General Principles of Pharmacology PDF

Pharmacology (PHCO 310) General Principles of Pharmacology Bio A driven individual with a strong academic background in Pharmaceutical Sciences. Education/Academic qualification Doctor of Philosophy, Pharmacology, The University of Manchester, UK (Award Date: Apr 2023) Master in Science...

Pharmacology (PHCO 310) General Principles of Pharmacology Bio A driven individual with a strong academic background in Pharmaceutical Sciences. Education/Academic qualification Doctor of Philosophy, Pharmacology, The University of Manchester, UK (Award Date: Apr 2023) Master in Science, Drug Discovery and Pharmaceutical Sciences, University of Nottingham, UK (Award Date: Dec 2016) Bachelor of Science, Pharmacy , Umm Al-Qura University, KSA (Award Date: Jun 2013) Research interests My recent research has focused on uncovering the role of nuclear hormone receptor (NHR) cofactors in breast cancer progression. I am also highly interested in cancer metabolism, EMT, and metastasis. When I am not immersed in my work, you can find me cycling, running or getting lost in a book of poetry. These Hobbies keep me grounded and bring balance to my life. LECTURE OBJECTIVES ▪ At the end of the lecture, the student is going to identify general principles of Pharmacology (history and drugs nature) ▪ At the end of the lecture, the student is going to compare different phases in Drug Development ▪ At the end of the lecture, the student is going to define and interpret Drugs Pharmacokinetics Parameters ▪ At the end of the lecture, the student is going to identify principles of Pharmacodynamics ▪ At the end of the lecture, the student is going to be able to identify Drug-Drug Interaction and Drugs Adverse Effects 3 What is Pharmacology? Pharmacology comes from the Greek word Pharmacology can be defined as the study of pharmakos = drug or medication, logos = substances that interact with living systems study of. through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. What is Pharmacology for Nursing? Whether administering medications or supervising drug use, the nurse is expected to understand the pharmacotherapeutic principles for all medications received by each patient. The nurse's responsibilities include knowledge and understanding of the following: ▪ What drug is ordered ▪ Name (generic and trade) and drug classification ▪ Intended or proposed use ▪ Effects on the body ▪ Contraindications ▪ Special considerations, such as how age, sex, weight, body fat distribution, genetic factors, and pathophysiological states affect pharmacotherapeutic response ▪ Expected and potential adverse events ▪ Why the drug has been prescribed for to this patient ▪ How the drug is supplied by the pharmacy ▪ How the drug is to be administered, including dose ranges ▪ What nursing process considerations related to the drug apply to this patient 5  The Nature of Drugs Drug: is any substance that is taken to prevent, cure or reduce symptoms of a medical condition Drug can be an inorganic ions, non-peptide organic molecules, small peptides, proteins, nucleic acids, lipids and carbohydrates In order of a drug to have a good fit to only one receptors, the drug molecule must be sufficiently unique in shape, charge, and other physical properties to prevent binding to other receptors 6  Characteristics of an Ideal Drug Characteristics of an Ideal Drug Effectively treats, prevents, or cures the patient’s condition Produces a rapid, predictable response at relatively low doses Produces no adverse effects or long-term adverse effects Can be taken conveniently, usually by mouth Can be taken infrequently, usually once a day, and for a short length of time Is inexpensive and easily accessible Is quickly eliminated by the body after it produces its beneficial effect 7 Does not interact with other medications or food In real practice, there is no such thing as a perfect drug  Process of Drug Development The safety and efficacy of a drug must be determined before it reach patients! Preclinical Phase: laboratory work (3-5 years) Clinical phase: Phase 1: (20-100 healthy participants) to assess dosage and pharmacokinetics Phase 2: (100-300 participants with disease) to determine efficacy and safety of the dosage Phase 3: (1000-3000 participant with disease) to determine its efficacy compared to the agents or placebo Phase 4: Post marketing Due to the urgent need in treating life-threatening disease, 8 certain drugs require less clinical evidence of safety, such as, anticancer, antibiotics, and vaccine.  Pharmacology subdivisions Pharmacokinetics: Pharmacodynamics: What the body does to drug What the drug does to body Absorption, Distribution, Metabolism and Excretion Physiological and biochemical effects of drug at organ system (ADME) Pharmacokinetics (Absorption) For a drug to be effective, it must reach its target cells in sufficient quantities Drugs face numerous obstacles (membranes) in reaching their targeted cells It is purely dependent on drugs chemical and physical characteristics to cross through lipid membrane; such as: size, ionisation, and solubility Bioavailability is the fraction of a drug reaches circulation after absorption Drugs pass through this membrane through these mechanisms: 1. Diffusion (passive transport) is the movement of chemicals from an area of high concentration to an area of lower concentration. 10 2. Active transport is when a carrier or transport helped the drug to cross through the membrane.  Pharmacokinetics (Absorption) An example of active transport: P-glycoprotein transporter (comprise a family of ATP-dependent transporter) It is mainly located in the epithelium of GI, Blood-Brain Barrier (BBB) and cancer cells These transporters decrease drug absorption (uptake) from the cells 11  Pharmacokinetics (Absorption) Factors affecting the absorption process: Route of administration: Enteral vs parenteral administration Drug concentration and dose: higher dose means higher concentration, thus better diffusion Characteristics of absorption site: how it can affect the physical and chemical characteristics of a drug or (ionisation, surface area and motility) Blood flow to the absorption site: highly perfused tissue means high absorption rate (IM and SC) Drug interaction 12 A. Enteral 1. Oral Advantages: Safest and most common Convenient Economical Disadvantages: Limited absorption of some drugs Food may affect absorption Patient compliance is necessary Drugs may be metabolized before systemic absorption 2. Sublingual Placement under the tongue allows a drug to diffuse into the capillary network to enter the circulation directly. Advantages: Avoid/ Bypasses first-pass effect Avoid/ Bypasses destruction by stomach Disadvantages: Limited to certain types of drugs May lose part of the drug dose if swallowed B. Parenteral Used for drugs that are poorly absorbed from the GIT (e.g., heparin) and for agents that are unstable in the GIT (e.g., insulin) Used for treatment of unconscious patients and under circumstances that require a rapid onset of action Not subject to first-pass metabolism or harsh GI environments 1. Intravenous (IV) The most common parenteral route. For drugs that are not absorbed orally. Absorption not required. Advantages: Can have immediate effects Ideal if dosed in large volumes Suitable for irritating substances Used in emergency situations Disadvantages: Unsuitable for oily substances Strict aseptic techniques needed 2. Intramuscular (IM) Drugs can be in aqueous solutions, which are absorbed rapidly or in specialised depot preparations, which are absorbed slowly. Depot preparations often consist of a suspension of the drug in a nonaqueous vehicle. Advantages: Suitable if drug volume is moderate Suitable for oily vehicles Preferable to intravenous if patient must self Administer Disadvantages: Painful Cause intramuscular hemorrhage 3. Subcutaneous (SC) Slower than the IV route. Advantages: Minimises the risks of hemolysis or thrombosis associated with IV injection and provide constant, slow, and sustained effects Disadvantages: Pain or necrosis if drug is irritating Unsuitable for drugs administered in large volumes  C. Others 1- Inhalation Provide rapid delivery of a drug, producing an effect almost as rapidly as does IV injection. Advantages: Absorption is rapid; can have immediate effects Ideal for gases Effective for patients with respiratory problems Localised effect to target lungs Fewer systemic side effects Disadvantages: Patient may have difficulty regulating dose Some patients may have difficulty using inhalers 2. Intrathecal: When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. 3. topical: Used when a local effect of the drug is desired. For example: cream, ointment... 4. Transdermal: Systemic effects by application of drugs to the skin, usually via a transdermal patch. used for the sustained delivery of drugs, such as the antianginal drug nitroglycerin Nicotine patches, which are used to facilitate smoking cessation. Advantages: Avoid/bypass the first-pass effect Convenient and painless Disadvantages: Some patients are allergic to patches, which can cause irritation 5. Rectal Advantages: Avoid/ Bypasses destruction by stomach acid Ideal in patients who are vomiting, or comatose Disadvantages: Drugs may irritate the rectal mucosa Not a well-accepted route  Recap 1. The second phase of the clinical testing of drug development involves testing the new drug on 100 -300 patients to determine a) Drug adverse effects b) Drug pharmacokinetics c) Drug efficacy and potency d) Drug post marketing surveillance 2. An ideal drug is any substance that can produce the following, except: a) Taken less frequently b) Eliminated slowly from the body c) Effectively treat or prevent the disease d) Does not interact with other medications  Recap 4. Which one of the following routes of administration is the safest and most common way of given the drug? a) Oral b) Intramuscular c) Intravenous d) Sublingual 5. Which of the following is not a parenteral drug administration? a) Intravenous b) Transdermal c) Intramuscular d) Subcutaneous 6. An Intrathecal route, is administering the drug into: a) Organ b) Venous circulation c) Muscle d) Cerebral spinal fluid Q. List two advantages and two disadvantages of Intravenous drug administration?  Pharmacokinetics (Distribution) It is the process of drugs movement throughout the body after they were absorbed. Once they reach blood, drugs may interact with blood component which may change their chemical or physical characteristics before reaching their target site. Many factors influence drugs distribution: 1. Blood flow to tissues: tissues with high blood perfusion (heart, kidney and liver) receive a high concentration of drugs compared to other tissues(skin, bone and adipose tissues) 2. Drug solubility: lipid soluble molecules are distributed better than water soluble because of the lipid structure of the membrane 3. Tissue storage: Some tissue have the ability to accumulate and store drugs in high concentration relative to other 24 tissues. Bone marrow and adipose tissue are examples  Pharmacokinetics (Distribution) 4. Drug-protein binding Many drugs bind reversibly to plasma proteins, mainly albumin They stay in an inactive form, until they unbound from the protein Some drugs compete with another for plasma protein binding site Some have a greater affinity for these binding site than other drugs causing the displaced medication to reach high levels in the blood and produces adverse effects 25  Pharmacokinetics (Distribution) Volume of distribution: this parameter helps to determine the extent of a drug and to distribute in the body. Small value indicates the drug is most likely to remain in the circulation Large value indicates the drug is distributed outside the circulation 26 Pharmacokinetics (Metabolism) It is also known as biotransformation process that changes the activity of a drug or its chemical structure and makes it more likely to be excreted The liver is the primary site of drug metabolism Metabolism converts lipid soluble molecules into water soluble to be easily excreted from the body Metabolite: is the end product of drug metabolism. It can be less pharmacological active compared to the original drug, but sometimes they are more potent. Prodrug: these drugs have no pharmacological activity until they undergo metabolism 27  Pharmacokinetics (Metabolism) There are two phases of drugs metabolism: Phase 1 (Hepatic Microsomal Enzyme system) include oxidation, reduction, deamination and hydrolysis Phase 2 involves addition of functional groups to drugs chemical structure to make it more water soluble and easily excreted through kidney 28  Pharmacokinetics (Metabolism) Substrates refers to drugs undergo CYP metabolism. Inducers refer to drugs have the potential to induce the activity of specific CYP enzyme, leading to fast metabolism of substrates. Inhibitors refer to drugs have the potential to inhibit the activity of specific CYP enzyme, leading to slow metabolism of substrates. 29 Pharmacokinetics (Metabolism) First-pass effect describes the process of drug absorption directly into the hepatic-portal circulation, which carry the drug to liver before it is distributed to other tissues. First-pass effect can lead to drugs inactivation before they reach the general circulation. 30 Pharmacokinetics (Metabolism) Patient variation in metabolism Infant do not develop mature CYP system until at least 1 year of age Older people generally have a reduced CYP activity Patient with liver impairment have a reduced CYP activity Lifestyle (smoking, grapefruit) may influence CYP activity 31 Pharmacokinetics (Excretion) Drugs will continue to act on the body until they are either metabolized to inactive form or removed from the body by excretion manly from the kidney Elimination is the process of drugs inactivation or excretion Excretion of inactivated or activated drug is mainly mediated by kidney Rate of drug excretion will determine its concentration in the blood and its duration of action Liver and kidney diseases often increases the duration of intensity of drug action in the body Other routes of drug excretion: Renal excretion Pulmonary excretion Glandular secretion Biliary excretion 32 Pharmacokinetics (Time-Response Relationship) Therapeutic effect of most drugs depends on their concentration in the plasma. Therapeutic drug monitoring is a process involving frequent blood tests to confirm therapeutic dose and reduces risk of adverse effects for drugs with narrow therapeutic margin. Minimum effective concentration is the minimal effective drug plasma concentration to produce a therapeutic effect. Toxic concentration is the level of drug that result in serious adverse effect Half-life is the length of time required for the plasma concentration of a drug to decrease by one half after administration. 33  Pharmacokinetics (Time-Response Relationship) In general, medications are used on regular bases When a drug is being administered on multiple doses over an extended periods, the goal is to keep the drug plasma level continuously within the therapeutic range Loading dose is a high dose (amount) of a drug administered to reach therapeutic range faster Maintenance dose is an intermittent dose given on regular bases to keep the plasma drug concentration in the therapeutic range 34 Recap You are comparing two drugs based on their volume of distribution. Drug A has a volume of distribution equal to 4 where drug B has a volume of distribution (Vd) equal to 7. This means: 1. Drug A distributed throughout the body more than drug B 2. Drug A distributed throughout the body less than drug B 3. They are distributed in a similar pattern 4. None of the above All the following are true about drug-protein binding, except: 1. Albumin is main protein involved in this mechanism 2. Some drugs will compete with other to bind to plasma protein 3. Drug bound to plasma protein remains active and produce its pharmacological activity 4. Important mechanism of drug-drug interaction Therapeutic drug monitoring involves the following, except: 1. Multiple blood sampling to test drug concentration 2. Ensure that the drug plasma concentration is below the minimum effective concentration 3. Describes drug’s effectiveness based on their plasma concentration 4. Ensure that the drug plasma concentration is below the toxic concentration A patient received a dose of 400 mg of amoxicillin for treating sore throat. After one hour, a blood sample was collected and showed that only 300 mg of amoxicillin had reached the circulation. This means that the bioavailability of amoxicillin is 1. 90% 2. 80% 3. 75% 4. 50% Pharmacokinetics (PK) involves all the following except 1. Metabolism 2. Elimination 3. Drug-receptor binding 4. Absorption Drug elimination means 1. Drugs metabolism to be inactive 2. Drugs excretion 3. 1 and 2 4. All above  Pharmacology subdivisions Pharmacokinetics: Pharmacodynamics: What the body does to drug What the drug does to body Absorption, Distribution, Metabolism and Excretion Physiological and biochemical effects of drug at organ system (ADME) Pharmacodynamics Describes how the drug bind to the targeted receptor and change the body Interpatient variability Patients have widely different response to drugs which can be illustrated by examining a frequency distribution curve Some patients will require more or less dose than average dose for optimal therapy 38 Pharmacodynamics (Therapeutic index) Median effective dose (ED 50) is the dose required to produce a specific therapeutic response in 50% of a group of patients Median lethal dose (LD50) is the dose of a drug that will kill 50% of a group of animal Therapeutic index (TI) describes a drug’s margin of safety Therapeutic index is the ratio of drug’s LD50 to ED50 Large therapeutic index value means the drugs is relatively safe Small value means the drug has a low therapeutic window and risk of toxicity is high 39 Pharmacodynamics (Drug-Receptor Bond) For a drug to work, it should bind to the receptor For a drug to be specific, receptors must be selective in their ligand-binding characteristics A drug binding to a limited group of receptor types may b classified as selective An example as described in the figure, where drug a is selective to receptor A whereas drug b is nonselective to both receptors 40 Pharmacodynamics (Receptor theory) This theory explains the mechanism of action many medications Cell signaling is part of a complex system of communication that enables cells to perceive and correctly respond to their environment and carry out basic cellular activities Errors in cell signaling are responsible for diseases such as diabetes and cancer Receptor is a class of molecule that cells use to receive information Ligand is a molecule that activate (or inhibit) the receptor 41 Pharmacodynamics (Receptor theory) Once a drug bind to the receptor, it triggers a series of second messenger events within the cell, such as: Conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cyclic AMP) Release of intracellular calcium Activation of specific G proteins and associated enzymes Non-specific cellular response drugs exert their action independently of cellular response. Their mechanism include changing the permeability of cellular membranes, depressing membrane excitability or altering the activity of cellular pump. General anesthesia and osmotic diuretics. 42  Pharmacodynamics (Agonist and antagonist) When a drug binds to a receptor, several possible consequences can result. Agonist refers to a drug that activates the receptor and produces the same type of response as the endogenous substance. Partial agonist refers to a drug that produces a weaker or less efficacious response than an agonist. Antagonist refers to a drug binds to a receptor and prevent the endogenous chemical from binding to produce action. 43 Pharmacodynamics (Receptor regulation) The number of receptors in the biological system is not fixed. The variables responsible for this receptor regulation include repeated short- or long-term activation. Change can occur in short (minutes) or long periods (days). Downregulation is a term describing diminished of the receptor response. Upregulation describes the process of chronic blocking of a receptors. 44 Pharmacodynamics (Potency and Efficacy) Potency is the strength of a drug at a specified concentration or dose. A potent drug will produce its therapeutic effect in a lower dose compared to another drug in the same class Efficacy is defined as the greatest maximal response that can be produced from a particular drug. 45  Recap A high therapeutic index (TI) means: 1. The drug is safe 2. The drug is toxic 3. The drug is not effective 4. The drug is potent Which of the following statements refer to what drug does to the body? 1. Drug indication 2. Pharmacodynamics 3. Pharmacokinetics If a drug (a) is known to be selective to receptor (A), this means the following except 1. Drug (a) can bind partially to receptor (B) 2. Drug (a) can not bind to receptor (B) 3. Drug (B) can not bind to receptor (A) 4. Drug (B) can bind to receptor (A) If 1 mg of lorazepam produces the same anxiolytic response as 10 mg of diazepam, which is correct? A. Lorazepam is more potent than is diazepam. B. Lorazepam is more efficacious than is diazepam. C. Lorazepam is a full agonist, and diazepam is a partial agonist. D. Lorazepam is a better drug to take for anxiety than is diazepam. If 10 mg of oxycodone produces a greater analgesic response than does aspirin at any dose, which is correct? A. Oxycodone is more efficacious than is aspirin. B. Oxycodone is less potent than is aspirin. C. Aspirin is a full agonist, and oxycodone is a partial agonist. D. Oxycodone and aspirin act on the same drug target. Pharmacodynamics (Drug-drug interaction) Drug-Drug Interaction is defined by concurrent intake of two drugs, in where one drug will affect the action of the other Drug-drug interaction may increase or decrease the effectiveness of the drugs or the side effects of the drugs Interaction can result when there is an increase or decrease in Absorption of a drug into the body Distribution of the drug within the body Alterations to drugs metabolism Elimination of the drug from the body 48 Pharmacodynamics (Adverse Effects) Drug reactions (Adverse effects/ side effects): is an unexpected or dangerous reaction caused by administration of a drug. Adverse effect is a term used to describe any unintended effect of the drug. Some side effects of drugs may go unnoticed or are not bothersome to the patients, whereas other reactions are deleterious to the patients. Severe side effect to the marketed drugs are uncommon. Mechanisms of adverse effect Extension of known pharmacological effects (predictable) 49 Might be immunological origin or unknown mechanism  Other pharmacological terms: Indication: Is the aim or purpose the drug is used for to treating, preventing or curing a particular disease with specific dose and direction to apply. Contraindication: is a specific situation in which a drug should not be used because it may be harmful to the person. 50  Generic name: Salbutamol is the generic drug named of a drug used as inhalation to treat asthma Trade Names: It is currently marketed by: Schering-Plough as Proventil-HFA Teva as Proair HFA. GlaxoSmith-Kline as Ventolin-HFA  Recap 1. Metoprolol as shown in the picture is known as a) Code name b) Brand name c) Generic name d) Chemical name 2. The drug name which is given by a particular manufacturer is known as: a) Chemical name b) Generic name c) Trade name d) Code name 3. Drug contraindication is referred to a) The aim or purpose of the drug is used for b) When one drug will affect the action of another drug c) A specific situation in which a drug should not be used d) An unexpected reaction caused by drug administration References: Lippincott's Illustrated Reviews: Pharmacology; Richard A. Harvey & Pamela C. Champe. Lippincott-Raven Publishers , 1997, 2nd edition Goodman & Gilman's The Pharmacological Basis Of Therapeutics, 11th Edition, McGraw-Hill Pharmacology for Nurses: A Pathophysiological Approach, Second Canadian Edition, 2nd edition, Pearson Pharmacology for the Physical Therapist, 2nd edition, McGraw-Hill