MBS-Pharmacology.pdf

Introduction to Pharmacology Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Objectives: 1. Describe the difference between an agonist and a pharmacologic antagonist. 2. Describe the basic pharmacodynamic and pharmacokinetic principles that govern...

Introduction to Pharmacology Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Objectives: 1. Describe the difference between an agonist and a pharmacologic antagonist. 2. Describe the basic pharmacodynamic and pharmacokinetic principles that govern drug action in the body including the Henderson– Hasselbalch equation herapy to 3. Compare and contrast the common routes of drug administration. pharmacot 4. Explain the concept of pharmacogenomics using drug examples. tailored genome > - 5. Describe the difference between a generic and proprietary drug 6. Outline the different phases of drug development  History Example honey : -based on on wounds as anecdotal antibiotic: Protective evidence of layer things working Prehistory – benefits vs toxic effects of plant and animal products. Written records list remedies of many types. Most, however, were worthless or actually harmful. British Library, Public domain, via Wikimedia Commons  17th century, concepts based on observation and experimentation began to replace theorizing and speculating in physiology and clinical medicine. Materia medica—the science of drug preparation and the medical uses of drugs—began to develop as the precursor to pharmacology. Advances and development in chemistry and physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and cellular levels. https://www.baus.org.uk/_userfiles/pages/images/ Museum/Time%20Corridor/Leeches.jpg  During the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were introduced, information accumulated about drug action and the drug receptor. During the last 60 years, many fundamentally new drug groups and new members of old groups have been introduced. Since the 1980’s an even more rapid growth of information and understanding of the molecular basis for drug action has been seen. he said really important  Terminology Pharmacology is the study of the actions of chemicals on biological systems. Drug- chemical substance that brings about a change in biological function through its chemical actions. Can activate or inhibit Medical pharmacology is the area of pharmacology concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease. - prevent prophylactic : Vaccines , dosagesaffects supplements/minerals Toxicology is the area of pharmacology concerned with the toxic As undesirable effects of chemicals on biological systems. - a low dose less likely  Pharmacokinetics describes the effects of the body onIf drugs. ADME (absorption, distribution, metabolism and excretion) Why lowest doses > - no excretion = toxic > - a - the given - are Kidneys via enzymes change first : ↑ can't localize effects of drug so / molecules based on Pt after metabolism they undergo biotransformation Pharmacodynamics describes the actions of the drug on the body including their mechanism of action and therapeutic/toxic effects. zu metabolism major is liver inhibit/activate : organ · 1stpass efte of the drug passing thru liver-chemically modified s changing amount available for effect · most common administration of meds : Oral other. Cr. direct : I V precise) tailored to pt needs I wants ways - :. availability cost Pt clinical state  Pharmacodynamic Principles some on membrane 4 types : some w/ in cell - Drugs must bind to a receptor to elicit an effect. Agonist drugs bind to the receptor and activate it. Pharmacologic antagonist drugs bind to a receptor, compete with and prevent binding by other molecules (agonists) blocking their actions.  Basic Pharmacokinetic Principles absorbedwhencirculatoryso considered A - After administration, a drug must be absorbed , it must then > - permeate through various barriers to reach its site of action. >most blc oral administration GI track → blood - common D - distributed to its site of action receptors > - to M - Drugs may be metabolized to active/inactive products to aid in its elimination from the body. (sopt w/ Kidney failure can need dif dose) > usually Kidneys via. ~ E - The drug must be eliminated from the body after it has brought about its effects. they become toxic or sol cell memb highly lipid drugs easily cross So goes to lot of cells not just · target. a. it pass effect 100mg of med pill 1 take pil oral Via admin Steps : :. :. S Yong lost to liver - drug point : dose 2 dissolves enzymatically they a. liver 100% was aborbed regimen based on assume drug lipophilic fat te If is : can become gets to 61 System a metabolizes Some resevior 3. & y circulation of the drug 60% enters systemic so understand amount in dose : distribution I E a drug has high affinity for - 4 active ingredient.. tissue concentrates in Kidney. released intestines drug has bioavailability so of Kidneys = neprotoxicity in 60 % intestinal capillaries site. 5 to that gets into fromy drug goes to other compartments -> absorb It Bioavailability : amount drug of drug is either. 3 Capillaries drain into systemic circulation bound orn Portal V. after 1st pass bound -. 7 Portal V. into liver blood - 34 anything goes into -most commonlyDRUG systemic circulation it I to liver first goes DOSE given orally- ( is metabolized attach to bloods ↳ product of active ingredient plasma proteins a side from biotrans- · : manys don't go Albumin ↑ - movesites bloodstream - * know they ist into eventually sys a tract into. goes in ↳ excreted form- form not just active dosage dosage : know more than active but packed to reach 6 ingredient ingredient Iso drug safe is is still vasculature optimal absorption enzymatic molecule processing in livething liver metabolizes most stuff effective) & · GI Va Free drug : Can more around to drug Is absorption compartments b/2 no large capillaries - liver attached · albumin made : by to regulate protein into Portal V. - liver osmotic Pressure drain Review of last slide ADME site of drug * major bio transform. are major * kidneys site elimination ADME bloodstream (systemic circ) admin site - from drug going Absorption- movement of drug from the site of administration into - the bloodstream. thru - capillaries move drug body Distribution- movement of drug from blood through capillary tubes into extracellular fluid, cells and tissues. biotrans Sites Cliver getting to Metabolism- movement of drug into hepatic tissues (site of > - biotransformation) > - via Kidney Excretion- movement of drug through kidney for removal from the body.  * review rate : ease - Drug passage through cell membranes depends on: mol like. for big harder peptides Molecular size and shape - S is designed drugs are pH : acids -e varying Degree of ionization Pass through easier than for ↳ Unionized (nonpolar/uncharged) important Ionized = rate Control movement Relative lipid solubility (of ionized and nonionized forms) > - distributed more lipid sol easily Passes memb easily - =.. Binding to serum and tissue properties  Channels how cells : drugs enter · via : Ion proteins the natural transportation methods glycoproteins · drugs take over globular/integral proteins receptors etc carbohydrates... Physicochemical Properties of Drugs Polarity (water solubility) of a drug determines its kinetic properties. sol. proportion of drug that's - lipid Sol. Described as a partition coefficient- measures the relative affinity of an agent for a polar aqueous medium versus a nonpolar, oil-like medium (water soluble versus lipid soluble). Lipid Solubility- Membranes are lipids and drugs must cross several membrane (lipid) barriers in order to reach their site of action. Determinants of Absorption, Distribution and Pass thru memb Elimination :smaller Moleculesas easier. Molecular Weight- Large molecules do not readily cross membranes. Ionization- The more charged a drug molecule, the more water soluble and the less lipid soluble it is. Uncharged drugs readily crosses membranes; charged molecules do not. degree of lonization depends pH on Many drugs are- weak acids or weak bases and their charge at any given moment 6depends on the pH of the medium they are in. drugs are mainly WA  henderson-hasselbach Influence of pH on the distribution of a weak acid between plasma and gastric juice separated by a lipid barrier. 1 E.. aspirin (W. A. ) ionized a is its dis mustofdrugation loodstream > - slower Mer As In oncepass crot neutral favors lonization - d low pH favors un-ionized # 5 form V. acidic GI enviro. - large un-ionized ↓ quickly easily goes s Conc > -. - small lonized Conc form. of E thro memb. -> Capillariese systemic Circ.  (W henderson-hasselbach 1 E aspirin A ) Influence of pH on the distribution of a weak acid between.... plasma and gastric juice separated by a lipid barrier. lonized drug is mostly bloodstrib in E absorption leven though Slower decimales. converter how WA/WB drugs move body concerned as for distrib ) longer. Interconversion crot ⑳ d & low pH favors un-ionized # 5 form ↳. V important slide Mechanisms of Drug Absorption/permeation key Point : Permeation: Movement of drug molecules across biological membranes allows Absorption few ways mainly passive dif (from higher membrane gradient) of passage drug bic the > - : lower. conc. -> conc via. Conc. Transfer of a drug from its site of administration into the systemic circulation. proportion of drug Is permeable can use the memb. Rate and efficiency Route of administration. Four Primary mechanisms for the passage of a drug through cell membranes: Aqueous (Passive) diffusion- Driven by concentration gradient Spontaneous and bidirectional. Occurs in large body interstitial space, cytosol, etc. Not saturable and cannot be inhibited. Shows low structural specificity no energet a Facilitated Diffusion- Requires specific carrier proteins. Can be saturated. Driven by concentration gradient. - limited # so it becomes · Passive dif Just gradient. = saturated needed no energy  Mechanisms of Drug Absorption/permeation if tissue hasa limiteda metabolism Active Transport - Specific carrier proteins involve in absorption. Can low energe be saturated. Energy dependent requiring ATP. Can move drugs against a concentration gradient (i.e. low to high) caper Endocytosis and exocytosis- Substance is engulfed by the cell S into F drug membrane and carried into the cell or out of the cell (buds off the cell membrane, and forms a vesicle containing the material, and is membforms vesicle around mol engulfs it ~ released)... Energy dependent, saturable process. Carries drugs that are large in size E not spontaneous W best way to get big molecules into cell Mechanisms of Drug Absorption · cotransporters make a conc. gradient highly lipid Sol. Nak"cotransporters) sol. endocytosis 11. 3 small H20 thru cell. · bin permeate - · , molecules. memb cells - - - Aqueous Diffusion Lipid Diffusion carrier-mediated ~ tosis extry transport. very important bin MEC defines If 20 given · time v Close to 0 = time my. z dosage regimens Via I V.. Conc. = almost 20 Therapeutic WindowEgraph - Plasm drugin shows onc of a · bell shape graft-oral admin (only 1 dose) toxicity pointWhere Cmax is Conc's effect are > - directly proportional MEC keeps too high the dose zo-30 when MEC is rising narrow therapeutic only taking ~ min window = 2x reached until Peak ((max) a (max Conc 9) causes toxic response m. important for making · a safe regimen drug decreases until MEC - b) again w/ wide therapeutic 2 effective conc. (reg to feel effect). window minimum - Plasma conc ↑ over time. butpt doesn't feel effect until mec & more - keeps loweringIf no doesb give subsequentthis below a @t 0 the going was oral so drug = It ble just took Conc = O  transported via blood except thor 1 V ]. Routes of Administration of Drugs. ble meds thru I V.. avoid 1st pass effect Drugs enter the body at sites distant from the target tissue or organ Oral, parenteral. rectal In most cases, drugs need to be be transported via blood to their site of action. Drugs must be absorbed from the site of administration unless injected intravenously. Route of administration determines the rate and efficiency of absorption. Selecting the route of administration depends on: desired site of action, drug properties, patient’s condition and clinical state, required rapidity and duration of response, convenience and cost, availability.  Su. quick bla longs - highly vascularized https://solutionpharmacy.in/wp-content/uploads/2021/08  except GI track anywhere Parenteral Injection - I.V.-Intravenous-rapid onset bioavailability S.C.-Subcutaneous Useful causes poorly absorbed drugs.corally) I.M.-Intramuscular than - more Vessels S C. patients that are unconscious. so absorbs mores Rate is limited by: faster Rapid onset. Vascularity - blood vessels per area Solubility of the substance in Can better control dosage of interstitial fluid blc that's where drug - is drugs. going Molecules sizelarge molecules take longer to get to target site Parenteral Administration- Intravenous pass Advantages bypassing Disadvantages Bioavailability is 100% Most dangerous route - Drug levels are more accurately Toxic reactions can be seen controlled immediately Extremely rapid Dosing errorScant removeitone can Particles Initial absorption step is by-passed Drug must be in aqueous solution Good for irritant drugs Must be performed slowly Suitable for large volumes Once injected the drug cannot be removed Inhalation Rapid onset Volatile drugs - anesthetics Access to systemic circulation is fast thanks to large lung surface area Management of local conditions broncho constriction, emphysema, COPD Solutions can be atomized into fine droplets Aerosols, nebulizer, inhalers Sublingual there's under a lot tongue of capillaries Rapid onset Sublingual Administration: Absorption from oral mucosa Venous drainage from the mouth is to the superior vena cava. - Ex: Nitroglycerin ist pass effect then R Side of to. bic ↳ given sublingual needs : into systemic circulation causes 80% loss! More oral to be taken when Rectal high insertion : travels thru ↳ after superior rectal veins goes to liver avoids low insertion travels thr inf :. mid rectal vans bypass liver Rectal absorption is often erratic and incomplete. It depends on location vasculature. Commonly used when oral administration is not possible ~Approximately 50% of the absorbed drug will bypass the liver (less first pass than oral route, PO) Many drugs irritate the rectal mucosa. Useful in pediatrics  Route of Administration- Oral Advantages Disadvantages The most convenient route Requires cooperation of patient herapeutic Administration by patient Absorption may be unpredictable bat 13 dow Generally the safest route Gastric irritation- Aspirin wilarge Cost Not useful if patient is vomiting No need for sterile equipment Drug may be destroyed by gastric Allows systemic distribution thanks acidity to GI tract blood supply Onset of action ↳ takes time  Pharmacogenomics Pharmacogenomics (PG) studies the genetic variations that influence drug metabolism and drug effects. It evaluates how a person’s genes affect their response to medications. PG involves the application of genomic analysis of individual patients to the selection of specific drugs and drug dosage (precision, personalized or tailored medicine) Tailored or personalized medicine is medical treatment that takes into account the genetic factors that contribute to pathology and the pharmacogenomic factors that influence the response to drug treatment. Pharmacogenetics studies the genetic basis for variations in drug response and it implies large effects of a small number of DNA variants vs Pharmacogenomics that studies a larger numbers of variants to explain the genetic component of variable drug responses. Generic and proprietary drug - aka : bioequivalent A generic drug dose : Strength must be same Same active ingredient as the brand-name drug Taken the same way Same effect Generic drugs do not need to contain the same inactive ingredients as the name- brand product and they can only be sold after the brand-name drug’s patent expires. Differences between generic and brand-name drugs: Inactive ingredients, such as flavoring or preservatives Cost Drug development Drug development usually begins with the discovery or synthesis of a potential new drug compound or discovering of a new drug target. After a new drug molecule is synthesized or extracted from a natural source, the drug’s interactions with its biologic targets is studied. This leads to the synthesis of related compounds with increased efficacy, potency, and selectivity. In the US, the safety and efficacy of drugs must be established before marketing. When not approved FDA by  In addition to in vitro studies, relevant biologic effects, drug metabolism, pharmacokinetic profiles, and relative safety of the drug must be characterized in vivo in animals before human drug trials can be started. Upon regulatory approval, human testing may begin before the drug is considered for approval of general public use. A fourth phase of data gathering and safety monitoring is becoming increasingly important and follows after approval for marketing. Once approved, the great majority of drugs become available for use by any appropriately licensed practitioner.