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

6. PHARMACOLOGY PHARMACODYNAMICS PHARMACOKINETICS
(SPECIFIC TO DRUG OR DRUG CLASS)
PHARMACOKINETICS
(NON-SPECIFIC, GENERAL PROCESSES)
Hand this out to the students.

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… http://www.youtube.com/watch?v=tnnoPedWO7M
…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