Pharmacokinetics 2024-2025 PDF

Block 1.2 lectures 2024-2025 Pharmacokinatics Highlighter key Writer Reviewer...

Block 1.2 lectures 2024-2025 Pharmacokinatics Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Mohammed Almousa Hamad Almuhanna 221-222-223 notes References Student explaintion Deleted  Pharmacology divided to: -Pharmacodynamics (pharma= drug , dynamics= power): it’s the study of drug mechanism of action (what the drug does to the body). -Pharmacokinetics (pharma= drug, kinetics= movement): it is the study of drug movement in the body includes(ADME: Absorption, Distribution, Metabolism and the Excretion of the drug) simply(what the body does to the drug). PRINCIPLES OF PHARMACOKINETICS Because of the pharmacokinetics , drugs are administered differently. For example: Block 1.2 -TL Why we should study pharmacokinetic? to understand 1- Digoxin(a drug used to treat heart failure): it will be more affect you if you’re administered it once daily. Dr. Girish Meravanige the principle of pharmacokinetic means what is concentration reach to mean circulation so that 2- paracetamol (a drug commonly used to treat fever): we normally used it 3-4 times a day in order to control the College of Medicine, KFU concentration will determined what is dose do we use, frequency, and route of administration for each drug body temperature. 3- insulin (used to treatment of diabetes): will be used less if you administered by oral route.  Brainstorming… Mrs Suzan aged 36 years having a hypertension for 2 years. Doctor advised her to take two doses of Tab.Propranolol (40mg) to control her high BP, after food. Once she had an episode of life-threatening arrhythmias and that was treated by injection Propranolol (1mg) by a slow intravenous route. Q.1 Why Tab.Propranolol should be taken with food? Q.2 Why there is difference in the dose of propranolol in oral and i.v route?  Learning Objectives 76. Define pharmacokinetics. 77. What are the principal mechanisms causing the movement of drugs in the body? Which of those is dependent on the chemical nature of the drug? 78. By what ways do small drug molecules cross cell membrane? How do lipophilic and hydrophilic drugs cross cell membrane? How does the pH influence the crossing of membrane by drugs? How is this principle used in accelerating the excretion of drugs in the urine? 79. What are the main routes of administration of drugs? How is the bioavailability of different administration routes determined? Which characteristics of a drug or patient influence bioavailability the most? 80. In drug metabolism, what are the main differences between phase I and phase II reactions? In what ways can a polymorphism of CYP genes (e.g. CYP2D6) ultimately affect the pharmacokinetic profile of a drug? 81. What are the main mechanisms involved in excretion of drugs via the kidney? Consider drugs with lipophilic and hydrophilic profiles. 82. In what units is drug clearance expressed and how is it calculated? Why is elimination of drugs expressed as drug clearance? How does clearance relate to half-life (t½)? What happens with the half-life of a drug when (only!) its volume of distribution is suddenly decreased by 50%? 83. What are the main differences in the pharmacokinetic profile of a single and equal dose of drug administered by (1) IV injection or (2) oral administration? 84. How long does it take for a repetitively administered drug to reach steady state plasma concentration when the drug is (1) administered orally and (2) by continuous infusion? 85. Considering a two-compartment linear kinetic model (first order processes); what is the normal graphical representation of drug concentration versus time? What does the alpha-phase usually represent? 86. Suppose a person is on a steady intake of a certain dose of drug ; it results in a constant average steady state drug level in plasma. What will happen with this steady state plasma concentration of the drug if the dose is doubled in case the drug is eliminated via (1) zero- order/saturation kinetics or (2) via first order kinetics?  Learning Objectives  Understand the processes involved and factors influencing the disposition of a drug which includes (ADME) : Absorption, Distribution, Metabolism, Excretion  Explain how bioavailability, rate of absorption, apparent volume of distribution, total clearance and elimination half- life affect the plasma concentrations of a drug  Pharmacokinetics  Definition: Study of the time course of drug absorption, distribution, metabolism, and excretion. Eliminate  Application of pharmacokinetic principles: Safe and effective therapeutic management of drugs in an individual patient. Routes of Drug Administration 1- Enternal mean deliver drug through digestive system 2- Praenteral mean bypassing drug through digestive system Transdermal  Drug factors: How can we select the appropriate route of drug administration? It depends on the physical and chemical The appropriate route of drug administration depends on two characteristics of the drug > some drugs are in important factors: the patient related factors and drug factors form of solid state, some are in form of liquid state and some are in form of gas state. And some of the drugs are stable with the body pH, some aren’t. and some are irritant and some aren’t. Patient related factors: Obviously, drugs in gas state have to It depends on the condition of the patient, rather the patient is in administered by inhalation route. an emergency state or in a nonemergency state. Also , large molecular weight and large molecular - If the patient is in the emergency state, the most size drugs ( drug is very big ) such as ; heparin , appropriate route is intravenous route because the can’t be administered orally(because it wont be action occur rapidly. absorbed). - If the patient is in the nonemergency state, the most commonly Similarly , drugs that are unstable at used route is oral route. acidic pH levels >as soon as they reach the Additionally, some patients are unconscious, uncooperative or stomach, they are destroyed by the acidity, such continuously vomiting (the drug is better to be administered by as: insulin and penicillin G, we can’t administer parenteral)+ as a doctor, we must mentor the dose of the drug orally. during administration.  Intravenous route : Advantages : 1. Faster action (immediate) (that is why it’s referred in case of emergency) 2. Very large amount of fluid can be administered 3. have an bioavailability (100%) (only route) 4. Irritant drugs(e.g. anti cancer drugs) can be administered 5. The accurate dose can be monitored Disadvantages : 1- Painful 2- Possibility of getting infection 3- Local inflammation 4- Most of the organs are exposed to the drug Oral route : Advantages : It is the most common route which is used for drug administration. Why ? 1. easy to administer 2. painless Disadvantages : 1. Slower action 2. Most of the drug will undergo first pass metabolism (most of the drug will be degraded before reaching the blood stream ) 3. Can’t be used in case of emergency , because the reaction will be delayed  Routes of drug administration Oral routes Sublingual e.g. Glyceryl trinitrate Most drugs are taken by mouth and The drug is placed under the tongue (keep the tablet under the tongue). swallowed. Little absorption occurs This is one of the routes commonly used in emergency cases. until the drug enters the small Such as: glyceryl trinitrate (used in cases of acute angina(chest pain) , intestine. nifedipine ( used for severe hypertension). the tablet is placed under the tongue , the drug will be absorbed through buccal mucus membrane then the drug gains access to systemic circulation and produce its affect immediately.  Intramuscular : - we have to insert the needle into the skeletal muscle Parenteral routes - 90 degree needs to be maintained - The most common muscle that is used in drug administration : 1- gluteus maximus 2- deltoid muscle 3- rectus femoris 4-triceps I.M S.C I.V I.D - The answer of action is much faster ( not equivalent to intravenous but much faster than the oral route ) - While injecting the drug ,we have to take proper recursion , otherwise there will be a possibility of abscess formation or damaging the nerves ( such as ; sciatic nerve ). Subcutaneous : - we have to insert the needle into the subcutaneous fat - 45 degree needs to be maintained - The most common sites that are used in drug administration : 1- Abdomen 2- thigh muscle E.g. insulin injection Intravenous : - The drug is administered into the veins. - 25 degree needs to be maintained in order to inject the drug into the veins - The most common vein that is used in drug administration : cubital fossa region in the elbow: Median antecubital, cephalic and basilic veins. Intradermal : - Drug is injected in the dermal layer - 10 - 15 degree needs to be maintained - It is not commonly used, It is mainly used for hypersensitivity tests.  Drug Absorption Means movement of the drug from the site of administration to the systemic circulation across cell membrane The drug in order to reach to its target it has to cross certain barriers the most important barrier is th biological membrane  Un-ionized, nonpolar drugs are lipid soluble –Diffusible (absorbed) Ionized, polar drugs are lipid  insoluble –Non diffusible (eliminated) 1/ Unionized means non electric charge and have more diffusiblity and absorption 2/lonized means electric charge and have less diffusiblity and absorption  Drug Absorption Routes by which drug molecules cross cell membranes  Types of transport 2| by aqueous channel ( are water channels so they’re selective e.g. - passive transport : doesn’t require energy water and ions molecules ) , only some selected drugs use this route (ATP) ( because the channel is narrow, so the drug molecular size must - active transport : required energy be smaller than the channel size ). mainly seen in : In drug absorption there are different Epithelial cells ( they have very tight junctions ) processes are involved: Three things u should glomerular filtration ( filtration of blood in kidneys) remember Jejunal part of small intestine 1| Most of the drugs (70%) cross the cell membrane by simple diffusion : from high 3 | by carrier mediated (they are protein mediated transport concentration to low concentration, system), only some selected drugs use carrier protein to cross the --- cell membrane ( by shifting the drug from extracellular into It’s not selective intracellular some of them required energy selective doesn’t require energy can’t be inhabited by any other substance  pH and Ionization Clinical implications:  Acidic drugs absorbed better in stomach while basic drugs in intestine Acidic drugs excreted faster in  alkaline urine whereas basic drugs in acidic urine. Drugs incapable of becoming  ionized e.g., Digoxin, steroid hormones Permanently ionized drugs  e.g., heparin, ipratropium Another important things in drug absorption are PH and ionization, they are important factors because they affect the rate and amount of absorption 1 | Ionization is the process by which an atom in molecule acquires a negative or positive charge by gaining or losing electrons to form the ion. the molecule undergo ionization: will lose lipid solubility and they become not able to diffuse easily in cell membrane (they may need channels)  Most of the dugs that we use are either weakly acidic Basic drugs undergo ionization in acidic mediumand (e.g. Aspirin) or weakly basic (e.g. Pethidine). acidic drugs undergo ionization in basic medium *Acidic drugs don’t undergo ionization in acidic medium (the drug remains in an unionized state à better diffusibilty to the biological membrane) - Weakly acidic will be ionized more in alkaline pH ln basic drug (e.g. morphine) poisoning or overdose we can– *basic drugs don’t undergo ionization in basic medium facilitate the elimination of the drug by making the urine acidic (the drug remains in an unionized state à better (giving the patient ascorbic acid (vitamin C) or ammoniochloride) diffusibilty to the biological membrane) In acidic drug (e.g. phenobarbital) poisoning or overdose we- - Weakly basic will be ionized more in acid pH can facilitate the elimination of the drug by making the urine alkaline(giving the patient sodium bicarbonate) So, for example, aspirin is weakly acidic and is administered orally, when it reaches the stomach, due to Some drugs will be coated to prevent degradation by stomach acids. its acidic nature it will remain in a unionized state (and o Some categories of drugs like corticosteroids remain in an unionized unionized drugs are absorbed better than ionized stat, in whatever pH, so they have better diffusibility every where drugs). o Other categories of drugs like heparin and aminoglycosides antibiotics In the other situation, if aspirin reach kidney (the pH is remain in an ionized state, these are called highly polar drugs. alkaline or basic) , it will undergo ionization > a losses Highly polar drugs cannot be administered orally, because they wont be its diffusibility (it won't be absorbed in the kidney) absorbed  Factors affecting drug absorption They will be more and better absorption in small intestine than the stomach because of the large surface area in small intestine Drug Factors Patient Factors 1. Lipid-solubility Vascularity and surface area of the absorbing surface liquid drug 2. pH& Degree of drug ionization Functional integrity of Patients who have proper will be better absorbed than absorptive surface epithelium they will have better absorption than a patient with not solid fully functioning epithelial cells 3. Pharmaceutical dosage form Diseases e.g., coeliac, achlorhydria, IBS, CCF 4. Route of administration Parenteral route will always be better than oral route in absorption  Only In intravenously inserted drugs the Bioavailability would be 100% because we are going to administer the drug to the systemic Bioavailability (F) circulation directly Plasma concentration-time curve (AUC) Defined as “ Fraction of a dose of drug that is absorbed from its site of administration and reaches the systemic circulation in an unchanged form” A drug given by i.v. will have a bio-availability (100%) while drugs given by other routes have