drug that reaches the marketplace. Only 3 of 10 marketed drugs return their research and development (R&D) investments. At the same time, the incentives to succeed in drug development can be equally enormous. The global market for pharmaceuticals in 2006 is estimated at about $640 billion. From 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling medication of all time, with more than $125 billion in sales over approximately 14.5 years. Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years." Pfizer's patent on atorvastatin expired in November 2011. Patent: pharmaceutical patent or drug patent is a patent for an invention in the chemical or pharmaceuticals industry, which doesn’t allow other companies to manufacture or sell that drug for some time (usually 20 years) since the start of the development, and then after that time period is over any company would be able to make that drug. Lipitor is from the statin family. It wasn’t the first statin drug to be released but it was more developed and advanced than the older ones. Statins are a class of drugs often prescribed by doctors to help lower cholesterol levels in the blood by inhibiting HMG-CoA reductases in the liver. 5|Page  Drug development steps and timeline Pre-clinical Testing 6|Page  Determine pharmacokinetic parameters ✓ Absorption, distribution, metabolism…etc Determine pharmacodynamics (MOA) Assessment of drug toxicity=safety ✓ Acute toxicity studies Determination of LD50; Margin of safety…etc ✓ Sub-acute and chronic toxicity studies. ✓ Repeated dose studies. The most important thing to test in the pre-clinical is the safety of the drug. Testing the blood toxicity in the pre-clinical: 1-Acute: giving the animals one high dose of the drug. 2-Sub-acute: giving them a smaller dosage 3-5 times. 3-Chronic: gives them a dosage that we usually give to humans but on a long period of time like 6 months so we can know what accumulate and the toxicity of the drug Pre-clinical safety and toxicity testing To correctly define the limiting toxicities of drugs and the therapeutic index comparing benefits and risks of a new drug. The most essential part of the new drug development process. 7|Page  Parameters measured during pre-clinical phase "No-adverse effect" dose: the maximum dose at which a specified toxic effect is not seen The minimum lethal dose: the smallest dose that is observed to kill any experimental animal, even if one. The Median lethal dose (LD50): the dose that kills approximately 50% of the animals... These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no- adverse effect dose in animals. Presently, the LD50 is estimated from the smallest number of animals possible. Example: We have 100 mice to test a new drug X At 11 mg: all mice developed acute renal failure and died At 10 mg: all mice developed acute renal failure and died At 9 mg: 89 mice developed ARF and died At 8 mg: 64 mice developed ARF and died At 7 mg: 50 mice developed ARF and died At 6 mg: 43 mice developed ARF and died At 5 mg: 30 mice developed ARF and only one died At 4 mg: 15 mice developed ARF but no one died At 3 mg: none of the mice developed ARF nor died At 2 mg: none of the mice developed ARF nor died Please determine the no adverse effect dose for the ARF, the minimum lethal dose and the LD50 for drug X Solution: No-adverse effect: 3 mg Minimum lethal dose: 5 mg LD50: 7 mg 8|Page  Drug development steps and timeline Clinical Trials Dosage forms 9|Page  Ethics of the use of drugs in humans Full detailed protocol has to be approved by the ethical committee, the institutional review board (IRB) All subjects should sign an informed agreement form All subjects should be insured for life and damage Clinical Trials Once a drug is judged ready to be studied in humans, a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA The IND must be available at the site of the experiment. IND contains: 1. information on the composition and source of the drug, 2. chemical and manufacturing information, 3. all data from animal studies, 4. proposed clinical plans and protocols, 5. the names and credentials of physicians who will conduct the clinical trials, and 6. a compilation of the key data relevant to study the drug in man made available to investigators and their institutional review boards. Drug development steps and timeline 10 | P a g e  Clinical Trials Phase 1: – observes the effect of drug as a function of dosage – small number of healthy volunteers (25-50) with age of 20-40s, because the drug has only been tested on animals. – Goal: find maximum tolerated dose & avoid severe toxicity. – Detect safety (Many predictable toxicities are detected in this phase). – If the drug is expected to have significant toxicity, as is often the case in cancer and AIDS therapy, volunteer patients with the disease are used in phase 1 rather than normal volunteers. – Pharmacokinetic measurements of absorption, half-life, and metabolism are often done in phase 1. – We can’t study the efficacy of the drug in phase 1 because it is only tested on healthy people. – Done in research centers by trained clinical pharmacologists – These trials are nonblind or "open"; that is, both the investigators and the subjects know what is being given, and they get informed if it’s the drug or it’s the placebo (placebo effect) and they need to report the side effects and every little single detail they have even if they think it is trivial or unrelated to the drug – A placebo is a substance or treatment which is designed to have no therapeutic value. – Placebo effect: a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself, and must therefore be due to the patient's belief in that treatment. 11 | P a g e  Phase II: – Drug studied in patients with the target disease to determine efficacy, (In this stage we experiment the drug on patients (unhealthy people) but they should only have the illness that the drug was designed for). – Number of patients is 100-200 – Detects broader range of toxicities – Done in special clinical centers (eg, university hospitals) i.e. Supervised by doctors – Single-blind design with a placebo & positive control – Single-blind; means that the investigator knows what the patients are getting while the patient doesn’t know if he's getting the real drug or the placebo (won’t have any real physical effects on the patient). – In advanced stages, we use the double-blinded technique in which neither the patient nor the investigator knows who is getting the drug and the placebo but a third party distributes the groups and that raises the accuracy and removes any bias behavior. – Another helpful technique we use beside the placebo is positive control. – A positive control is a part of good experimental design. A positive control receives a treatment with a known response (old drug that we know its effect), so that this positive response can be compared to the unknown response of the treatment (a new drug that we are developing). – For example: when testing a new drug for diabetes, the positive-control group are given Glucophage (Metformin) for comparison purposes. 12 | P a g e  Phase III: - Larger number of patients (e.g. Thousands) - In phase 3 the volunteers must have the illness that the drug was designed for but it’s acceptable if they suffer from other illnesses. - Conducted to minimize errors caused by placebo effects, variable cause of the disease etc. - Further study of safety & efficacy (Safety is studied in all phases while the efficacy starts from phase 2). - Double-blind & crossover techniques - cross over: switching the drugs so the patients that took the placebo over a period of time will be given the drug, and the patients that were using the drug get the placebo. - Investigators are specialists in disease being treated. - If results meet expectations: application is made for permission to market the agent (NDA-new drug application) - Food and Drug administration (FDA) review of New Drug application (NDA) may take up to 3 years - For serious diseases, the FDA may permit extensive but controlled marketing of a new drug before phase 3 studies are completed; - For life threatening disease, it may permit controlled marketing even before phase 2 studies have been completed; - In some cases, we might skip phases 1 & 2, such as when a disease suddenly becomes an epidemic. - Some drugs like anticancer and antiviral are cytotoxic (toxic/lethal to living cells) so we don’t try it on healthy volunteers and we skip phase 1 to phase 2 because it can be harmful to healthy humans. - Once approval to market the drug has been obtained, phase 4 begins… 13 | P a g e  Phase IV: – Constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients. – Has no fixed duration. – Some rare toxicities are revealed (low incidence) – Efficacy studies; by following up with patients who have used the drug. – Features averages & statistics. Phase 0: – Phase 0 or first-in-human trials is a recent phase approved in accordance with the United States FDA’s 2006 Guidelines – Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies – Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics and pharmacodynamics. – A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. – Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development – Phase 0 studies enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data – Questions have been raised by experts about whether Phase 0 trials are useful, ethically acceptable, feasible, speed up the drug development process or save money, and whether there is room for improvement 14 | P a g e  After all these clinical drug trials the drug is usually approved by national or International regulatory authorities and is licensed for General prescribing. Generic Drug Generic drug: a drug product that is produced by any pharmaceutical company after the patent of the originator drug is expired. All of these drugs have the same chemical formula but they can differ in price, taste and some may have less side effects. Also, some may be film-coated and others not. 15 | P a g e  Test Yourself Overdose midterm selected questions: 1. In which drug discovery phase the acute toxicity level is determined? a) Phase I b) Phase II c) Phase II d) Preclinical testing Answer: D Vagus midterm selected questions: 2. Regarding the drug development process, which one of the following combinations is correct? Answer: Phase ꓲꓲꓲ+ involves crossover techniques 3. " phase 0 " or " first in human " trials were approved by the FDA in 2006. which one of the following statements is correct regarding these trials during drug development process? Answer: these studies enable go / no go decisions to be based on relevant human models instead of relying on sometimes inconsistent animals’ data. 4. During drug development process and before testing drugs on human, a full detailed protocol has to be approved by the ethical committee. which of the following is considered as an ethical committee? Answer: IRB (institutional review board) 16 | P a g e  Pharmacology Mid Material – Lecture 3 - Part 1 Pharmacovigilance lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  Pharmacovigilance (PV) PV is concerned with detection, assessment & prevention of adverse reactions to drugs (ADRs) or any drug-related problems. Drug-Related Problems Lack of efficacy – Drugs differ in their efficacy, even if they are from the same class of drugs depending on the case of the patient, so we need to always make sure that the drug suits the case of disease. Manufacturing defects – Defects within the drug itself, or even the container that hold it. – For example, a container may have humidity leakage, or non-light proof Medication errors – A medication error is defined as "any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer ✓ Prescribing. ✓ Omission. ✓ Wrong time. ✓ Unauthorized drug. ✓ Improper dose. ✓ Wrong dose prescription/wrong dose preparation. ✓ Administration errors including the incorrect route of administration, giving the drug to the wrong patient, extra dose or wrong rate. 2|Page  Drug misuse and abuse – Drug misuse is defined as the use of a substance for a purpose not consistent with legal or medical guidelines. – Example: Antihistamines, which is used for allergic symptoms, and have side effect of increased appetite, so patients misuse it to gain weight, and this have many risks on long term use. – Drug abuse the use of illegal drugs or the use of prescription or over-the-counter drugs for purposes other than those for which they are meant to be used. – Example: Met-amphetamine is originally a stimulant drug, which can be abused by addiction. Overdose – A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities greater than are recommended. Typically, it is used for cases when a risk to health will potentially result. An overdose may result in a toxic state or death. Contamination – Mainly related to storage defects, which may again cause humidity or entrance of micro-organisms to the drug. Counterfeit products – Example: Plavix (Clopidogrel) is an antiplatelet medication used to reduce the risk of heart disease and stroke. This drug price was 75 jd, when a fake product went down to the markets with half the price. – These counterfeit products may miss the active ingredient, or even may be contaminated. 3|Page  Recently, the concerns of PV have been widened to include: 1. Herbal (Liver cirrhosis risk) 2. Traditional and complementary medicines (Cupping, Chinese needles) 3. Blood products (Whole blood, Fresh frozen plasma) 4. Biologicals (Drugs that affect the inflammatory process, in RA) 5. Medical devices 6. Vaccines Why Pharmacovigilance? The root of pharmacovigilance: ✓ Pharmaco (Greek)= Drug ✓ Vigilance (Latin)= to keep awake or alert Because information collected during pre-marketing phase are incomplete with regard to possible ADR. Tests in animals are insufficiently predictive of human safety. In animals, we may use mice, rats, monkeys, pigs and other bigger animals, to reach a state of similarity to the pathophysiology that occur in patients, for example, Sepsis pathophysiology that occurs in human being is very much similar to sepsis that occurs in mice, so we test the drug on them. 4|Page  Why Pharmacovigilance? In clinical trials: 1. Patients are limited in number 2. Conditions of use differ from those in clinical practice 3. Duration of trials is limited Why Pharmacovigilance? Information about rare adverse reactions, chronic toxicity, use in special groups (children, elderly or pregnant women) or drug interactions is often incomplete or not available Post-marketing surveillance by companies is therefore essential. Pre-marketing clinical trials have: 1. Statistical power to detect rare ADRs 2. To identify delayed ADRs 3. To identify effects from long-term exposure PV plays a prominent role in establishing safety profile of marketed drugs 5|Page  Definition of ADR ▪ Adverse reaction (ADR) is defined according to definition of WHO “any response to a drug which is noxious, unintended & that occurs at doses used in man for prophylaxis, diagnosis, or therapy of diseases’’. ▪ Difference between ADR & Toxicity: ▪ ADR: reactions that occurs with the recommended dose given. ▪ Toxicity: occurs when a person has accumulated too much of a drug in his bloodstream as a result to higher doses than needed, leading to adverse effects on the body. Epidemiology of ADRs ADRs represent a significant cause of morbidity & mortality ✓ Morbidity: quality of life, state of being diseased. ✓ Mortality: the state of being subject to death. Many ADRs are mild, sometimes serious & can cause death U.S, ADRs caused 100 000 deaths per year, 4th & 6th leading cause of death. Luckily, about 50% of ADRs are preventable. Importance of ADRs Prolong length of stay in hospitals Increase costs of patient care Commonest drugs withdrawal from market: – Reductil (Sibutramine) 2010 – a drug that’s used for weight loss, showed a risk of causing stroke to patients. – Valdecoxib (Bextra) 2005 – Rofecoxib (Vioxx) 2004 Both of these agents are cox-2 selective, were manufactured as anti- inflammatory drugs with no risk of bleeding, but in the same time drugs cause coagulation abnormalities which cause acute coronary syndromes & strokes. 6|Page  ADRs is considered serious if: Causes death of patient Life-threatening (Strokes, Pneumonia esp. in elderly) Prolong inpatient hospitalization (Electrolyte imbalance) Causes significant or persist disability (neurological defects after a stroke) Congenital abnormality ( Teratogenic drugs as tetracyclins ) Risk Factors predisposing to ADRs Age Long duration of treatment )Accumulation of drugs which causes chronic adverse effects) Polypharmacy Liver ( Metabolism function), kidney diseases ( Elimination function). Causes of ADRs 1. Patient (Age, education, disabilities) 2. Drug 3. Prescriber 4. Environmental factors The drug - Narrow therapeutic index, e.g. warfarin, digoxin - Antimicrobials have a tendency to cause allergy - Ingredients of a formulation, e.g. coloring, flavoring 7|Page  Drugs most commonly causing ADRs Warfarin Immunomodulators Diuretics Analgesics Digoxin Antibacterial Steroids Antihypertensives Anticancer drugs Why report suspected ADRs? Documentation of ADRs in patients’ records is often poor Physicians fear that reporting of ADR may put them at risk Under-reporting is common phenomenon Reporting Methods Spontaneous reporting: (Voluntary) - Doctors, nurses & pharmacists are supplied with forms to record suspected ADRs - Reporting ADRs to National Pharmacovigilance Centre - In UK, this is called ‘Yellow Card system’ Prevention of ADRs Taking a drug history Reduce number of prescribed drugs Remembering that certain patients (elderly, those with liver or renal diseases) more susceptible to ADRs 8|Page  Test Yourself Overdose Selected Question: 1. In which of the following pharmacovigilance is concerned with? A. Detection and assessment of the adverse effect. B. The patient should know the price of the drug. C. More than one answer is correct. Answer: A 9|Page  Pharmacology Mid Material – Lecture 3 – Part 2 Drug prescribing and drug compliance -- lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  2.idly, Purposes of Therapy- Therapeutic drug use could be for the following purposes: 1. Curative: seeking a cure for an existent disease or medical condition - ↳ healing Examples: O1. Upper respiratory tract infection. O2. Gastroenteritis - we should give the patient [antibioticsJto cure these diseases 2. Symptomatic: any medical therapy of a disease that only affects its - symptoms, not its cause. Here, we don’t cure the disease but we just reduce its *symptoms. Examples of symptoms: diarrhea, fever, vomiting. - - We can reduce these symptoms by ⑳ giving: antidiarrheal, antipyretic and - - antiemetic, respectively. Reduce Feuer - Prvent vomiting 3. Replacement: Administration of aT body substance to compensate for ↑ - the loss, as from disease or surgery, of a gland or tissue that would is it 3 - - - ris = normally produce the substance. - 810= W · 0 * Examples: = 1. Symptoms like diarrhea & vomiting will lead to many conditions such as: - dehydration (a state of lower minerals, electrolytes and fluids), we should give the patient normal saline (as a supplement) 2. Thyroid cancer (malignant - - tumor), we can cure this disease by thyroidectomy, after thyroidectomy, the patients should take the 2. - hormones (that were secreted from S thyroid gland such as & thyroxine) as a supplement. > · 2* , jd6n9 · 909. 2|Page  4. Supportive: is one that does not treat or improve the underlying - - condition, but instead increases the patient's comfort - ① ② The goal is to increase the patient’s comfort and resistance. - - - Example: patient with viral infection, we use supportive therapy instead of using curative therapy. So, we give them fluids and antipyretic which used to prevent makes them feel better. or reduce fewer. When the patients lose fluids (by diarrhea or vomiting), the new fluids - will be as a supplement, otherwise if they don’t lose fluids, the way of treatment will be supportive just to increase the patient strength. & Resistance. 5. Prophylactic or Preventive therapy: is a therapy that is intended to prevent a medical condition from occurring Example: when we take the& vaccines to prevent a disease from occurring, like aOr flu. biss later on, we will take about arthritic people; they take some drugs (such as DMARDs) which has an influence on the mechanisms of the actions of some diseases, resulting in reducing their immunity that leads - I to make them vulnerable for infections. so, we advise the diabetic and arthritic patients to take vaccines to avoid these disorders). - 6. Palliation: focuses on relieving and preventing the suffering of patients by addressing physical, emotional, spiritual and social concerns arising % with illness. usually for cancer patients to maintain their well-being state. - 3|Page  Rational use of drugs · 9- 01 , Rational use of drugs: "patients receive medications appropriate to - - & = their clinical * needs, in doses that meet their own individual requirements, - - for an adequate period of time, and at the [lowest costJ to them and their - -community". The Ddoses of drugs differ from patient to patient from drug to drug and - - from disease to disease - Choice of effective drugs should be based on: - D1. Efficacy % O e -2. Cost: affordable by patient and community = 3. G These are effective drugs that are Chosen from Essential Drugs: - commonly used in community, and must always be available - · Basis of rational drug prescribing - - Rational drug prescribing is based on a series of steps: T -.,, N 1. Making a specific diagnosis.* 2. Consider the pathophysiologic implications of the-diagnosis. O 3. Select the specific therapeutic⑤ objective. * Example: Case: 60 years old patient, with & - - high blood sugar, obese with a metabolic - - syndrome, most probably, he has type-2 diabetes. (diagnosis) - & Main causes &of type-2 - gdiabetes: insulin resistance and in advanced - g 55 stages beta cells destruction. (pathophysiology) : - - - · So, we should give him insulin or drugs that increase the sensitivity of :, j582S insulin also drugs that decrease the absorption of glucose. , ① & ⑭sulin The main target here: is to lower blood glucose and to protect him from e - further consequences, management not curing (therapeutic objectives). -diabetes (10 Just for management not for treatment. 4|Page  % 4. Select a drug of choice: Consider patient criteria (age, other drugs also - taken, other diseases, and nature of disease) as well as his clinical - presentation - · sid, Mid 1 1,so boy You should choose the most appropriate drug for - your patient -19 - Example: usually we consider - ----- the metformin (Glucophage) the first choice for diabetes, except in some cases; such as: > - - a patient with - kidney diseases (we can’t use it in this case, because the metformin has important side - -- effect which is called lactic acidosis ↳ - (accumulation of lactic acid) and it may lead ultimately to death). 6, 100 (18'sis - Kidney 0- E 5. Design the appropriate dosing regimen, based on patient - lactic acidosis. pharmacokinetics and if they are altered by - his illness -- - Design the appropriate dosing regimen: - S ✓ The minimum effective dose of metformin=1500mg - ✓ The maximum recommended dose of it=2550mg = ✓ The duration (unlimited because it is a chronic disease) & ⑮ G G patient compliance, and adverse 6. Monitor for therapeutic effect(s), - * effects i d - - sid How can we test the efficacy of the metformin? by measuring the blood sugar from e1)fasting 2)an HbA1c (‫)السكري التراكمي‬ Patient compliance: describes the degree to which a patient - correctly-follows medical advices E - Adverse effects: such as: GI upset (nausea, G vomiting, diarrhea …) - - - M j - 5|Page  & insi Types of prescriptions These are of two major types: I. Hospital prescription of drugs: This is written by the treating - - doctor on the & - Physician Order Sheet (POS) of the patient hospital chart. 1 - - It is preceded by the date. - The prescription includes the drug (s) and direction of use i.e. for each 6 drug: the dose to be --given to patient and its route, frequency of administration, and duration of use. This followed by signature of the treating doctor. - A typical chart order might be as follows: note: in-S hospitals usually, - the doctors write the scientific name of the - drug whereas in the office they write the trade name ex:A(paracetamol: Panadol) (respectively) we use: AlendronateG - & =>to treat or prevent - osteoporosis & lactulose =>to treat constipation C Su ; II. Office prescription: oo This is the physician request to the pharmacist aimed at dispensing - drug(s) in proper amount to patient together with directions for - - effective therapeutic use. 6|Page  The prescription includes the following parts: 1. Identification: - 195 it Doctor: Name, specialty, address, telephone(optional) Nat > bosis is - Patient: Name, age, address(optional), Date - & 2. Superscription: which includes the suffix Oa Rx: Recipe (Receive Thou) - - ① 3. Inscription (Body of- prescription): This includes the drug(s), dosea ⑤ - - - form and its strength in metric units, and directions for proper use by - - ⑪ patient, frequency and quantity. [ 4. Subscription: This includes Ge - - directions for dispensing the correct S amount of drug for the patient - - according to frequency of use and duration 15 0 Jos - of treatment. , - - - S - - 5. Re-fill directions: if needed; any special warning to be given to patient - - regarding drug storage or G - use, and if there is a need for child-proof - - container for drug(s) · 6. Signature of prescribing doctor & his license number: usually at > bottom of prescription. - identification J - the symbol (TT) means: the patient should take 2 tablets together orally 0905ou p.o: per oral t.i.d: three times ⑨ > - office" Prescription form Spell out: dispenseE -Dosage Refills: auto refill from the - ① times in day - - three -- ⑮ for 7days. pharmacy. O C = - -Per ora - - - shouln& - Patient - - - ↳ & ↳ i 7|Page  Some abbreviations, in Latin or Greek, that may be needed in writing directions of drug use in prescriptions: ✓ ac: ante cibum (before meals) ante cibum before meals -. ✓ pc: post cibum (after meals) post cibum- After meals > - ✓ bid: twice daily > - daily twice ✓ tid: three times daily three time daily - > - ✓ qid: four times daily four > - time daily. ✓ prn: when needed needed > - When ✓ qd:- every day every day - ✓ qh: every hour > - every hour -! night ✓ qhs: every night at bedtime Ex: patient with constipation is given ✓ stat: at once C enema for only one time. · o once G we Some Measurements that may be used in directions of drug use - - - in prescriptions: one tea spoonful = 5 ml 5M) - one table spoonful = 15 ml > - 15m/ one ounce (oz.) = 30 ml 30m/ => one quart = 1000 ml > - 1000 m one drop = 0.05 ml > - 0. 05 my one ml = 20 drops drop > - 20 Common errors in prescription writing are due to: Jet's & - , 1. Omission of information. ⑮is 2. poor prescription writing. i bis] is - · 8|Page ac-ante cibum- before meals PC-post Gibum -> After meals. bide twice daily- Pin > - When needed -ab1s  DRUG-RELATED PROBLEMS - 1. Untreated condition. 2. Improper drug selection. 3. Subtherapeutic dosage. 4. Overdosage/toxicity. 5. Failure to receive drug. 6. Adverse drug reactions/events. 7. Interactions. 8. Drug use without indication. 9. Non-compliance. - 4/ Untreated condition➔ ex: a patient with excessive asthma, after - taking a lot of drugs(cortisone) the patient will suffer from electrolytes - disaid - imbalance Improper drug selection➔ ex: there are a lot of antibiotics, so the doctor should choose the most appropriate one. Subtherapeutic dosage➔ ex: if the patient takes less than the minimum effective dose then he/she won’t get better. & Overdosage /toxicity➔ warning: the doctor should know about all - - conditions that the patient has and about all drugs that the patient takes - (because these conditions or drugs may react with new drugs which may lead to toxic effects (by increasing the concentration of that drug)) - - Failure to receive drug➔ex-1:di high cost of drug YS) ex-2: like when we give arthritic patient a pain killer and he/she can’t · open the bottle of the drug. ↳ 5 ,8 s i , sid , Adverse drug reactions/events➔ex: metformin has many side effects such as: GI upset Interactions ➔ ex: if the patient takes the iron after eating a diary product, they will interact to each other (calcium and iron) then the precipitation will occur (the iron won’t be absorbed) Iron is absorbed the best on an empty stomach 9|Page  : /159 Drug Compliance is Drug Compliance: means the extent to which the patient follows the - instructions of- - proper drug(s) use, as given by his prescribing doctor on - - the prescription form. Main causes of poor compliance: A 1. Lack of patient education by the prescriber on details of proper drug use or lack of understanding by patients of the instructions when - & taught to them. 2. Failure of patient to obtain the drug due to problems of cost or - - handicap. - 3. Patient forgets to take drug or loss of drug. = 4. Polypharmacy (taking multiple drugs): due to many diseases - -O esp. in a elderly; this is esp. when multiple doses of each drug is needed daily 5. Frequent doses00 - (> 3 / d) and long duration of treatment (months or years) - 6. Age: neonates, infants, children, and elderly - 7. Disabling adverse effects occur - 10 | P a g e  2 The five dimensions of adherence zi · his Health system/HCT factors ➔ weak capacity of the system to = educate patients and provide follow-up jith - Social/economic factors & 3 - Ga✓ Economic ➔ the cost of drugs - Social ➔ it may be related to the & => ✓- - religion (ex: insulin from pork) = Condition-related factor ➔ (such as: depression) - - therapy-related factor ➔ the side effects of drugs - - E patient-related factor ➔ because the patient has many diseases that - E effect on acne - - Consequences of poor compliance: - & 1. Reduced or loss of therapeutic effect, esp. with drugs having short half-life - i 2. Recurrence of disease. - - 3. Withdrawal syndrome occur with some drugs. 145 Some drugs are dangerous to stop suddenly such as: - - - a. beta-blockers (used for hypertension) :(may lead to L - hemi-deteriorate). b. Cortisone from external resources: which weakens D => our glands (our S - - bodies used to take cortisone from⑤ - external resources) so we shouldn’t - - stop it suddenly otherwise we will face many problems. c. antidepressants and antipsychotics. - - - 5581 / 11 | P a g e E  Test Yourself Overdose Midterm Selected Question: 1. Regarding the prescriptions, choose the best statement: > - Answer: Generic name is used in hospital prescription - - Vagus Midterm Selected Question: - - 1. 20. Mr.TA is a 45 years old patient that came to your clinic with an - acute GI (=gastrointestinal) infection accompanied with a high-grade fever and vomiting. you prescribed for him an antibiotic (Ciprofloxacin), antipyretic (paracetamol) to control the fever, and an& antiemetic (Loperamide) to stop vomiting. In this regimen, Loperamide is - considered as ………. Drug. Answer: Symptomatic 2. 42. A 36 old female patient came to your private clinic complaining from bacterial bronchitis. you decided to treat her infection with Azithromycin. the best regimen for her case is to give L 250 mg orally - (tablet), once daily for 3 days on a full stomach. which one of the following abbreviations would you write on her prescription to the - pharmacy? PG-After mea - ⑳ Answer: Azithromax 250 mg tablet, p.o, qd * 3 days, pc. 12 | P a g e  Pharmacology Mid Material – Lecture 4 Pharmacodynamics – Part 1 lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  Pharmacodynamics Pharmacodynamics is the study of the biochemical and physiological effects of drugs, in certain period. It explains how the drug works in our body, reaching to the site of action and how the drug works in order to give the desirable effect In brief, it can be described as what the drug does to the body: 1. Drug receptors 2. Effects of drug 3. Responses to drugs 4. Toxicity and adverse effects of drugs Pharmacodynamics describes: 1. The actions of a drug on the body 2. The influence of drug concentrations on the magnitude of the response. Most drugs exert their effects, both beneficial and harmful, by interacting with receptors (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction. Inactive Active Agonist: maybe a drug or molecule in the body (example; hormone) 2|Page  Mechanisms of Drug Action Drugs can act through: 1. Physical action: – Drug can produce a therapeutic response because of its physical properties e.g.: Mannitol as diuretic because it increases osmolarity. – When mannitol is given, firstly it is absorbed then it is filtered in the glomerulus in kidney, when it reaches to the tubules of the kidney, osmolarity increases → which leads to increase in the Fluid excretion from the body, that’s why we call it an Osmotic Diuretic. 2. Simple chemical reaction: – Drug may act through a chemical reaction. e.g.: Gastric antacids work by neutralizing the stomach acidity with a base, also Chelating agents that bind heavy metals in body. – Chelating agent: we usually use them for toxicity cases – such as: EDTA it binds to the drug/toxic substance we want to get rid of → then elimination of both. 3. Receptors: – Binding to different receptors and causing a biological response. – Most common mechanism – drug-receptor interaction Signal transduction Signal transduction (also known as cell signaling) is the transmission of molecular signals from a cell's exterior to its interior. Drugs act as signals, and their receptors act as signal detectors. Receptors transduce their recognition of a bound “agonist” by initiating a series of reactions that ultimately result in a specific intracellular response. “agonist” refers to a naturally occurring small molecule or a drug that binds to a site on a receptor protein and activates it. “Second messenger” or effector molecules are part of the cascade of events that translates agonist binding into a cellular response. 3|Page  The drug–receptor complex Cells have many different types of receptors, each of which is specific for a particular agonist and produces a unique response. (compatibility) In each organ there’s different types of receptors For example: Cardiac cell membranes, contain β receptors that bind and respond to epinephrine or norepinephrine, as well as muscarinic receptors specific for acetylcholine. These different receptor populations dynamically interact to control the heart’s vital functions by maintaining a balance between their actions, to reach the functional state of the heart. The magnitude of the response is proportional to the number of drugs– receptor complexes. Usually the magnitude of effect we get depends on how many receptors were activated. small amount of drug → activates less receptors → Subtherapeutic drug and vice versa The drug–receptor complex concept is closely related to the formation of complexes between enzyme and substrate or antigen and antibody. These interactions have many common features, perhaps the most noteworthy being specificity of the receptor for a given agonist. Most receptors are named for the type of agonist that interacts best with it (the receptor for histamine is called a histamine receptor). 4|Page  Receptor states Receptors exist in at least two states, inactive (R) and active (R*), that are in reversible equilibrium with one another, usually favouring the inactive state. Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect. Antagonists occupy the receptor but do not increase the fraction of R* and may stabilize the receptor in the inactive state R. Some drugs (partial agonists) cause similar shifts in equilibrium from R to R*, but the fraction of R* is less than that caused by an agonist (but still more than that caused by an antagonist). The magnitude of biological effect is directly related to the fraction of R* meaning R* more → HIGHER response. Agonists, antagonists, and partial agonists are examples of ligands, or molecules that bind to the activation site on the receptor rather than allosteric site. Major receptor families Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes, nucleic acids, and structural proteins can act as receptors for drugs or endogenous agonists. However, the richest sources of therapeutically relevant pharmacologic receptors are proteins that transduce extracellular signals into intracellular responses. Different types of receptors – depend on organ, tissue, desirable response. When we take drug → reaches the plasma → absorption → reaches the interstitial area (between cells) → if this drug is Lipophilic it will enter the cell, but if it wasn’t lipophilic it won’t enter the cell (hydrophilic) Some type of receptors has extracellular and intracellular part Extracellular part binds to the hydrophilic drug → signal transduction 5|Page  These receptors may be divided into four families: 1. Ligand-gated ion channels, 2. G protein–coupled receptors, 3. Enzyme-linked receptors, and 4. Intracellular receptors. To determine what receptor a drug must interact with: A. Drug-Receptor specificity. B. The chemical nature of the ligand. Hydrophilic ligands interact with receptors that are found on the cell surface. In contrast, hydrophobic ligands enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells. Type of receptors according to location: Extracellular Intracellular A-B-C Have extracellular part so they are activated by hydrophilic drugs D only has intracellular part that is only activated when the drug diffuses to the inside and binds to it. 6|Page  Transmembrane ligand-gated ion channels Ion channels have two types, either Ligand-gated ion channels, or Voltage gated ion channels. These two types have characteristics in common: 1. regulated by membrane potential of a cell. 2. Generate action potentials. 3. Have short duration of action (few milliseconds) A. ligand-gated ion channels extracellular portion of usually contains the ligand binding site. This site regulates the shape of the pore through which ions can flow across cell membranes. The channel is usually closed until the receptor is activated by an agonist, which opens the channel briefly for a few milliseconds. Depending on the ion conducted through these channels, these receptors mediate diverse functions, including neurotransmission, and cardiac or muscle contraction. Thus, Trans membrane ligand-gated ion channels are very common in Nerves for generating action potential. B. Voltage-gated ion channels: are transmembrane proteins that play important roles in the electrical signalling of cells. The activity of VGICs is regulated by the membrane potential of a cell, and open channels allow the movement of ions along an electrochemical gradient across cellular membranes. These channels may also possess ligand-binding sites that can regulate channel function, as agonists or antagonists. 7|Page  Examples on Transmembrane Ligand-gated ion channels: 1. stimulation of the nicotinic receptor by acetylcholine results in sodium influx and potassium outflux, generating an action potential in a neuron or contraction in skeletal muscle. – found in many places such as on muscles in somatic nervous system on neuromuscular junctions, in CNS and in ganglia in autonomic nervous system. 2. agonist stimulation of the γ-aminobutyric acid (GABA) receptor increases chloride influx and hyperpolarization of neurons. – are Inhibitory receptors; mainly found in CNS in spinal cord – Binding of GABA molecules or agonists such as muscle relaxants → receptors open → chloride ions influx (negative ions) →the voltage became more negative than the normal voltage → hyperpolarization (inhibition) – *note* resting potential: inside of cell is negative compared to the outside 3. local anaesthetics bind to the voltage-gated sodium channel, inhibiting sodium influx and decreasing neuronal conduction. – Local anesthetic (antagonist) → stabilizes the inactive form of receptor – (even if there was an action potential it will remain inactive) 8|Page  Transmembrane G protein–coupled receptors The extracellular domain of this receptor contains the ligand-binding area (agonist- binding area), and the intracellular domain interacts (when activated) with a G protein or effector molecule. There are many kinds of G proteins (for example, Gs, Gi, and Gq), but they all are composed of three protein subunits. The α subunit binds guanosine triphosphate (GTP), and the β and γ subunits anchor the G protein in the cell membrane Takes longer time than Ligan-gated ion channels, from few seconds to minutes. Functional unit = alpha subunit Binding of an agonist to the receptor increases GTP binding to the α subunit, causing dissociation of the α- GTP complex from the βγ complex. These two complexes can then interact with other cellular effectors, usually an enzyme, a protein, or an ion channel, that are responsible for further actions within the cell. 9|Page  A common effector, activated by Gs and inhibited by Gi, is adenylyl cyclase, which produces the second messenger cyclic adenosine monophosphate (cAMP). Gq activates phospholipase C, generating two other second messengers: inositol 1,4,5-trisphosphate (I P3) and diacylglycerol (DAG). DAG and cAMP activate different protein kinases within the cell, leading to a myriad of physiological effects. IP3 regulates intracellular free calcium concentrations, as well as some protein kinases. Enzyme-linked receptors This family of receptors consists of a protein that may form dimers or multisubunit complexes. When activated, these receptors undergo conformational changes resulting in increased cytosolic enzyme activity, depending on their structure and function. This response lasts on the order of minutes to hours. The most common enzyme linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) possess tyrosine kinase activity as part of their structure. The activated receptor phosphorylates tyrosine residues on itself and then other specific proteins. Phosphorylation can substantially modify the structure of the target protein, thereby acting as a molecular switch. For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates other peptides or proteins that subsequently activate other important cellular signals. This cascade of activations results in a multiplication of the initial signal, much like that with G protein–coupled receptors. 10 | P a g e  Intracellular receptors The receptor is entirely intracellular, and, therefore, the ligand must diffuse into the cell to interact with the receptor. In order to move across the target cell membrane, the ligand must have sufficient lipid solubility (Lipophilic). The primary targets of these ligand–receptor complexes are transcription factors in the cell nucleus. Binding of the ligand with its receptor generally activates the receptor via dissociation from a variety of binding proteins. The activated ligand–receptor complex then translocates to the nucleus, where it often dimerizes before binding to transcription factors that regulate gene expression. The activation or inactivation of these factors causes the transcription of DNA into RNA and translation of RNA into an array of proteins. The time course of activation and response of these receptors is on the order of hours to days. For example, steroid hormones exert their action on target cells via intracellular receptors. Other targets of intracellular ligands are structural proteins, enzymes, RNA, and ribosomes. Examples: 1. Tubulin (intracellular protein) is the target of antineoplastic agents such as paclitaxel 2. The enzyme dihydrofolate reductase is the target of antimicrobials such as trimethoprim 3. The 50S subunit of the bacterial ribosome is the target of macrolide antibiotics such as erythromycin. 11 | P a g e  Some characteristics of signal transduction Signal transduction has two important features: 1) the ability to amplify small signals 2) mechanisms to protect the cell from excessive stimulation. – As an adaptation or response (to high dosages of a certain drug for example), body will try to minimize the effect of the agonist. To protect cells from excessive stimulation Signal amplification A characteristic of G protein–linked and enzyme-linked receptors is their ability to amplify signal intensity and duration. For example, a single agonist–receptor complex can interact with many G proteins, thereby multiplying the original signal many folds. Additionally, activated G proteins persist for a longer duration than does the original agonist–receptor complex The binding of albuterol (salbutamol), for example, may only exist for a few milliseconds, but the subsequent activated G proteins may last for hundreds of milliseconds. Further prolongation and amplification of the initial signal are mediated by the interaction between G proteins and their respective intracellular targets. Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response (effect of the drug may last to 8 hours) Systems that exhibit this behaviour are said to have spare receptors. Spare receptors are exhibited by insulin receptors, where it is estimated that 99% of receptors are “spare.” This constitutes an immense functional reserve that ensures that adequate amounts of glucose enter the cell. 1% of insulin receptor is enough to give the maximum response On the other hand, in the human heart, only about 5% to 10% of the total β-adrenoceptors are spare. 12 | P a g e  An important implication of this observation is that little functional reserve exists in the failing heart, because most receptors must be occupied to obtain maximum contractility. Desensitization and down-regulation of receptors Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of the receptor. To prevent potential damage to the cell (for example, high concentrations of calcium, initiating cell death), several mechanisms have evolved to protect a cell from excessive stimulation. Desensitization When a receptor is exposed to repeated administration of an agonist, the receptor becomes desensitized resulting in a diminished effect. This phenomenon, called tachyphylaxis, is due to either phosphorylation or a similar chemical event that renders receptors on the cell surface unresponsive to the ligand. Drugs of nervous system such as; drugs that treat epilepsy or depression and drugs that treat Parkinson's disease drugs that work on nerves are more commonly to be desensitized. Down-regulation In addition, receptors may be down-regulated such that they are internalized and sequestered within the cell, unavailable for further agonist interaction. These receptors may be recycled to the cell surface, restoring sensitivity, or, alternatively, may be further processed and degraded, decreasing the total number of receptors available. 13 | P a g e  The mechanism of down regulation (what exactly happens?) 1. The transmembrane receptors (that has an extra and an intra cellular sides)→the extra cellular part will hide inside the plasma membrane →when this happens the agonist won’t have the ability to bind to the receptor (down regulation) 2. The receptor itself will be degraded In other cases, the agonist will be stopped → the cell will retain its normal state (how??) (either the extra cellular part will appear again (after it was hidden) or the cell will generate new receptors (because some of them were degraded) → normal state of the cell). Refractory period Some receptors, particularly ion channels, require a finite time following stimulation before they can be activated again. During this recovery phase, unresponsive receptors are said to be “refractory.” Such as neurons, it is activated → action potential is propagated → refractory period (even if the neurotransmitters are present – no conduction will happen) Up-regulation Similarly, repeated exposure of a receptor to an antagonist may result in up-regulation of receptors, in which receptor reserves are inserted into the membrane, increasing the total number of receptors available. Up-regulation of receptors can make the cells more sensitive to agonists and/or more resistant to the effect of the antagonist. 14 | P a g e  Test Yourself Overdose Midterm selected questions: 1. if there were spare 𝜷1- adrenergic receptors on cardiac muscle cells, which statement would be correct? a) The number of 𝜷1- adrenergic receptors determines the size of the maximum effect of the agonist epinephrine. b) Spare 𝜷1- adrenergic receptors make the cardiac tissue less sensitive to epinephrine. c) A maximal effect of epinephrine is seen when only a portion of 𝜷1- adrenergic receptors are occupied. d) Spare receptors are active even in the absence of epinephrine Answer: C Vagus Midterm selected questions: 1- Which one of the following statements is TRUE regarding enzyme – linked receptors? Answer: The activated receptor phosphorylates Tyrosine residues on itself and then other specific proteins. 2- Which one of the following statements is FALSE regarding G protein coupled receptors? Answer: The responses result from these receptors activation usually last for a few milliseconds. (Seconds to minutes). 3- Steroid hormones exert their action on target cells via Answer: Intracellular receptors (they are lipophilic) 15 | P a g e  Pharmacology Mid Material – Lecture 5 Pharmacodynamics – Part 2 lecturer: Yaman Karajeh Contact me on Facebook or 0788330810 for any queries  Dose–Response Relationships Agonist drugs mimic the action of the original endogenous ligand for the receptor, for example, isoproterenol mimics norepinephrine on β1 receptors of the heart. isoproterenol norepinephrine The magnitude of the drug effect depends on the drug concentration at the receptor site. Factors affect the drug concentration at the receptor site: 1. The dose of drug administered. 2. The drug’s pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and elimination. Graded dose–response relations As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect). Plotting the magnitude of response against increasing doses of a drug produces a graded dose–response curve that can be described as a rectangular hyperbola. Two important properties of drugs, potency and efficacy, can be determined by graded dose–response curves 2|Page  Potency Potency is a measure of the amount of drug necessary to produce an effect of a given magnitude. The concentration of drug producing 50% of the maximum effect (EC50) is usually used to determine potency. The EC50 for Drugs A and B indicate that Drug A is more potent than Drug B, because a lesser amount of Drug A is needed when compared to Drug B to obtain 50-percent effect. Potency depends on EC50, when EC50 decreases, the potency increases because we needed little concentration to give 50% of its effect. Antihypertensive Therapeutic preparations of drugs reflect their potency. candesartan and irbesartan are angiotensin receptor blockers that are used to treat hypertension. The therapeutic dose range for candesartan is 4 to 32 mg, as compared to 75 to 300 mg for irbesartan. Therefore, candesartan is more potent than is irbesartan (it has a lower EC50 value, similar to Drug A). At the end they will have the same effect (Same efficacy) 3|Page  Since the range of drug concentrations (from 1% to 99% of the maximal response) usually spans several orders of magnitude, to decrease the range we have to take the Log of concentration and it will give a new curve which is called semilogarithmic plots. This curve is used so that the complete range of doses can be graphed which simplifies the interpretation of the dose– response curve. Efficacy Efficacy is the magnitude of response a drug causes when it interacts with a receptor. Efficacy is dependent on: 1. The number of drugs–receptor complexes (DR) formed 2. The intrinsic activity of the drug (its ability to activate the receptor and cause a cellular response). when a drug effect stops increasing it may have been reached the maximum efficacy. 4|Page  Maximal efficacy of a drug (Emax) assumes that all receptors are occupied by the drug, and no increase in response is observed if a higher concentration of drug is obtained. Therefore, the maximal response differs between full and partial agonists, even when 100% of the receptors are occupied by the drug. Similarly, even though an antagonist occupies 100% of the receptor sites, no receptor activation results and Emax is zero. The response to drugs of differing potency and efficacy Efficacy is a more clinically useful characteristic than is drug potency, since a drug with greater efficacy is more therapeutically beneficial than is one that is more potent. 5|Page  Effect of drug concentration on receptor binding The quantitative relationship between drug concentration and receptor occupancy applies the law of mass action to the kinetics of the binding of drug and receptor molecules: Increasing in concentration increases the binding and therefore the effect. By making the assumption that the binding of one drug molecule does not alter the binding of subsequent molecules and applying the law of mass action, we can mathematically express the relationship between the percentage (or fraction) of bound receptors and the drug concentration: kd is inversely proportional to affinity. [D] = the concentration of free drug, [DR] = the concentration of bound drug, [Rt] = the total concentration of receptors and is equal to the sum of the concentration