4Learning outcomes Define and discuss pharmacokinetic factors Discuss the factors that affect absorption, distribution, metabolism and excretion-how they affect drug therapyDefine and discuss pharmacodynamic mechanisms of drug actionsApply pharmacokinetic and pharmacodynamic concepts to patient scenarios.
5DefinitionsPharmacokinetics is what the body does to the drugs, for almost all drugs the magnitude of pharmacological effect depends on its concentration at its site of action.Pharmacodynamics is what the drug does to the body, ideally includingthe molecular mechanism (s)by which the drug acts“Pharmacokinetics determines the actions of drugs, how they are administered, absorbed, onset and duration of action,the metabolic changes (inactivation or activation!) that may occur and the manner and duration of excretion”Once taken the drug must gain access to it’s site of action-pharmacokineticsTo exert it’s effect the drug must act at sight of action, must act at cellular level-pharmacodynamics
6PHARMACOLOGY PHARMACODYNAMICS PHARMACOKINETICS (SPECIFIC TO DRUG OR DRUG CLASS)PHARMACOKINETICS(NON-SPECIFIC, GENERAL PROCESSES)Hand this out to the students.
7Arrange the phrases!!! Factors determining response of a patient to a drug Drug interactionsDuration of effectUnwanted effectsReduction in symptomsModification of disease progressionAccumulation on repeat dosageAbsorption from the site of administrationElimination from the bodyDelivery to the site of actionEffects at the site of actionInteraction with cellular componentArrange the phrases on their handout. Test again at the end of the session.
8Pharmacokinetics:considering such terms as RouteAbsorptionDistributionHepatic MetabolismMetabolic productsProtein BindingRenal ExcretionHalf-lifeToxicityWe are going to come to each one in turnRoute-Oral, Parenteral- inhalation, rectal, transdermal, injectionAbsorption-Entry into body-acidity and solubilityFirst-pass-Metabolic change due to liver enzymes- Question what do we mean by that?Significant, patients with liver disease, poor metabolism, build up of hepatically metabolised drug-resulting in toxicityExtent of protein binding important as only free (unbound) drug can have effect. Penicillin is highly protein bound. Two drug co-administered, degree of protein binding can be altered, displaced? Toxicity?Excretion-removal or clearance of drug from body-Is drug excreted by Urine or bileHow long does it take the Plasma concentration of drugs to go down to 50%Consider the pharmacological routes to adverse drug effects
9Absorption Distribution Metabolism Excretion Pharmacokinetics refers to the handling of a drug within the body and includesTHE BODIES RESPONSE TO MEDICATIONTo achieve the pharmacological response desired, the drug must first be in an available and suitable form and then administrated by an appropriate routeUnless the drug acts locally it will need to be absorbed, distributed and circulated before reaching the site of actionFor the effect of the drug to wear off, it must be metabolised and the metabolic products excreted.SPEND 2 MINUTES DISCUSS THE VARIOUS ROUTES THAT CAN BE USED FOR DRUG ADMINISTRATION?
10Absorption Route Distribution Enteral Parenteral IV Topical Absorption oralsublingualtransdermalinhalationAbsorptionAbsorptionSystemic circulation
11AbsorptionProcess of drug movement from the administration site to the systemic circulation.The amount and rate of absorption aredetermined by several factors:Physical nature of the dosage formPresence or absence of food in the stomachComposition of the GI contentsGastric or intestinal pHMesenteric blood flowConcurrent administration with other drugsDosage form refers to tablet/liquid etc. AND SHOULD NOT BE ALTERED IN ANY WAY BY PERSON GIVING TABLET AS CAN AFFECT THE WHOLE PROCESS. DON’T CRUSH TABLETS, SPLIT CAPSULES. Where would you seek advice?Disintegration and dissolution of the released drug into the correct part of the GI tract is required for the drug to be absorbed. Drugs in liquid dose form require no disintigration and often dissolution are already accomplished and therefore absorb more rapidly with faster effectsFood effect on some drugs affects the bioavailability – look at this in greater depth shortly.Impacted faecesGI motility effects the thorough mixing in the GI tract which increases the efficacy in which the drug makes contact with surfaces that are available to engage absorptionThe level of mesenteric blood flow directly affects the rate of removal of the drug from the site of absorptionDrug absorption is mainly in the upper small intestine that is facilitated by the large surface area of villi and the rich blood supplyAlteration in the rate of gastric emptying will result in corresponding alterations in the rate of absorption, as in diarrhoea and vomiting can affect whether therapeutic levels achieved-EG ORAL CONTRACEPTIVES!E..g. Migraine – reduced rate of gastric motility = delayed response to oral analgesia. Delay can be lessened by use of metoclopramide that increases gastric emptying .All of theses will be considered when advising patients on administration of the prescribed drugNot all oral drugs are absorbed? When would it be desirable for an oral drug to have minimal absorption characteristics? Eg vancomycin, UC.
12Bioavailability“Bioavailability is the proportion of the administered dose that reaches the systemic circulation.”Dale and Haylet, Pharmacology Condensed. 2004Refers to the amount and the rate of appearanceof the drug in the blood after administration inits initial dose formOrally administered drug bioavailability is directly related to the individual solubility in body fluids.Poor solubility = low bioavailabilityTo become affective i.e. produce a therapeutic effect, a drug must reach an adequate concentration in the blood. Drugs administered by the IV route are bioavailable in 100% of cases as it is administered directly into the bloodSome drugs with the same active principle, made by different manufacturers may differ in the bioavailability, dependant on the degree of compression or nature of excipients ( added substances), that may affect the disintigration and dissolution of the drug.Drugs licensed for use in the UK (including parallel imports) the manufacturing processes are controlled to ensure bioavailability across drug production is consistent.Brand vs generic prescribing. Bioequivalence should be similar with a few exceptions.
13Effect of FoodBioavailability of some drugs is affected by the presence of food. E.g penicillin's, erythromycin, rifampicin, thyroxineSome drugs are taken before meals to allow time for drug to act before food is takenGastric irritation can be caused by drugs taken on an empty stomachEffect of food on the absorption of drugsThe importance in considering gastric content is the causative effects on the bioavailability of drugs in the presence of absence of foodFood can alter the dissolution and intestinal transfer time of the drugAllowing time for drug to act e.g the anaesthetic property of oxethazaine in Mucaine in the calming of oesophagitis before eatingGastric irritating properties of metformin and levodopa can be reduced by the protective properties of food.Bioavailability can be increased by food due to1 reduced 1st pass, eg. Propranolol2poor water solubility but high fat solubility eg griseofulvin3 delayed gastric emptying increases time for disolutione,.g viagra absorption slowed down by fatty food! Another reason not to have sex on full stomach!QUESTION?Why are drugs not given orally to patients in shock?Answer: patients in shock have delayed gastric emptying so oral drugs will not reach small intestine. Therefore will not be absorbed so won’t workSome drugs are totally unaffected by presence or absence of food!
14First Pass Effect Drugs that are absorbed via the GIT are circulated to the liver first viathe hepatic portal veinLiver then acts as a filterOnly part of the drug iscirculated systemicallyThe combination ofprocesses is termedthe ‘First Pass’ effectThe liver protects the body from systemically circulating toxins that are absorbed via the GIT by filtering drugs through a range of detoxification mechanisms seeking for natural toxinsAll drugs taken orally that are absorbed pass by the hepatic portal vein and can be subject to a degree of metabolism, this is a defence mechanism to detoxify substances coming into the body.As a result only part of the administered drug reaches the systemic circulation via the hepatic artery.the extent can explain the difference between oral an injectable dose e.g propranolol, salbutamol verapamil undergo substantial first pass metabolismGTN first-pass breakdown is complete so cannot be taken orally-sublingual preparation!!
16Distribution Factors affecting Absorption Metabolism Low albumin Problems with: HeartCirculationDiabetesPlasma proteins affect the distribution of drugs in the:Plasma proteins can affect movement from blood to tissue, reduced in some diseases, role in polypharmacyAdditional factors that affect distribution:Cardiac output, Regional blood flow,Bound drugs are pharmacologically inactive because the drug-protein complex is unable tocross cell membranes. However this complex can quickly dissociate and release unbound drugs as it is released from the plasma. The degree of protein binding will thus affect the intensity and duration of a drug’s action.Effect in some diseasesDeficiency of plasma proteins occur in disease of the liver and malnutrition. This means that more of the drug is free to enter the tissue. This could lead to dangerous drug levels being attained even when normally drug doses are delivered. In reality this is only important in drugs that depend on high protein binding with a narrow therapeutic window e.g. warfarin and phenytoin.Role in polypharmacyDifferent drugs may have same protein binding receptor sites. If 2 drugs are administered concurrently, the drug with the higher affinity will be preferentially bound and displace the drug with the lower affability from the protein binding site. EG clofibrate drugs (affect triglyceride levels) will displace Warfarin, this increases levels of free Warfarin that increases risk of haemorrhage.Additional factors.cardiac output and regional blood flowWarm atmosphere = better blood flow=improved drug distributionInflamed tissue=increased vascularity and permeability=increased passage of drugs. Both important considerations in anti-biotic therapy.CNS barrier: many drugs can’t cross.Placenta: importance of knowing which drugs cross.Bound drugs are pharmacologically inactive because the drug-protein complex is unable to cross cell membranes.
17Metabolism Drugs are metabolised in the liver, lungs, kidneys, blood and intestines.In order for drugs to pass across the lipid cell membrane they must be lipophilicThe higher the solubility in lipids compared to water, the more rapid the tissue entryMetabolic rate determines the duration of the action of the drugsThe primary metabolic site is the liver. If enzyme function is inadequate the metabolic effect can be compromised and cause toxicity. Eg in liver disease, very young and very old who have diminished hepatic microsomal enzyme activity.Lipophilic means fat soluble. Hydrophilic means water solubleTo excrete the drug needs to become more hydrophilic (water loving) than lipophilicThe speed with which a drug is metabolised will determine the duration of the action of the drugThis in turn will determine how often the drug is administered.Which BNF appendix relates to patients’ ability to metabolise?
18Excretion Drugs are primarily excreted by the kidneys In order for drugs to be excretedthey need to become hydrophilicExcretion of drugs can be affectedby the urinary pHHow the drug is excreted caninfluence prescribing decisionsMostly kidneys, but also skin, bile, lungs.The excretion rate varies from hours to weeks and on the condition of the kidneysAgeing patient with reduced renal capacity more prone to build up (toxicity) of drugs excreted renally, more of problem with drugs narrow therapeutic range e. g digoxin. some beta blockers (celiprolol, sotaolol)etcExcretion and prescribing influence. Eg ampicillin is excreted in high concentrations in bile, so is a good chioce for biliary tract infectionWhen lipid soluble drugs pass through the kidneys they are re-absorbed in the distal tubule and return to the plasma. In order to be excreted they need to become more hydrophilic. This occurs in the Bowman’s capsule, converted to less active metabolites more easily excreted.Which BNF appendix relates to patients’ ability to excrete?
19Half Life of DrugsDrug excretion is commonly expressed in terms of half life (t1/2)This is the time required for the concentration of the drug in the plasma to decrease by one-half of it’s initial valueDrug half life is variable and can be long or shortSubsequent doses are given to raise the concentration levels to a peakIn theory, the optimal dosage interval between drug administration is equal to the half-life of the drugHalf Life of Drugs – aspirin 6 hours, metronidazole 9 hours, digoxin 36 hoursHalf-life is affected by:Extensive tissue uptake, Rapid metabolism, Rapid excretion- Short half lifeLong half lifeExtensive protein binding, slow metabolism, poor excretionKnowledge of half-life is essential when determining drug dose intervalsConcentration falls after metabolism and excretion. If dose interval is too long, effect is not achieved, too short an interval leads to toxiciIdeally dose interval is equal to half life. Not practical for drugs with short half life eg penicillin 30mins, but wide therapeutic range and not toxic so high dose 6 hourly. Or slow release prep given once or twice daily.
20Example Drug 100mgs with a 6 hour half life 1st dose 100 mgs2nd dose 100mgs + 50 mgs still present = 150mgs3rd dose 100mgs + 75 mgs still present = 175mgs4th dose 100mgs + 88mgs still present = 188mgs5th dose 100mgs + 94mg still present = 194mgs6th dose 100mgs + 97mg still present = 197mgAs can be seen, accumulation becomes less ateach dose- “steady state” is achieved after 3 to 5 half lives.1st dose 6am2nd dose 12pm3rd dose 6pm4th dose 12 midnightIn ‘steady state’ the plasma level rises and falls between doses but remains in therapeutic levels. I.e. the quantity of drug supplied by each dose is equal to the amount excreted.In steady state the maximum concentration is reached after approx 5 doses.Draw graph!!Therapuetic range-maximum level before toxic, minimum level to achieve effect
21Loading DosesAre used when the medical condition demands high concentrations very quicklyThis is achieved by an initial dose that is twice the maintenance doseEXAMPLE ACUTE INFECTIONSUSE STAT DOSE OF ANTIBIOTIC, 2 TIMES THE NEXT DOSE.DIGOXIN LOADING DOSEThe figure 5. To reach steady state, or to eliminate almost 97% of drug.
23Which ONE of the following affects absorption? Drug formulationTime of administrationMode of action of the drug
24A patient with renal impairment, taking a renally excreted drug, will require which ONE of the following?Dose reductionDose increaseSame dose
25Which ONE of the following describes bioavailabilty? The proportion of drug reaching the circulationThe extent of first pass metabolismThe quantity of drug absorbed in the GI tract
26Tea break… http://www.youtube.com/watch?v=tnnoPedWO7M …best to leave now if easily offended!
27Pharmacodynamics Receptors Ion channels Enzymes Carrier molecules “is the detailed study of the mode of action of drugs in the body” or how drugs exert their effect at a cellular levelReceptorsIon channelsEnzymesCarrier moleculesChemotherapyPharmcodynamics is about that, how drugs work-its about how drugs taken orally or parentally actually work in the body at cellular levelWe won’t go into too much detail today but its important to have an awareness of the terms which sometimes find their way into drug nomenclatureH2 antagonists and B2 agonists are telling you how those groups of drugs workUnderstanding the pharmacodynamics of drugs will enable you to predict drug interactions and toxicities.The pharmacology of a drug is not always known-but where it is, it would be nice if you had a handle on how the drugs you will be prescribing exert their effect
28Considering Receptors-agonist, partial agonist and antagonist Ion channels-gating of intracellular ionsEnzymes-drugs act to inhibit or potentiateCarrier molecules-allow molecules not lipid soluble to cross cell membraneChemotherapeutic agentsDrug tolerance/dependenceEffects of pathological state and biological variability
29ReceptorsReceptors are a target molecule that a drug molecule has to combine with to produce a specific effectReceptors must be compatible –like 2 pieces of a jigsaw e.g. neurotransmissionMain types of action at receptor:Receptor agonistsReceptor antagonists
30Types of receptorsG-protein-couple receptors, secondse.g. Muscarinic ACh receptors, adrenoceptors, histamine receptorsKinase linked receptors, hourse.g. Insulin, Growth factorNuclear intracellullar receptors, hourse.g. steroid, thyroid hormoneG protein receptors work in secondsKinase (enzyme) linked receptors can take hours.
31Ion Channels Carrier molecules Drugs act to affect cellular gating mechanism in cell wallLigand-gated ion channels, millisecondse.g GABA benzodiazepines, Nicotinic AChCarrier moleculesDrugs act on carrier transporters which allow molecules, not lipid soluble to cross cell membraneSome ion channels are gated by receptor (open only when receptor is occupied by an agonist) while other are voltage-gated-drugas affect the permage or flow of for example, potassioum, sodium or calcium in and out of the cellDrugs acting at ion channels includeBenzodiazpeines that act at GABA (gamma amino butyric acid receptor) chloride channel return over excitable receptor to constitutive (normal) level of activationCalcium channel blockers prevent diffusion of calcium through cell membraneNicorandil acts at potassium channelsCarrier molecules allow transport of small organic molecules that are too polar-not sufficiently lipid soluble to penetrate cell membranes on their own. Eg. Glucose and amino acidsExamples of drugs that act in this way includeLoop diuretics which inhibit sodium, potassium and chlorine passage in the lop of HenleAnother example Omeprazole inhibits proton pump in the gastric mucosaTricyclics inhibit noradrenaline uptake
32Enzyme inhibitorsAn enzyme is a protein that can promote or accelerate a biochemical reaction with a substrateWhen the enzyme mistakes the drug for a substrate, a drug-enzyme interaction occursThis interaction could increase or decrease the rate of the biochemical reactionAs an example lets look at how levodopa is used in the treatment of Parkinson's diseaseDopamine is the required drug to combat Parkinson's disease. Cannot cross blood brain barrier but acts in brain tissue.Levodopa is used as a precursor to dopamine as it can cross the blood brain barrier where as dopamine cannot.Levodopa is broken down in to dopamine by the enzyme dopa decarboxylase.Dopa decarboxylase is is present in the gut and liver.This results in a proportion of the levodopa being broken down before it enters the brain.By combining levodopa with carbidopa or benzerazide, the action of the dopa decarboxylase is inhibitedThis results in the reduction of the breakdown of levodopaThis means a lower dose of levadopa can be given, reduce risk of side effectsMany drugs target enzymes acting as false substrates to competitively inhibit either reversibly e.g.neostigmine or irreversibly e.g AspirinSimvastatin inhibits HMG CoA REDUCTASE
33The cell is rupturedArachidonic acid is released-this is a precurser, or building block to Prostaglandins, which lead to inflammation and escalate the sensation of pain.COX enzymes-cyclo-oxygenase converts arachidonic acid to prostaglandinsAll NSAIDs inhibit COX enzymes
34Chemotherapeutic agents Cytotoxic drugs act by interfering with cell growth and division at different stages of the cycleAnti-infective drugsExamples.Folic acid is required for DNA synthesis.Methottrexate inhibits the formation of folic acidPenicillins and cephalosporins inhibit synthesis of bacterial cell wallsNyastatin acts by increasing the permeability of of cell membranes of invading organismsErythromycin inhibits bacterial protein synthesisAdditional drugs classifiedPotassium citrate alters the pH of urine, making it more alkaline, relieves discomfort of cystitisDesferrioxamine chelates(combines and neutralises) with ferrous iron in the treatment of iron poisoning
35Metabolism of bacterial cell Cell wallCell membraneDNAMetabolism of bacterial cellClass 2 reactionsClass 1 reactionsNucleotidesClass 3 reactionsProteinsRNADNAPrecursormoleculesGlucoseChemotherapy-exploiting the differences between host and bacteriaClass 1 reactions are not good targets for chemotherapy no marked difference in the way humans and bacteria obtain energy from glucose.Also if blocked glucose as energy source bacteria could use alternatives-amino acids, lactate as alternative source.Class 2 are better targets as some pathways converting precursor molecules to amino acids occur in bacteria but not in man. E.g. man cannot manufacture own folate (needed for DNA synthesis) and needs to take from diet. Bacteria make their own folate and cannot transport into cell from environment.Class 3 reactions are excellent target for chemotherapy because every cell makes its own macromolecules,e.g. needed for manufacture of bacterial cell wall, different from human cells.Aminoacids
36Physiological Variability Liver diseaseChronic alcoholismRenal diseaseAllergyLiver diseaseDamage of liver cellsReduced hepatic blood flowDecreased plasma proteinsMay all require avoidance (e.g. lignocaine)or reduction in dose(e.g. propranolol) of certainDrugsAlcoholismInduces microsomal oxidation enzymes that participate in metabolism of certain drugs e.g. theophyline. If given in normal doses more rapid metabolism due to higher level of enzymes. This will result in inadequate plasma levels and doses need to be altered accordinglyRenal diseasePotential to reduce the elimination of drugs if eliminated largely by the kidneys. This could lengthen the half life of drugs if the metabolites are pharmacologically active. Dosage adjustments are requiredAllergy incidence is increasing with multiple drug therapy. Penicillin groups most commonly involved.Initial reaction is the formation of antibodies. Subsequent exposure causes chemicals to be releases e.g. histamine that causes the allergic responseIatrogenic effectIs the domino effect of 1 drug taken as a prophylactic or treatment that causes another condition. E.g. OCP causes a 5% raise in BP over a 5 year period.These can be expected an tolerated or unexpected and not tolerated e.g.urticaria with penicillinFinally for every rule there is an exception-people vary!
37Exam Style MCQs A receptor antagonist: binds to a receptor and activates itbinds to a receptor without causing activationblocks an enzyme
38The pharmacodynamics of salbutamol can be explained by its: activity on enzymesactivity on ion channelsactivity on receptors
39Warfarin has a:Narrow Therapeutic IndexWide therapeutic rangeNeither are important
40Write brief notes on any TWO of the following modes of drug action: Receptor agonistsReceptor antagonistsAction at enzymesIon channelsCarrier moleculesChemotherapy
41Short answer questions: What is a narrow therapeutic index?What is bioavailability?What is half life?What is a loading dose?What is pharmacodynamics?
42Further readingDownie, George (2008) Pharmacology and medicine management for nurses George Downie, Jean Macke 4th Edition , Edinburgh. Churchill LivingstoneORTrounce, J, Greenstein, B, Gould, D. Trounces Clinical Pharmacology For Nurses. 18th Edition Churchill Livingstone Edinburgh.British National FormularyRang Dale Ritter and Moore (2003) Pharmacology Churchill Livingstone Bath Press 5th edition