Week 3 Sem - Pharmacokinetics PDF

SCH1105 Introduction to Pharmacology Week 3: Pharmacokinetics  PLEASE GO TO www.kahoot.it Enter the PIN on the showing on the screen Pharmaceutical preparations Pharmaceutical preparations or dosage forms are drug products suitable for administration of a specific...

SCH1105 Introduction to Pharmacology Week 3: Pharmacokinetics  PLEASE GO TO www.kahoot.it Enter the PIN on the showing on the screen Pharmaceutical preparations Pharmaceutical preparations or dosage forms are drug products suitable for administration of a specific dose of a drug to a patient by a particular route of administration. Drugs can be given via a local route or a systemic route LOCAL ROUTE SYSTEMIC ROUTE One of the simplest routes Drug reaches the blood and Given at the site of desired action produces systemic (whole body) effects Minimal side effects e.g. Enteral or parenteral e.g. topical Summary of medicine preparations ▪ Medicines can be formulated in many different forms, from tablets to capsules and powders to liquids. ▪ Medicines can be administered to the body by routes involving the gastrointestinal tract (‘enteral’ administration) ▪ Medicines administered avoiding the gastrointestinal tract are termed ‘parenteral’ medicines. ▪ Almost any part of the body can be used to administer medicines parenterally. Stages of drug action Administration Pharmaceutical Pharmacokinetic Pharmacodynamic IV Dissolution of the drug Absorption Pharmacological effect Intraosseous Amount of drug available Distribution Receptor Intramuscular for absorption Metabolism Enzyme Subcutaneous Excretion Chemical Inhalation Bioavailability – amount of Physical Sublingual drug available for action Buccal Oral Routes of administration? What factors determine the choice Factors determining route Drug characteristics Type of use – emergency/routine/acute/chronic Patient condition – unconscious, vomiting, diarrhea Age Co-morbid diseases Patient/doctor choice Local administration - topical This is where the drug is applied to the skin/mucous membrane for local actions. A wide variety of preparations can be used e.g. creams, ointments, gels, lotions, patches, sprays, powders, foams, solutions, pastes. Can also be administered to a wide variety of places: Oral cavity (for oral conditions) GIT (non-absorbable tablet e.g. antibiotic before gut surgery) Rectum and anal canal as an enema (liquid) or suppository (solid) Eye, ear, nose as drop, ointments or sprays (allergies) Bronchi as inhalation for asthma Vagina as a pessary Urethra (local anaesthetic for catheterisation) Deeper areas are reached using syringe and needle (infiltration of local anaesthetic) Systemic routes - enteral vs parenteral Systemic routes of administration – where the drug reaches the blood and produces systemic effects throughout the body. Enteral – any administration of a substance by GI tract. The enteral comes from the word ‘entero’ which means intestines e.g., oral, sublingual and rectal route. Parenteral – a route of administration into an organism other than through the GI tract e.g., injection, inhalation, and transdermal route. Enteral route - oral Most common and accepted route Preparations include tablets, capsules, syrups etc. (refer to Week 1 content). ADVANTAGES DISADVANTAGES Cheap Slow onset, not good for emergency Self-administered Unpalatable or highly irritant drugs cannot be given Convenient for repeat and long-term use Potential destruction of drugs by stomach acid Relatively safe Cannot be given to unconscious/uncooperative Painless patients Not suitable for patients with vomiting or diarrhea Susceptible to hepatic first pass effect Hepatic first-pass effect First-pass metabolism - drugs that have been taken orally reach the gut. From here they enter the hepatic portal vein and are taken to the liver where they are extensively converted to inactive metabolites. Therefore, they have low bioavailability. Bioavailability refers to the fraction of drug that enters systemic circulation unchanged after being administrated by particular route of administration. Bioavailability and first pass metabolism Bioavailability and first pass metabolism First pass metabolism Bullock & Manias 2022 Activity Ibuprofen (an anti-inflammatory analgesic) can be obtained as a solution in a gelatine capsule for the treatment of acute, painful conditions. In the treatment of rheumatoid arthritis, it is usually given in the form of an enteric coated tablet. What is the difference between these two formulations and why are they used in each instance? Enteric coating is a polymer barrier applied to oral medications to prevent the drug from being released in the stomach, but instead in the small intestine Activity Ibuprofen like all anti-inflammatories can cause gastric problems, partly due to their acidic nature. As the stomach is acid, the combination of two acids could work synergistically. To avoid this, the drug can be enteric-coated to avoid release into the stomach. This is useful for long- term treatment with ibuprofen e.g., rheumatoid arthritis. If ibuprofen is to be used as a simple analgesic to treat an acute condition, giving it in liquid form will lead to a large dilution in the gastric fluids and lessen a direct effect on the gastric mucosa. The drug would also be absorbed more rapidly, being already solvated, and thus would act more rapidly. Oral route – enteric coating of tablets Enteric coating Prevents gastric irritation Protects drug from gastric acid/digestive juices Slows down drug absorption therefore ↑ duration of action Done by cellulose, acetate etc. Can also have sustained/controlled release version (SR or CR) Consists of different coatings dissolving at different time intervals ↑ Duration of action ↓ dosing frequency ↑ Patient compliance Enteral route – sublingual/buccal Drug is kept under the tongue or in the cheek cavity and absorbed through the sublingual or buccal mucosa Bypasses first-pass metabolism ADVANTAGES DISADVANTAGES Rapid onset Not suitable for irritant and lipid insoluble Action can be terminated by spitting out drug drugs Bypasses first-pass metabolism Not suitable for unpalatable drugs Self-administration is possible Not suitable for children Bullock, S., & Manias, E. (2022). Fundamentals of pharmacology (9th ed.). Pearson Australia. Enteral route – rectal Solids and liquid dosage forms can be used. Can be used for local effect e.g., retention enema or evacuant enema. Can also be used for systemic effect. ADVANTAGES DISADVANTAGES Local effect in required location. Local effect may be irritant. Systemic effect suitable for unconscious or Systemic effect susceptible to first pass vomiting patients. metabolism if not administered correctly. Systemic effect avoids first pass metabolism Uncomfortable. if administered in the lower part of the rectal canal. Parenteral routes Route of administration into an organism other than through the GI tract e.g., injection, inhalation, and transdermal route. ADVANTAGES DISADVANTAGES Rapid onset therefore suitable for emergency Requires sterilisation and aseptic conditions Suitable for unconscious/uncooperative Invasive technique, painful patients Can cause local tissue injury e.g., nerves, Suitable for use in patients with vomiting or vessels, etc. diarrhea Requires technical experts therefore limiting Suitable for irritant drugs self-administration Drugs with high first pass metabolism can be Expensive given Drugs destroyed by digestive juices can be given Parenteral route - inhalation Suitable for volatile liquids and gases e.g., general anaesthetics. ADVANTAGES DISADVANTAGES Rapid onset. Can cause local irritation. Localised to target organ for respiratory Rapid termination of effect. drugs therefore minimising side effects and allowing lower doses to be used. Dose regulation is possible. Bullock, S., & Manias, E. (2022). Fundamentals of pharmacology (9th ed.). Pearson Australia. Parenteral route - transdermal Patches deliver drug into circulation for systemic effects. ADVANTAGES DISADVANTAGES Self-administered Expensive formulation Good patient compliance Local irritation (itching, dermatitis) Prolonged action Patch may become dislodged if not applied Minimal side effects correctly Constant plasma concentration Bullock, S., & Manias, E. (2022). Fundamentals of pharmacology (9th ed.). Pearson Australia. Parenteral route – injection types Most used injections are illustrated below however there are others e.g., intra-arterial, intraosseous, intra-articular, intrathecal. What determines type of injection? Drug properties Chemical nature - Some drugs are more stable or effective when delivered via a particular route. Solubility - Water-soluble drugs might be administered intravenously, while oil-based drugs might be given intramuscularly. pH and osmolarity - These factors influence the drug's compatibility with the injection site. Desired Speed of Action: Rapid Onset: Intravenous (IV) injections provide the fastest onset of action as the drug is delivered directly into the bloodstream. Moderate Onset: Intramuscular (IM) and subcutaneous (SC) injections provide slower absorption compared to IV but faster than oral administration. What determines type of injection? Drug volume Large volumes – Often administered intramuscularly or intravenously. Small volumes – Suitable for subcutaneous or intradermal injections. Patient factors Age and size: Paediatric or geriatric patients might require different injection techniques or needle sizes. Physical condition: Certain conditions (e.g. poor peripheral circulation) may affect the choice of injection route. Site of action Systemic effect – IV or IM injections for widespread throughout the body. Local effect – Injections like intra-articular (into a joint) for localised treatment. What determines type of injection? Duration of effect Short-term – Drugs that need to act quickly and be cleared quickly are often given via IV. Long-term – Depot preparations given intramuscularly can release the drug slowly over time. Formulation requirements Viscosity: Highly viscous solutions are better for IM injections. Irritation potential: Drugs that are irritating to tissues may require a route that minimises discomfort. Risk of complications Infection risk – IV injections carry a higher risk of infection compared to other routes. Tissue damage – Repeated injections may cause tissue damage. Parenteral route – injections Intradermal Injected into dermal layer of skin e.g., BCG vaccination, drug sensitivity testing Subcutaneous Injected into subcutaneous tissue e.g. insulin, adrenaline Adv - can be self-administered, depot preparations can be used (slow release) Dis – unsuitable for irritants, slow onset (unsuitable for emergency) Parenteral route – injections Intramuscular Injected into large muscles e.g., deltoid, gluteus maximum Administering vaccines, hormonal medications (depo-provera) Adv – faster onset compared to oral, good for gradual absorption Dis – requires aseptic condition, painful, may lead to abscess, self administration not possible, local tissue injury can occur Intravenous Bolus administration (single large dose), slow IV injection, IV infusion e.g., morphine for rapid pain relief Adv - 100% bioavailability, rapid onset (suitable for emergencies), large volume can be given, highly irritant drugs can be given (chemotherapy), constant plasma levels can be maintained Dis – once injected action cannot be stopped, may cause local irritation, strict aseptic conditions mandatory, self-administration not possible Parenteral route – injections Intra-arterial Rarely used now, mainly used diagnostically e.g. coronary angiography Direct administration into artery therefore targeted delivery e.g. hepatic artery for liver cancer treatment minimizes systemic exposure. Intrathecal/epidural Both injections into the spine but different specific locations (subarachnoid vs outside dural membrane) Injection into epidural space (outside subarachnoid space) e.g. good for administering pain medications Into subarachnoid targets the central nervous system e.g. methotrexate for cancers in CNS Bypasses the blood brain barrier Parenteral route – injections Intra-articular Direct injection into joint space e.g. hydrocortisone for rheumatoid arthritis Localised treatment to target joint inflammation or pain Minimises systemic effects Intra-osseus Injection through cortex of bone into medullary space used as an alternative to IV when venous access difficult Provides rapid access when IV is challenging or not feasible e.g. cardiac arrest Humeral head or proximal medial head of tibia are the best sites due to rich blood supply and non-collapsible entry point Activity Morris Jones, a 50-year-old executive, takes sublingual glyceryl trinitrate tablets when he has an attack of angina, and applies a glyceryl trinitrate transdermal pad every morning as a preventive measure against angina. With reference to the formulations (tablet versus transdermal pad), describe how they act to either treat angina or prevent an attack of angina. Activity Tablet The tablet is allowed to dissolve under the tongue, therefore absorbing quickly through the blood vessels surrounding the sublingual gland. The drug is then able to act rapidly to vasodilate the systemic veins and coronary blood vessels, thereby treating angina. Mustn't swallow tablet. Transdermal pad The drug slowly leaches out of the pad during the course of a few hours, providing a more sustained and gradual activity. This preparation is therefore more suitable for preventing an attack of angina. Ensure the area is free of hair. Place the patch firmly against the skin. Wash your hands immediately following the procedure. Activity – do at home Administration Route Advantages Disadvantages Oral Sublingual Buccal Rectal Intramuscular Subcutaneous Intravenous Transdermal Topical Inhaled Pharmacokinetics Pharmacokinetics is the movement of drugs inside the body. It describes the physiological processes that act on a drug once it enters the body i.e. how the body handles a drug. Absorption of drugs How does it get into the body? Distribution of drugs Where will it go in the body? Metabolism of drugs How is it broken down? Excretion of drugs How does it leave? Pharmacokinetics Pharmacokinetics Pharmacokinetics WHY is this important???????? Why is pharmacokinetics important? 1. Drug development: Understanding pharmacokinetics is essential for drug developers to determine the appropriate dose, route of administration, and dosing frequency. By studying pharmacokinetics, drug developers can ensure that the drug reaches the target site of action and is not metabolized too quickly or too slowly. 2. Drug prescribing: Pharmacokinetics is also critical in drug prescribing. Healthcare professionals need to know how a drug will behave in the body to determine the appropriate dose and dosing schedule for a particular patient. For example, a drug that is rapidly metabolised may require more frequent dosing to maintain therapeutic levels, while a drug with a long half-life may only need to be dosed once a day. Why is pharmacokinetics important? 3. Drug administration: Understanding pharmacokinetics is also important in drug administration. Different sublingually routes of administration, such as oral, intravenous, or intramuscular, can affect how a drug is absorbed and distributed in the body. For example, intravenous administration delivers drugs directly into the bloodstream, resulting in rapid onset of action, while oral administration requires absorption through the gastrointestinal tract, which can be affected by various factors such as food and gastric pH. 4. Drug interactions: Knowledge of pharmacokinetics is important in identifying potential drug interactions. Certain drugs may compete for the same metabolic pathway or protein binding sites, which can lead to altered pharmacokinetics and potentially harmful effects. Overall, an understanding of pharmacokinetics is essential for safe and effective drug development, prescribing, and administration.  Drug absorption “Transport of drug from site of administration to blood circulation.” Drugs are transported across various biological membranes by the following mechanisms: Passive Diffusion Filtration Specialised transport Does not require energy Does not require energy Active transport Movement down a Pressure driven movement Requires energy concentration gradient through specialised Movement of drug against structures concentration gradient Mainly lipid soluble drugs as they are able to move Depends on molecular size Facilitated diffusion through lipid portion of and weight of drug. Does not require energy membrane Drugs are easily filtered if Carrier-mediated transport they are smaller than pores down concentration gradient Drug absorption – important points Absorption is an important factor for all routes except IV. There are many factors that can modify drug absorption. Physiochemical properties Physical state – liquids are absorbed better than solids. Particle size – smaller particle size better absorbed than larger size. Disintegration time – time required to disintegrate into fine particles. Dissolution time – time required for particles to dissolve into solution. Lipid solubility – lipid soluble drugs will pass through membrane phospholipids more easily. Drug absorption – important points pH and ionisation – ionised drugs (charge associated to them) are poorly absorbed. Unionised drugs are lipid soluble therefore better absorbed. Degree of ionisation will depend on pH of medium i.e., acidic drugs remain un-ionised in acidic medium whereas basic drugs remain un- ionised in alkaline medium. Area and vascularity of absorbing surface – larger area, more vascularity leads to better absorption. Gastrointestinal motility – two components, gastric emptying time and intestinal motility. The faster the gastric emptying time, the faster the drug will reach intestine and the faster it will be absorbed. The faster the intestinal motility,  absorption as there is less contact time with intestinal surface. Presence of food -  gastric emptying time dilutes the drug and slows absorption. Or drug food complex is incompletely absorbed. Factors affecting drug absorption 1. Blood supply 2. Rate of gastric emptying 3. Degree of peristaltic activity 4. Presence of food/digestive enzymes 5. Absorptive surface 6. Drug molecular size and solubility 7. Active drug transport system Question Theoretically aspirin is absorbed better in the stomach. In actual fact, most is absorbed in the small intestine. Why? Question Theoretically aspirin is absorbed better in the stomach. In actual fact, most is absorbed in the small intestine. Why? Aspirin (acetylsalicylic acid) is an acidic drug therefore will be less ionised in the stomach (also acid) and more lipophilic. This is why it is theoretically absorbed better in the stomach. However, the stomach does not have a large surface area for good absorption, and the transit time is often short therefore most will end up being absorbed in the intestine. Question Medicine A is known to prolong gastric-emptying time. In the presence of medicine A, would oral absorption of another medicine, medicine B, be faster or slower than usual? Prolonging gastric emptying time will slow the rate of absorption as it delays the movement of the drug into the intestine where most of the absorption occurs (see slide 41). Question Insulin is a protein used in the treatment of diabetes. It cannot be given orally. Why is this so? Insulin is broken down by the gastric secretions of the gastrointestinal tract. It therefore needs to be given parenterally. Insulin is given via subcutaneous injection. It tends not to be given IV or IM. Absorption will depend on the part of the body you inject it into. Fastest is the abdomen. Insulin pump – small electronic device providing a convenient and precise way to manage insulin delivery. Question Indicate whether you think the absorption of the following medicines would be relatively poor or good, based on the information provided. 1. Medicine A is a weak base in an 1. Relatively poor absorption acidic environment 2. Medicine B has a small 2. Relatively good absorption molecular weight 3. Medicine C is injected into a 3. Relatively poor absorption body site with a poor blood flow Drug distribution Once absorbed into systemic circulation a drug requires distribution to different tissues. This involves the drug crossing many barriers until it the reaches the site of action. Therefore, distribution involves the same processes as absorption; i.e., filtration, diffusion and specialised transport. Factors determining distribution Lipid solubility Ionisation Vascularity Binding to plasma and cellular proteins Drug distribution is generally uneven because of differences in blood perfusion, tissue binding (e.g., because of lipid content), regional pH, and permeability of cell membranes.  Drug distribution – plasma protein binding (PPB) Once in the systemic circulation, drugs can bind to plasma proteins in the blood. Plasma protein binding is variable for each drug. Only drug that is NOT bound to plasma proteins is available for action, metabolism, and excretion. Bound drug acts as a reservoir for drug. When free drug concentration , bound drug is released. Clinical significance of plasma protein binding (PPB) High PPB affinity will  drug half-life and hence duration of action. Co-administered drugs will compete for same protein binding sites, and one may therefore displace another and potentially increase the free amount of that drug (could increase toxicity). the same dose can have toxic effect in repeated administration Saturation of binding sites can occur after repeated administration. Renal failure or chronic hepatic dysfunction may decrease number of plasma proteins. Question What is the function of the blood brain barrier? The blood–brain barrier protects the brain, the ‘most important organ’, from any noxious substances, including many drugs, that may get into the bloodstream. The endothelial cells create a barrier between the capillaries and brain tissue therefore only substances that are highly lipophilic or that are actively transported can pass into the central nervous system. Question Normally the blood brain barrier provides a protective coating for the central nervous system. Explain why penicillin can still be used to treat meningitis in neonates. The blood–brain barrier is incompletely formed in neonates, so penicillin can cross into the brain tissue. Question Why may a person suffering from severe burns respond badly to some medicines? during severe burns you can lose a lot of tissue fluid and plasma proteins Lack of proteins in the blood, (especially the albumins) may cause high concentrations of the free drug, the result of which can be dangerous as it is the free drug that is active. This would be particularly so for drugs that have high protein binding e.g. warfarin, some antibiotics, some anti-inflammatories. If a drug has protein binding of 90% then only 10% is normally free to exert its pharmacological effect. Changes in fluid levels and low plasma proteins would increase free drug to potentially toxic levels. Volume of distribution It is useful to know how much of a drug gets distributed from the blood into other compartments. The volume of distribution is helpful in establishing the initial, or loading, dose required to produce quick therapeutic effects. Low volume of distribution means drug remains predominantly in the plasma whereas high volume of distribution means the drug has high concentrations in the extracellular tissue. Volume of distribution = Total amount of drug in body Drug blood plasma concentration high VD means it takes time for it to come into the plasma and excrete out later Drug metabolism (biotransformation) “Chemical alteration of drug in living organism.” Conversion of lipid-soluble unionised drugs to water-soluble, ionised drugs. Water-soluble, ionised drugs will NOT be reabsorbed by kidneys (refresh from kidney function from anatomy and physiology if necessary) and therefore will be excreted. If drug is ionised on initial administration, it may not get metabolised and will therefore be excreted unchanged. Sites of metabolism Primary site is liver (remember already discussed in relation to ‘first pass effect’). Others include GIT, kidneys, lungs, blood, skin, placenta etc. Metabolism (biotransformation) Consequences of metabolism 1. Active drug to inactive metabolite (most common) 2. Active drug to active metabolite e.g. codeine to morphine 3. Inactive drug to active metabolite (prodrug) e.g. prednisone to prednisolone 4. Active drug to toxic metabolite Advantages of prodrug (paracetamol)  Bioavailability  Duration of action Enhance taste Site-specific drug delivery Phases of metabolism There are two pathways of drug metabolism. Phase I 1. This involves chemical alteration of the drug by either oxidation, reduction or hydrolysis. 2. Metabolite at the end of phase I reaction may be inactive or active. Phase II 1. Many metabolites at the end of phase I are still lipophilic therefore they undergo phase II metabolism which consists of conjugation reactions. 2. Following conjugation, the drug will be inactive, polar and water soluble hence excreted. Phases of metabolism Compare and contrast phase I and phase II metabolism. Can a drug be subjected to both phases of metabolism? Phase I metabolism is where it is acted upon by an enzyme (oxidation, reduction or hydrolysis). Phase II metabolism is where a drug or its metabolite is conjoined to a polar molecule. YES, a drug can be subjected to both phases of metabolism. conjugation- add sulphate/acetyl/methyl groups to make the drug water soluble Drug metabolism reactions Enzymes for metabolism Microsomal enzymes Non-microsomal enzymes 1. Found in the endoplasmic reticulum of 1. Present in cytoplasm and cells (typically hepatocytes). mitochondria of liver cells. 2. Catalyse most Phase I reactions. 2. Catalyse most Phase II reactions. 3. Cytochrome p450 enzymes. in hepatocytes 3. Show genetic polymorphism. 4. Can be inducible. 4. Are non-inducible. Enzyme induction and enzyme inhibition are of clinical importance as they can cause unintended drug effects e.g. may either speed up drug metabolism or may slow it down. Factors modifying drug metabolism Age Neonates and elderly will have compromised liver function, therefore  metabolising capacity and potential  drug toxicity. Diet Protein deficiency  metabolism. Protein rich food may  metabolism of some drugs e.g., caffeine. Carbohydrate rich food  metabolism. Diseases Liver diseases  metabolism of drugs, therefore  duration of action. Pharmacogenetics Study of genetically determined variation in drug response. Drug excretion “Removal of drug and its metabolite from the body.” Major route is the kidney. Minor routes include lungs, bile, faeces, sweat, saliva, milk. Lecture content provides additional information. Relates to amount of drug removed from the body per unit time. Clearance Related to excretion but not the same. Can be calculated by dividing the rate of elimination of a drug by the concentration of that drug in the plasma. Drug half-life The half-life of a drug is the time taken for the plasma concentration of the drug to be reduced by half its maximal level. time taken to reduce original conc. into half Half-life is a useful and commonly used parameter to describe an individual’s exposure to a medication. Half-life is the major determinant of : The duration of action of a drug after a single dose. The time taken to reach steady state concentration with ongoing dosing. The dosing frequency required to avoid big fluctuations in plasma drug concentration (maintain concentration in therapeutic range). rate of elimination of drug/ conc of that drug in plasma The two processes that influence half-life are distribution and clearance*. *Clearance is the ability of a drug to eliminate a drug and depends on both metabolism and excretion. Why is half life important? Half life is important as it helps work out the dosing intervals for when we need to maintain a therapeutic certain concentration of drug over time. You have a chronic condition/disease that requires drug treatment for it to be managed. The drug used to treat your condition requires a concentration of 500 mg minimal therapeutic for it to have a therapeutic effect. conc. As the drug is metabolised it will lose its therapeutic effect therefore, we must give repeated doses for it to continue being effective. What happens if you miss a dose?? When a dose of medication is missed, the drug's concentration in the body begins to fall below the therapeutic range, potentially reducing its efficacy. The specific dilemma of a missed dose includes: Impact on Drug Levels: If a drug has a short half-life, its concentration will decrease rapidly, leading to a significant drop below the therapeutic level when a dose is missed. This can quickly result in subtherapeutic effects or a return of symptoms. For drugs with a long half-life, the concentration decreases more slowly. Missing a dose may not have an immediate significant impact, but over time, the levels may drop enough to reduce efficacy. Decision to Double the Next Dose: Patients might be tempted to double the next dose to "catch up." However, this can be dangerous, especially for drugs with a narrow therapeutic index, where a small increase in dose can lead to toxicity. For drugs with a long half-life, doubling the next dose can lead to accumulation and potential adverse effects, as the drug takes longer to be cleared from the body. Maintaining Steady-State Concentration: The goal of regular dosing is to maintain a steady-state concentration where the amount of drug administered equals the amount eliminated. A missed dose disrupts this balance, particularly in drugs with a short half-life, making it challenging to quickly regain steady-state levels without precise management. Why is half-life important? Steady state concentration This is when the amount of drug being absorbed is the same as the amount being cleared from the body. For most drugs, the time to reach steady state is four to five half-lives if the drug is given at regular intervals—no matter the number of doses, the dose size, or the dosing interval. Dose Plasma concn 1 6mg/L 2 9mg/L 3 10.5mg/L 4 11.25mg/L 5 11.625mg/L 6 11.8mg/L Development of steady-state concentration If we assume we are administering a dose every half-life, half of the first dose will be cleared from the body before the next dose. So, after the second dose, there will be 1.5 doses in the body etc. After Dose 1: There are 0.5 doses left at the end of the dosing interval. This means we’re at 50% steady state. After Dose 2: There are 1.5 doses in the body, then half is eliminated to leave 0.75 doses (75% steady state). After Dose 3: There are 1.75 doses in the body, then half is eliminated to leave 0.875 doses (88% steady state). After Dose 4: There are 1.875 doses in the body, then half is eliminated to leave 0.9375 doses (94% steady state). After Dose 5: There are 1.9375 doses in the body, then half is eliminated to leave 0.96875 (97% steady state). At 97% we’re considered to be at approximate steady state, where the rate of input equals the rate of elimination at one dose per dosing interval.  Effects of circumstances on drug therapy For each of the following situations, indicate whether you would expect the drug effects to be increased or decreased: a. Warfarin treatment when the levels of plasma proteins are decreased (e.g., burns) Warfarin binds strongly to plasma proteins therefore you would expect increased drug effects. More of the drug will be unbound and free to exert its effect. b. Morphine treatment in a person with liver disease. Increased drug effects, as the rate of metabolism is reduced. c. An intramuscular drug injection just prior to a running race Increased drug effects as the exercise will increase blood flow speeding up the rate of absorption. Also increases temperature which will accelerate absorption. d. Penicillin therapy in a person with renal disease Increased drug effects, as penicillin is excreted unchanged in the urine. The penicillin will persist in the body longer. Question Name a circumstance that may increase the rate of a drug’s metabolism. Exposure to chemical agents in the workplaces can induce microsomal enzymes, increasing the rate of metabolism. Other main reason for increased cytochrome p450 activity is drug-drug interactions where the effects of one drug cause induction of the CYP enzyme responsible for metabolising the other drug. Lower than normal levels of plasma proteins can indirectly lead to increased rates of metabolism for drugs that bind strongly to plasma proteins. Case study Mary Williams is suffering from acute renal failure following a very severe bleeding episode. How would this condition be expected to alter the effects of any medicines she may need to take during this time? How would her drug treatment have to be modified to minimize these effects? The consequence for drugs where the major route of elimination from the body is via the kidneys is that they will accumulate within the body, increasing the potential for toxicity. The dose of frequency of administration of drugs may have to be reduced. Case study Peter Jenkins is a small property owner in north Queensland. To protect his crops from locust attack, he has been periodically spraying insecticides around his property. He is currently in hospital receiving treatment for an ongoing heart condition. The drug Mr. Jenkins is receiving is not as effective as expected at the standard dose range, and his dosage has been increased. The drug is subject to significant liver metabolism. How do you account for Mr. Jenkins poor responsiveness to his therapy? The pesticide chemical has probably induced microsomal enzymes in the liver that are responsible for the metabolism of the drug Mr. Jenkins is taking. The drug is being metabolised faster, leading to poorer than expected drug effects.  Liver Enzymes Kidney Active Metabolites of Urine excretion Drug Drug Case study Sarah Donald, an 18-year-old student, has been taken to the doctor by her mother. She is concerned that her daughter does not eat a balanced diet. Ms. Donald is currently taking amoxycillin (an antibiotic) for a persistent chest infection. How might Ms. Donald’s diet affect the metabolism of amoxycillin? Microsomal enzyme activity is dependent on the adequate intake of vitamins, fatty acids, proteins and minerals. While Ms. Donald maintains a poor diet, the blood levels of drugs metabolised by these enzymes would be higher than normal therefore having potential adverse or toxic effects.