1. Pharmacology Pharmacokinetics

2. Outcomes Explain how drugs may cross cell membranes
Describe factors affecting drug
absorption
distribution
metabolism
excretion
Explain modes of drug interaction
Explain the meaning of half life and factors affecting this
Describe the concept of a therapeutic window
Outline the process dynamic equilibrium that determines the actual concentration of drug in the body

3. Pharmacokinetics Pharmacokinetics is the study of drug Absorption
Distribution
Metabolism
Excretion

4. Crossing Lipid Bilayers
For drugs given by all routes other than the intravenous route, several lipid cell membrane barriers will have to be passed before the drug reaches the circulation. Oral drugs have to cross for e.g. mucous membranes of the GI tract and walls of small blood vessels surrounding the GI tract These barriers are semi permeable lipid bilayers
Gut
Blood vessel
Cell

5. Cell Membranes: Phospholipid bilayers
‘Lipid soluble’ substances will get through
Outside Cell
Aqueous Medium
Inside Cell
H2O
Lipophilic
Hydrophilic
(General Anaesthetics are very lipid soluble)
The phospholipids are arranged so that the membrane serves as a barrier separating two watery environments

6. Transport mechanisms
Four major transport mechanisms exist to facilitate this process:
Passive diffusion (most important and most common.)
Facilitated diffusion
Active transport (only used by drugs which closely resemble natural body substances.)
Pinocytosis or ‘cell-drinking’

7. Transport mechanisms: Passive and Active transport
Passive transport: Molecules move down concentration gradient - no energy required (most drugs pass through membranes by passive transport) Active transport: Used if molecules have to move against concentration gradients or if molecules are large - requires energy (involved in drug excretion in kidney)

8. Simple Diffusion Semi permeable membrane Low concentration
High concentration

9. Simple Diffusion through a phospholipid bilayer
High Solute Low Solute
Concentration Concentration
Small, uncharged molecules
O2 CO2H2O
Large uncharged, molecules
Glucose
Sucrose
Ions
H+, Na+, HCO3-
Extracellular fluid Intracellular fluid

10. Facilitated diffusion across cell membranes
Molecules (which includes drug molecules) move from areas of high concentration to areas of low concentration without requiring energy but using a carrier protein
Rate of diffusion faster if molecule:
Is highly permeable
Has a high concentration

11. Fat soluble Vitamins enter cells in this way
Active transport example: Pinocytosis
Drug now
within cell membrane
Fat soluble vitamin entering cytoplasm
Fat soluble Vitamins enter cells in this way

12. Pharmacokinetics: Absorption
Mostly, for drugs to have the desired effect they must enter the BLOODSTREAM
What happens to the drug from when it is introduced into the body until it reaches circulating fluid and tissues
= ABSORPTION
How quickly and how much of a drug reaches its target site of action = BIOAVAILABILITY

13. Factors influencing absorption
ADMINISTRATION METHOD e.g. Oral, sublingual, IV DRUG PROPERTIES e.g. lipid or water soluble? size of drug particle? ionised? unionised? acid? base? PHYSIOLOGY of the person taking the drug e.g. pH in the stomach how long the stomach takes to empty

14. Sites for Administration of Drugs
Topical – SKIN, EYES
Oral – MOUTH
Nasal - NOSE
Rectal (PR) - RECTUM
Vaginal - VAGINA
Injections – IV, IM, S/C 14

15. Administration method
Absorption time? Topical ………….. Nasal ………….. Rectal ………….. Vaginal ………….. Lungs ………….. IV ………….. IM ………….. S/C …………..

16. Drug properties and lipid solubility
Lipid solubility is a function of:
Electrical charge
Size of molecule Large or Small?
+ Cation or
- Anion or
Uncharged

17. Drug properties - solubility of drug
NON Lipid soluble drugs will not pass through from the gut to the bloodstream (e.g. gentamycin must be given by injection )

18. Drug properties and size of particles
Small molecules move more easily than large molecules across biological membranes
Biological membrane

19. Drug properties and electrical charge
Molecules can be: Non Polar (without an electrical charge) or Polar (one part has a - ve charge while another part has a + ve charge but the molecule as a whole is neutral) – most drugs belong to this group +
– –

20. Drug properties and ionized or un-ionized?
Ions
are electrically charged particles
can have a positive charge e.g. Na+, H+
can have a negative charge e.g. Cl-, OH-, HCO3-
Positively charged particles have lost an electron
Negatively charged particles have gained an electron
Ionized molecules (including drugs) have difficulty crossing lipid membranes
highly ionized drugs cannot cross lipid membranes and unionised drugs can cross freely.
Morphine is highly ionised, fentanyl is the opposite. Consequently the latter has a faster onset of action.
The degree of ionisation depends on the pKa of the drug and the pH of the local environment.
The pKa is the pH at which the drug is 50% ionised.
Most drugs are either weak acids or weak bases.
Acids are most highly ionised at a high pH (i.e. in an alkaline environment).
Bases are most highly ionised in an acidic environment (low pH). For a weak acid, the more acidic the environment, the less ionised the drug, and the more easily it crosses lipid membranes.

21. Acids and Bases An acid is a substance that donates H+ ions
Acid molecules dissociate to form ions e.g.
HCl  H+ + Cl-
H2CO3  H+ + HCO3-
(A base is a substance that accepts H+ ions)

22. Strong acids dissociate more than weak acids e.g.
HCl H2CO3
HCl
H2CO3 H+
Which acid is more ‘ionised’?

23. pH value
1 = strong acid Lots of H+ ions 6 = weak acid 7 = neutral e.g. Water 8 = weak base 14 = strong base Very few H+ ions

24. Drug properties and pH in Digestive Tract
Stomach pH = 1 - 3
Duodenum pH = 6
Small intestine pH = 7-8

25. Drug properties and pH of the Environment
Most drugs are either weak acids or weak bases In acid environments like the stomach weak acid drugs remain largely un-ionized Aspirin is a weakly acidic drug - in the acid stomach aspirin will be un-ionized, favouring diffusion through the gastric mucosa In basic (alkaline) environments like the small intestine weak acid drugs are more likely to dissociate  ‘ionized’
Un-ionised drug molecule HA
Ionised drug
A - H+

26. Drug properties and pH
Absorption of aspirin in stomach Morphine is a weakly basic drug These drugs in the basic environment of the lower GI tract will be less ionized, favouring diffusion through the intestine mucosa

27. Drug properties and pH in the stomachHA A- H+
Stomach lining
Stomach cavity

28. Physiology affecting Absorption
STOMACH EMPTYING (E.g. how long the stomach takes to empty)
SURFACE AREA (E.g. absorption reduced if small intestine surgically removed)
TRANSIT TIME (E.g. Diarrhoea will decrease transit time and so decrease absorption)
STRESS (Increased SNS activity will reduce blood flow to the gut)

29. Physiology affecting Absorption
Absorption from the GI tract also affected by: Factors that reduce blood flow to the GI tract e.g. Hypovolaemia / Shock What are the clinical signs of shock?

30. Absorption - Oral drugs
Surface area of the small intestine > surface area of the stomach  Most oral drugs are absorbed from the small intestine

31. Absorption - Oral drugs
Only a proportion (or possibly none) of the drug will reach the circulation
This is due to factors relating to:
ABSORPTION and / or FIRST PASS EFFECT
[IV Drugs - 100% will reach circulation!]

32. Absorption: ‘First pass’ effect
The majority of drugs given ORALLY are absorbed across the gastro intestinal epithelium into the hepato-portal venous system
Hepatic Portal Vein
gut
liver
Liver
GUT

33. Absorption: First Pass Effect
S/L administration IV administration
Oral administration
Stomach
Small intestine
Large Intestine
Rectum
Systemic circulation
Rectal administration
Liver
Hepatic portal vein

34. Absorption: First Pass Effect
The metabolism of orally administered drugs by gastrointestinal and hepatic enzymes
a significant reduction of the amount of unmetabolized drug reaching the systemic circulation
is called the first pass effect.

35. Absorption: First Pass Effect
In the liver the drug is ‘transformed’ and ‘detoxified’ (made less active and more easily eliminated from the body)
So, a substantial proportion of orally administered doses may be deactivated before reaching the site of action
(dose for oral drugs higher than dose for parenteral drugs)
This is very significant for some drugs
e.g. Opioids - after a single dose, only 15-30% reaches the systemic circulation
15-30%

36. Drug administration and absorption
************************************… *
Oral
Commonest, cheapest, safest
Drug diffuses from gut  blood vessel (high  low concentration)
Barriers – acid stomach, food binding to drugs, reduced stomach emptying
Problem solving – drugs should be given 1 hr before or 2 hrs after meals
Absorption time = * **
Diffusion of drug

37. Drug administration and absorption
Sublingual Enters blood stream quickly  onset of action rapid Enters chiefly by passive diffusion
Avoids the acid medium and digestion process of stomach
Absorption time =

38. Absorption of drugs in an infant
Feature Effect on Drugs
Gastric Cells are immature  Gastric pH is less acid
Slow / irregular peristalsis  Emptying is slowed
Increased body surface +  Topical absorption is
thin skin layers greater
Lack of muscle maturity  IM absorption is faster and unpredictable

39. Absorption of drugs in an elderly adult
Reduction in gastric cells  Reduced gastric pH Decline in muscle tone  Gastric emptying slower Peristalsis is slowed Decreased C.O. and  Blood flow to the GI decreased blood flow tract is reduced Villi in gut become ‘blunt’  GI absorptive surface area is decreased

40. Drug Distribution
After absorption, drugs are distributed to tissues and organs i.e. DISTRIBUTION
This process involves the transportation of the drug to the target site of action.

41. Factors influencing distribution
Lipid Solubility e.g. blood brain barrier only allows lipid soluble drugs to pass Protein Binding e.g. drug bound to protein forms a large particle that cannot leave blood stream Perfusion e.g. person with diabetes prescribed antibiotics for a leg wound infection

42. Lipid solubility and volume of distribution
Water soluble  Higher blood concentration and smaller volume of distribution
Lipid soluble  Lower blood concentration and larger volume of distribution
Women have more fat cells  fat soluble anaesthetics may have more prolonged effect

43. Volume of distribution
The smaller the volume of distribution, the more likely that the drug is confined to the circulatory system.
The larger the volume of distribution, the more likely that the drug is found in the tissues of the body.
The volume of distribution (VD) is a theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma

44. Protein Binding
Proportion of drug bound to PLASMA PROTEINS (albumin and globulin) – drug can be up to 99% bound
(only the ‘unbound’ portion is free to leave the blood and exert an effect)
Reduced protein binding in:
Burns, malnutrition, kidney disease

45. Distribution of drugs in an infant
Affected by: Total Body Water Fat content Protein binding (less protein produced in immature liver)
Blood brain barrier immaturity means that more drugs can enter the brain

46. Distribution of drugs - Elderly adult
Total Body Water Fat content
 Wider distribution of drugs
 Fat soluble drugs accumulate in brain
Protein binding (less protein produced in ageing liver)

47. Pharmacokinetics: Metabolism
In the LIVER many drugs are metabolised by a series of ENZYMES  only a proportion of the dose absorbed reaches the circulation
(e.g. GTN is rendered almost inactive if swallowed)

48. Pharmacokinetics: Metabolism
Enzyme induction Some drugs INCREASE enzyme activity  rate of metabolism of that drug and also other drugs is increased  reduced effect (morphine needs to be taken in bigger doses for same effect) Enzyme inhibition Some drugs DECREASE enzyme activity  making other drugs more toxic Liver Disease Reduces drug metabolism  Increased toxicity

49. Metabolism of drugs - infant
Immaturity of liver and Reduced liver Enzymes  First pass elimination limited and reduced ability to detoxify drugs Metabolism of drugs - Elderly adult The ageing liver is less able to produce microsomal enzymes + liver blood flow is decreased by 1.5% per year after the age of 25 years  Decreased ability of liver to detoxify and metabolize drugs

50. Excretion: removal of drugs from body
Sites for drug elimination:
Kidneys / urine – most important
GI / faeces
Lungs / exhaled gases (e.g. GA drugs
(other sites - sweat, saliva and milk)

51. Renal drug excretion
For drug excretion to occur drug metabolite must be: Water soluble Preferably in ionised form (in aspirin O/D alkalisation of urine with HCO3- will speed up elimination of the drug in the urine)

52. Drug excretion Water Soluble drugs excreted by glomerular filtration
Other drugs may be secreted by active transport processes
(Kidney dysfunction  toxic levels of drugs)

53. Excretion of drugs - infant
Immaturity of kidneys  reduced renal function
Decreased rate of drug excretion
Excretion of drugs - Elderly adult
Renal excretion is decreased as GFR is reduced and number of nephrons decreases

54. Elimination: Drug half life
Time taken for amount of drug in the body to reduce to half of peak level (important in determining frequency of drug dose) 4 3 2 1 x
Drug conc. in blood
Time (hrs)
IV Administration

55. Therapeutic Window
Response
Therapeutic window
Blood level of the drug

56. Therapeutic Window Dose THERAPEUTIC RANGE Time Loading dose
Loading dose

57. Dose of drug and frequency of administration
Need to consider: * Rate of METABOLISM via the LIVER * Rate of EXCRETION via the KIDNEYS Therefore, dose of drug and frequency of administration may vary in: Children Elderly Clients with liver or kidney problems

58. Laboratory test of organ function
Kidney Function Tests
Urea (Blood urea nitrogen - BUN)
(Normal Range = 2.5 – 6.6mmol/L)
Creatinine clearance – blood creatinine levels are compared to creatinine in the urine
Liver Function Tests
Measure various enzymes
Measures Albumin levels
The main point is to keep the dose a low as possible to minimise side effects

59. Side Effects
A drug, once absorbed to the circulation, will be distributed throughout the body  affecting other parts  SIDE EFFECTS

60. Side Effects
Drug Side effect Clozapine Constipation, Hyper salivation Iron Constipation, Nausea Codeine Constipation Morphine Constipation Beta blocker Look in BNF under specific beta blocker!

61. Adverse Reactions
‘Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or therapy’ (WHO 2005) Antibiotics can develop antibodies to antibiotics  allergic reactions can occur on second exposure (Rash  Anaphylaxis  Death)
The WHO Adverse Reaction Terminology – WHO-ART [Internet]. Uppsala (Sweden): The Uppsala Monitoring Center; 2005 Dec [cited 2010 Jul 30]. 8p. Available from:

62. Drug Interactions related to pharmacokinetics
These interactions may be beneficial or harmful and include: 1. Alterations in ABSORPTION 2. Competition for PROTEIN BINDING SITES 3. Altered METABOLISM of other drugs

63. Drug Interactions related to pharmacokinetics
1. Alterations in ABSORPTION e.g. tetracycline not absorbed from GI tract if Ca++ in the stomach 2. Competition for PROTEIN BINDING SITES e.g. one drug cannot bind to plasma protein (displaced) more drug ‘free’  increased toxicity 3. Altered METABOLISM of other drugs e.g. one drug might block or stimulate metabolism of other drugs (look up Warfarin)

64. Generally, drugs should be prescribed by the generic (approved) name
Names of Medicines
Two systems in place for generic / approved drug names:
International Non-proprietary name (rINN)
E.g. Dosulepin
British Approved name (BAN)
E.g. Dothiepin
(Proprietary / Brand = Prothiaden)
All familiar with the generic and the brand name BUT
Directive 92/27/EEC requires use of the RECOMMENDED INTERNATIONAL NON-PROPRIETARY NAME (rINN) for medicinal substances
in most cases the BRITISH APPROVED NAME (BAN) and the rINN are identical
BUT some names have changed e.g. beclomethasone to beclometasone
dothiepin to dosulepin
Just when it wasn’t confusing enough
more info at the front of the BNF
A British Approved Name (BAN) is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP). The BAN is also the official name used in many countries across the world, especially those of the Commonwealth of Nations.
Generally, drugs should be prescribed by the generic (approved) name