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Introducing Pharmacokinetics and Pharmacodynamics

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1 Introducing Pharmacokinetics and Pharmacodynamics
Janice Davies Pharmacist Room 23 Maudland Building

2 eLearn

3 DVD Any problems / questions?

4 Learning outcomes Define and discuss pharmacokinetic factors
Discuss the factors that affect absorption, distribution, metabolism and excretion-how they affect drug therapy Define and discuss pharmacodynamic mechanisms of drug actions Apply pharmacokinetic and pharmacodynamic concepts to patient scenarios.

5 Definitions Pharmacokinetics 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 including the 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-pharmacokinetics To exert it’s effect the drug must act at sight of action, must act at cellular level-pharmacodynamics


7 Arrange the phrases!!! Factors determining response of a patient to a drug
Drug interactions Duration of effect Unwanted effects Reduction in symptoms Modification of disease progression Accumulation on repeat dosage Absorption from the site of administration Elimination from the body Delivery to the site of action Effects at the site of action Interaction with cellular component Arrange the phrases on their handout. Test again at the end of the session.

8 Pharmacokinetics:considering such terms as
Route Absorption Distribution Hepatic Metabolism Metabolic products Protein Binding Renal Excretion Half-life Toxicity We are going to come to each one in turn Route- Oral, Parenteral- inhalation, rectal, transdermal, injection Absorption-Entry into body-acidity and solubility First-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 toxicity Extent 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 bile How long does it take the Plasma concentration of drugs to go down to 50% Consider the pharmacological routes to adverse drug effects

9 Absorption Distribution Metabolism Excretion
Pharmacokinetics refers to the handling of a drug within the body and includes THE BODIES RESPONSE TO MEDICATION To achieve the pharmacological response desired, the drug must first be in an available and suitable form and then administrated by an appropriate route Unless the drug acts locally it will need to be absorbed, distributed and circulated before reaching the site of action For 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?

10 Absorption Route Distribution Enteral Parenteral IV Topical Absorption
oral sublingual transdermal inhalation Absorption Absorption Systemic circulation

11 Absorption Process of drug movement from the administration site to the systemic circulation. The amount and rate of absorption are determined by several factors: Physical nature of the dosage form Presence or absence of food in the stomach Composition of the GI contents Gastric or intestinal pH Mesenteric blood flow Concurrent administration with other drugs Dosage 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 effects Food effect on some drugs affects the bioavailability – look at this in greater depth shortly. Impacted faeces GI 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 absorption The level of mesenteric blood flow directly affects the rate of removal of the drug from the site of absorption Drug absorption is mainly in the upper small intestine that is facilitated by the large surface area of villi and the rich blood supply Alteration 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 drug Not all oral drugs are absorbed? When would it be desirable for an oral drug to have minimal absorption characteristics? Eg vancomycin, UC.

12 Bioavailability “Bioavailability is the proportion of the administered dose that reaches the systemic circulation.” Dale and Haylet, Pharmacology Condensed. 2004 Refers to the amount and the rate of appearance of the drug in the blood after administration in its initial dose form Orally administered drug bioavailability is directly related to the individual solubility in body fluids. Poor solubility = low bioavailability To 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 blood Some 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.

13 Effect of Food Bioavailability of some drugs is affected by the presence of food. E.g penicillin's, erythromycin, rifampicin, thyroxine Some drugs are taken before meals to allow time for drug to act before food is taken Gastric irritation can be caused by drugs taken on an empty stomach Effect of food on the absorption of drugs The importance in considering gastric content is the causative effects on the bioavailability of drugs in the presence of absence of food Food can alter the dissolution and intestinal transfer time of the drug Allowing time for drug to act e.g the anaesthetic property of oxethazaine in Mucaine in the calming of oesophagitis before eating Gastric irritating properties of metformin and levodopa can be reduced by the protective properties of food. Bioavailability can be increased by food due to 1 reduced 1st pass, eg. Propranolol 2poor water solubility but high fat solubility eg griseofulvin 3 delayed gastric emptying increases time for disolution e,.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 work Some drugs are totally unaffected by presence or absence of food!

14 First Pass Effect Drugs that are absorbed via the GIT are
circulated to the liver first via the hepatic portal vein Liver then acts as a filter Only part of the drug is circulated systemically The combination of processes is termed the ‘First Pass’ effect The 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 toxins All 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 metabolism GTN first-pass breakdown is complete so cannot be taken orally-sublingual preparation!!

15 Absorption animation

16 Distribution Factors affecting Absorption Metabolism Low albumin
Problems with: Heart Circulation Diabetes Plasma proteins affect the distribution of drugs in the: Plasma proteins can affect movement from blood to tissue, reduced in some diseases, role in polypharmacy Additional factors that affect distribution:Cardiac output, Regional blood flow, Bound drugs are pharmacologically inactive because the drug-protein complex is unable to cross 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 diseases Deficiency 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 polypharmacy Different 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 flow Warm atmosphere = better blood flow=improved drug distribution Inflamed 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.

17 Metabolism 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 lipophilic The higher the solubility in lipids compared to water, the more rapid the tissue entry Metabolic rate determines the duration of the action of the drugs The 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 soluble To excrete the drug needs to become more hydrophilic (water loving) than lipophilic The speed with which a drug is metabolised will determine the duration of the action of the drug This in turn will determine how often the drug is administered. Which BNF appendix relates to patients’ ability to metabolise?

18 Excretion Drugs are primarily excreted by the kidneys
In order for drugs to be excreted they need to become hydrophilic Excretion of drugs can be affected by the urinary pH How the drug is excreted can influence prescribing decisions Mostly kidneys, but also skin, bile, lungs. The excretion rate varies from hours to weeks and on the condition of the kidneys Ageing 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)etc Excretion and prescribing influence. Eg ampicillin is excreted in high concentrations in bile, so is a good chioce for biliary tract infection When 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?

19 Half Life of Drugs Drug 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 value Drug half life is variable and can be long or short Subsequent doses are given to raise the concentration levels to a peak In theory, the optimal dosage interval between drug administration is equal to the half-life of the drug Half Life of Drugs – aspirin 6 hours, metronidazole 9 hours, digoxin 36 hours Half-life is affected by: Extensive tissue uptake, Rapid metabolism, Rapid excretion- Short half life Long half life Extensive protein binding, slow metabolism, poor excretion Knowledge of half-life is essential when determining drug dose intervals Concentration falls after metabolism and excretion. If dose interval is too long, effect is not achieved, too short an interval leads to toxici Ideally 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.

20 Example Drug 100mgs with a 6 hour half life
1st dose 100 mgs 2nd dose 100mgs + 50 mgs still present = 150mgs 3rd dose 100mgs + 75 mgs still present = 175mgs 4th dose 100mgs + 88mgs still present = 188mgs 5th dose 100mgs + 94mg still present = 194mgs 6th dose 100mgs + 97mg still present = 197mg As can be seen, accumulation becomes less at each dose- “steady state” is achieved after 3 to 5 half lives. 1st dose 6am 2nd dose 12pm 3rd dose 6pm 4th dose 12 midnight In ‘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

21 Loading Doses Are used when the medical condition demands high concentrations very quickly This is achieved by an initial dose that is twice the maintenance dose EXAMPLE ACUTE INFECTIONS USE STAT DOSE OF ANTIBIOTIC, 2 TIMES THE NEXT DOSE. DIGOXIN LOADING DOSE The figure 5. To reach steady state, or to eliminate almost 97% of drug.

22 Some exam style MCQs:

23 Which ONE of the following affects absorption?
Drug formulation Time of administration Mode of action of the drug

24 A patient with renal impairment, taking a renally excreted drug, will require which ONE of the following? Dose reduction Dose increase Same dose

25 Which ONE of the following describes bioavailabilty?
The proportion of drug reaching the circulation The extent of first pass metabolism The quantity of drug absorbed in the GI tract

26 Tea break…
…best to leave now if easily offended!

27 Pharmacodynamics 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 level Receptors Ion channels Enzymes Carrier molecules Chemotherapy Pharmcodynamics is about that, how drugs work-its about how drugs taken orally or parentally actually work in the body at cellular level We 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 nomenclature H2 antagonists and B2 agonists are telling you how those groups of drugs work Understanding 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

28 Considering Receptors-agonist, partial agonist and antagonist
Ion channels-gating of intracellular ions Enzymes-drugs act to inhibit or potentiate Carrier molecules-allow molecules not lipid soluble to cross cell membrane Chemotherapeutic agents Drug tolerance/dependence Effects of pathological state and biological variability

29 Receptors Receptors are a target molecule that a drug molecule has to combine with to produce a specific effect Receptors must be compatible –like 2 pieces of a jigsaw e.g. neurotransmission Main types of action at receptor: Receptor agonists Receptor antagonists

30 Types of receptors G-protein-couple receptors, seconds e.g. Muscarinic ACh receptors, adrenoceptors, histamine receptors Kinase linked receptors, hours e.g. Insulin, Growth factor Nuclear intracellullar receptors, hours e.g. steroid, thyroid hormone G protein receptors work in seconds Kinase (enzyme) linked receptors can take hours.

31 Ion Channels Carrier molecules
Drugs act to affect cellular gating mechanism in cell wall Ligand-gated ion channels, milliseconds e.g GABA benzodiazepines, Nicotinic ACh Carrier molecules Drugs act on carrier transporters which allow molecules, not lipid soluble to cross cell membrane Some 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 cell Drugs acting at ion channels include Benzodiazpeines that act at GABA (gamma amino butyric acid receptor) chloride channel return over excitable receptor to constitutive (normal) level of activation Calcium channel blockers prevent diffusion of calcium through cell membrane Nicorandil acts at potassium channels Carrier 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 acids Examples of drugs that act in this way include Loop diuretics which inhibit sodium, potassium and chlorine passage in the lop of Henle Another example Omeprazole inhibits proton pump in the gastric mucosa Tricyclics inhibit noradrenaline uptake

32 Enzyme inhibitors An enzyme is a protein that can promote or accelerate a biochemical reaction with a substrate When the enzyme mistakes the drug for a substrate, a drug-enzyme interaction occurs This interaction could increase or decrease the rate of the biochemical reaction As an example lets look at how levodopa is used in the treatment of Parkinson's disease Dopamine 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 inhibited This results in the reduction of the breakdown of levodopa This means a lower dose of levadopa can be given, reduce risk of side effects Many drugs target enzymes acting as false substrates to competitively inhibit either reversibly e.g.neostigmine or irreversibly e.g Aspirin Simvastatin inhibits HMG CoA REDUCTASE

33 The cell is ruptured Arachidonic 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 prostaglandins All NSAIDs inhibit COX enzymes

34 Chemotherapeutic agents
Cytotoxic drugs act by interfering with cell growth and division at different stages of the cycle Anti-infective drugs Examples. Folic acid is required for DNA synthesis.Methottrexate inhibits the formation of folic acid Penicillins and cephalosporins inhibit synthesis of bacterial cell walls Nyastatin acts by increasing the permeability of of cell membranes of invading organisms Erythromycin inhibits bacterial protein synthesis Additional drugs classified Potassium citrate alters the pH of urine, making it more alkaline, relieves discomfort of cystitis Desferrioxamine chelates(combines and neutralises) with ferrous iron in the treatment of iron poisoning

35 Metabolism of bacterial cell
Cell wall Cell membrane DNA Metabolism of bacterial cell Class 2 reactions Class 1 reactions Nucleotides Class 3 reactions Proteins RNA DNA Precursor molecules Glucose Chemotherapy-exploiting the differences between host and bacteria Class 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. Amino acids

36 Physiological Variability
Liver disease Chronic alcoholism Renal disease Allergy Liver disease Damage of liver cells Reduced hepatic blood flow Decreased plasma proteins May all require avoidance (e.g. lignocaine)or reduction in dose(e.g. propranolol) of certain Drugs Alcoholism Induces 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 accordingly Renal disease Potential 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 required Allergy 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 response Iatrogenic effect Is 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 penicillin Finally for every rule there is an exception-people vary!

37 Exam Style MCQs A receptor antagonist:
binds to a receptor and activates it binds to a receptor without causing activation blocks an enzyme

38 The pharmacodynamics of salbutamol can be explained by its:
activity on enzymes activity on ion channels activity on receptors

39 Warfarin has a: Narrow Therapeutic Index Wide therapeutic range Neither are important

40 Write brief notes on any TWO of the following modes of drug action:
Receptor agonists Receptor antagonists Action at enzymes Ion channels Carrier molecules Chemotherapy

41 Short answer questions:
What is a narrow therapeutic index? What is bioavailability? What is half life? What is a loading dose? What is pharmacodynamics?

42 Further reading Downie, George (2008) Pharmacology and medicine management for nurses George Downie, Jean Macke 4th Edition , Edinburgh. Churchill Livingstone OR Trounce, J, Greenstein, B, Gould, D. Trounces Clinical Pharmacology For Nurses. 18th Edition Churchill Livingstone Edinburgh. British National Formulary Rang Dale Ritter and Moore (2003) Pharmacology Churchill Livingstone Bath Press 5th edition

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