Nursing teaching

1. Pharmacokinetics
Dr. Ankit Bhardwaj
MBBS, MD (Gold Medalist)
Dept. of Pharmacology

2. Pharmacology is the scientific study of drugs (origin,
composition, effects, therapeutic uses and toxic effects).
Pharmacology can be divided into:
• Pharmacokinetics
• Pharmacodynamics.
Introduction

3. • Pharmacokinetics provides a mathematical basis to
assess the time course of drugs and their effects in the
body.
• In other words, pharmacokinetics deals with what the
body does to the drug.
• It enables the following processes to be quantified:
• Absorption
• Distribution
• Metabolism
• Excretion.
PHARMACOKINETICS

4. • Absorption describes how much and how fast the drug leaves its
site of administration.
• Absorption sites: The most common routes of drug
administration are oral, upper GIT in particular.
• Other routes are lungs, skin, nasal cavity, eyes and ear. The
fastest route of absorption is inhalation.
• Absorption of drugs takes place by transport across cell
membranes, i.e. either by
 Passive diffusion
 Active diffusion or endocytosis.
 Facilitated diffusion.
 Pinocytosis (Endocytosis).
ABSORPTION OF DRUGS

6. • Passage of drug through lipid cell membrane by
dissolution in concentration gradient.
• Drugs exist in two forms ionized (water soluble &
nonionized forms (lipid soluble) in equilibrium.
Drug ionized + nonionized
 Only nonionized form is absorbable.
 Nonionized / ionized fraction is determined by pH
and pKa according to Henderson-Hasselbach
pKa- pH= log protonated / non-protonated.
• Rate of diffusion depends on lipid: water partition
coefficient of drug, i.e. diffusion rate is higher for
unionized form of weak electrolyte because of its higher
lipophilicity than the ionized form.
Simple or Passive diffusion

7. • Diffusion or passage of drug is facilitated by an energy
dependent membrane carrier mechanism, i.e. against a
concentration gradient.
• Drug may be transported by ATP-dependent proteins, such
as p-glycoprotein.
• Drugs diffuse in various gradients,
 In intestinal mucosa from cell to lumen
 In choroid plexus from CSF to blood
 In proximal renal tubular cell from blood to urine
 In hepatocyte from blood to bile, etc.
• Active transport gets saturated over a time and there is a
competition between structural analogues and genetic
variants.
Active Transport

8. • Occurs along concentration gradient.
• Requires carriers
• Selective.
• Saturable.
• No energy is required.
Carrier mediated facilitated diffusion

9. Active transport Facilitated transport
Against concentration
gradient (from low to
high )
Along concentration
gradient (from high to
low)
Needs carriers Needs carrier
Selective, saturable Selective, saturable
ATP consumed as energy
source
No energy is required

10. • It is one of the important mechanism for particulates and high
molecule weight compounds, such as proteins.
• Passage of drug takes into cell within membrane invagination,
i.e. consists of folding of an area of the exterior sheet of cells
towards the inside of the cell.
Diffusion by Endocytosis

12. Oral (enteral): absorption from mouth, stomach and small intestine •
Stomach: minority
• Small Intestine: majority
 Passive > Active
 Rate ~ 75% in 1-3 hours.
Depends on:
• Motility e.g. diarrhea decreases absorption
• Blood flow
• Food – enhance or impair
• Particle size and formulation
• Physio-chemical factors
 Unionized
 Lipid soluble
• Rate of gastric emptying rate limiting step
Oral (enteral): absorption

13. • Poor acid stability: prolonged gastric exposure → degradation
e.g. erythromycin, azithromycin, isoniazid
• Require acid environment
e.g. itraconazole, ketoconazole
• Fat or bile acids enhance absorption
e.g. tacrolimus, carbamazepine
• Bind to fiber, reducing absorption
e.g. digoxin
• Bind to calcium (chelate), reducing absorption
e.g. tetracyclines, quinolones
Effects of Food on Oral Drug Absorption

14. • Rate of disintegration of tablet
Tablet compression
 Bulk excipients
• Rate of dissolution of drug particles in intestinal fluid
Particle size: smaller dissolve quicker
• Modified Release
Reduce frequency of oral administration e.g. morphine,
nifedipine, paracetamol extend
Deliver contents to site of action e.g. mesalamine: pH sensitive
coating – 5-ASA released in distal small bowel and colon
Formulation

15. Oral controlled release formulations
Advantages
• Frequency of dosing reduced as drug
released over a longer time period .
• Avoid breakthroughs as maintain
persistent serum level .
• Reduction or avoidance of side
effects due to high plasma drug
concentrations or ’dose dumping’
• Improvement in patient compliance
due to reduced dosing
• Cost-effective manufacturing as the
amount of tablets needed per
patient can be reduced and manage
accordingly
Disadvantages
• Expensive
• Drug release rate can be altered by
food and gastric transit time .
Cannot crush or chew products
Crushing an extended release
preparation may change the drug
release and toxicity.

16. Advantage Disadvantage
Easy Slow effect
Self administration No/incomplete absorption (low bioavailability) -
Safe Destruction by GIT - streptomycin, d-
tubocurarine, suxamethasonium, Penicillin G,
Insulin
Convenient First pass effect - morphine, isoprenaline
Cheap GIT irritation
No issues of contamination • Food- Drug interaction
• Drug-drug interactions
Not suitable for vomiting, unconscious and
emergencies
CAN NOT CRUSH or CHEW – can lead to lass of
slow release characteristic as well as toxicity

17. Parenteral route of Administration
Intramuscular
Advantages
• Good absorption, specially for drugs with a
low oral bioavailability
• Onset is more rapid compared to oral route
• Depending on oral route can have very long
duration of action e.g. depot of antipsychotics
and contraceptives
Disadvantages
• Absorption may still be unpredictable if peripheries are poorly perfused
• Perfect aseptic conditions are needed
• Chances of abscess at site of the injection
• Chances of nerve damage leading to paresis
• Large volume cannot be administered

18. Intra-arterial
Advantages
Greater concentration of drug can
be delivered at the desired site of
action.
e.g. radiopaque contrast,
chemotherapeutic agents like
nitrogen mustard
Disadvantages
Great expertise and aseptic
conditions are required

19. Subcutaneous
Advantages
• Smooth but slower absorption for a longer
period compared to intravenous or
intramuscular route
• Depot injection can also be given.
• Preferred route for some vaccines.
Disadvantages
• Suitable for only small volumes of drugs
(maximum 2 ml)
• Finding suitable site for repeat injections can
be problem
• Irritant drugs can cause local tissue damage –
sloughing and necrosis
• Not suitable in the states of shock as reduced
peripheral circulation decrease the rate of
absorption.

20. Intradermal
Advantages
• The amount of drug required is
small.
• Mainly used for testing
sensitivity to drugs e.g.
penicillin, ATS (anti-tetanus
serum)
Disadvantages
• Required expertise
• Painful

21. Sublingual/buccal Administration
• From blood vessels at base of
tongue/gums and cheeks
• Lipid soluble drugs only Nitroglycerin,
nicotine chewing gums
• Small surface area - potent drugs only
• Avoids first pass metabolism
• Rapid absorption: minutes
• Quick termination of action
• Disadvantages – unpalatable,
inconvenience, mucosal irritation, small
dose limit, only a few drugs can be given

22. Rectal Formulations
• Avoid first pass metabolism
• Erratic absorption because of rectal
contents
• Unacceptable to patients
• Useful if unable to take oral medications
e.g. paracetamol, oxycodone, NSAIDs
• Useful if unable to get IV access e.g.
diazepam in status epilepticus
• Direct effect on large bowel e.g.
corticosteroids in Inflammatory Bowel
Disease

23. Vaginal pessary
Advantages
• Easy to use
• Local Action
Disadvantages
Increased risk of vaginal discharge
vaginal irritation
Ulceration
Bleeding
Dyspareunia

24. Inhaled Medications
• Formulations:
 Powders
 Aerosol solutions
 Nebulized solutions
• Advantages
 Rapid absorption
 Can be self administered
 Drug targeted to lungs with low
levels of systemic absorption.
Disadvantages
 Bioavailability depends on patient
inhaler technique and the size of
drug particles ( >20 micron impact in
the mouth and throat whereas <0.5
micron passes easily)

25. Inhaled Medications

26. • Common reason for failure of response is
incorrect inhalation technique.
• Best practice is to use MDI with spacers.
• If pump has not been use for a week or more, it
should be shaken well and one puff released into
the air.
• Local side effects e.g. oral candida (rinsing
mouth after every use can prevent local side
effects)
• Systemic side effects
Salbutamol: tremor
Corticosteroids: osteoporosis
Ipratropium bromide: anticholinergic ‘dry mouth’
in 15% patients

27. • Direct therapeutic effect
Sodium cromoglycate for rhinitis
• Systemic effect
Sumatriptan in migraine (vomiting)
• Local toxicity
Cocaine – necrosis of nasal septum
Topical: Intranasal Formulations

28. • Absorption through conjunctival sac
epithelium
• Local effects in eyes with minimal systemic
effects
• Systemic side effects e.g. timolol for
glaucoma may precipitate bronchospasm in
asthma
Topical: Eye Drops
• Local effect on skin e.g. Steroids
 Small amount of drug is required
• Slow systemic absorption (patch)
 Lipid soluble drugs only
 Estrogen
 Opioids – Fentanyl, Buprenorphine
Topical: Cutaneous Administration

29. Bioavailability
• Bioavailability: the % of an ingested dose of a drug
that enters systemic circulation
• Bioavailability: implications for oral and parenteral
dosing
• High bioavailability, dose same for IV and po routes
e.g. metronidazole, fluconazole, amoxicillin
• Low bioavailability, lower dose for parenteral than po
routes e.g. morphine: 10 mg s/c or IM = 30 mg po

30. • Molecular weight of drug.
• Drug Formulation (ease of dissolution).
(solution > suspension > capsule > tablet)
• Drug solubility of the drug
• Chemical instability in gastric pH (Penicillin & insulin)
• First pass metabolism reduces bioavailability
• Blood flow to absorptive site
 Greater blood flow increases bioavailability
 Intestine has greater blood flow than stomach
Factors Affecting Bioavailability

31. • Surface area available for absorption.
 Intestinal microvilli increases it
• Rate of gastric emptying
 rapid gastric emptying
• pH of gut - fast transit to intestine
• Intestinal motility (Transit Time)
 Diarrhea reduce absorption
• Drug interactions
• Food
 slow gastric emptying
 generally slow absorption
 Tetracycline, aspirin, penicillin V

32. Half life
• Half life is the time required for the body to eliminate one
half the amount of the drug in the body (T1/2)
• Important parameter for estimation of time required to
reduced by half of its original concentration.
• Drug clear from body within 4-5 half life which give an
estimation for how long a drug should be stopped if
patients has toxic drug levels e.g. Antiepileptics drugs like
phenytoin, valproic acid.
T1/2= 0.693 X V/CL

33. Bioequivalence
• Pharmaceutically equivalent and equal systemic
bioavailability
• Generics - must be bioequivalent to innovator (80-
125%)
• Phenytoin toxicity outbreak (Australia 1968)
‘Inert’ excipient changed: CaSO4 to lactose
 Increased solubility and systemic availability

34. Drug Binding and Distribution
Protein binding
• Many drugs bind to plasma proteins
 Albumin (acidic drugs, e.g. warfarin, NSAIDs)
 Alpha-1 acid glycoprotein (basic drugs, e.g.
quinine)
 Lipoproteins (basic drugs)
 Globulins (hormones)
• Only free drug can bind to receptors

35. • Changes in protein binding
 Disease and nutrition
 Protein binding displacement interactions e.g.
valproate displaces phenytoin – increases free
phenytoin, compensate with increased clearance
• Clinically relevant effects if
 >90% of drug is protein bound -e.g. phenytoin,
warfarin
 Small volume of distribution
Clinical implications of changes in protein binding

36. • Body Fat
 Lipid soluble drugs
 Stable reservoir - e.g. anesthetics
• Bone
 Adsorption onto bone-crystal surface
 Reservoir – slow release e.g. tetracyclines, heavy
metals
Tissue Binding

37. Apparent Volume of Distribution (Vd)
• Vd: volume of fluid required to contain the total amount of
drug in the body at the same concentration as that in the
plasma
Vd = amount of drug in body
plasma concentration
• Loading dose = Vd x desired plasma concentration

38. • Blood brain barrier
 Only lipid soluble drugs can enter brain and CSF
 ‘Leaky’ in disease – e.g. penicillin in meningitis
• Placenta
 Allows passage of lipid and some water soluble
drugs – e.g., opioids, antiepileptics
 Enzymes in placenta inactivate some drugs
Barriers to Drug Distribution

39. Metabolism (biotransformation)
• Metabolism is chemical inactivation of drug by converting it to more water
soluble compound.
• Products of metabolism have greater lesser or qualitatively different
pharmacological activity from parent compound.
• Enzymatic activity is generally highest in liver;
• Physiological factors affecting drug metabolism
Age
Individual variation
Gender
Nutrition

40. Factors affecting drug metabolism
• First Pass’ effect
• Hepatic blood flow
• Liver disease
• Genetic factors (pharmacogenetics)
• Other drugs
– Hepatic enzyme inducers
– Hepatic enzyme inhibitors

41. Factors affecting drugs metabolism
Enzyme inducing drugs
• Enhance the (production of) liver
enzymes which breakdown drugs
resulting in faster rate of drug
breakdown
• larger dose of affected required to get
the same clinical effect.
• Examples of enzyme inducing drugs—
phenytoin, phenobarbitone,
carbamazepine, rifampicin, griseofulvin,
chronic alcohol intake, smoking.
Enzyme inhibiting drugs
• Inhibit the enzymes which breakdown
drugs decreasing rate of drug
breakdown.
• Smaller dose of affected drug needed to
produce the same clinical effect.
• Enzyme inhibitors are erythromycin,
ciprofloxacin, metronidazole,
chloramphenicol, sulphonamides, acute
alcohol, allopurinol, phenylbutazone,
isoniazid, sodium valproate, oral
contraceptives, fluconazole.

42. Elimination
• Elimination is the removal
of drugs and their
metabolites from the body.
• Main site of drug excretion
is kidney.
• Drugs are also excreted in
bile, sweat, lungs, breast
milk, tears, genital
secretions, saliva.

43. Factors affecting Renal excretion of drugs
• Decreases in effective circulating blood volume
Pre-renal
With-in kidney
Beyond the kidney
• Nephrotoxic drugs
• Diseases precipitating acute renal failure (ARF).

44. Significance of route of elimination
• Care should be exercised with renally excreted drugs
• Ampicillin is excreted in high concentrations in bile, so is a good
choice for biliary tract infection.
• Care with drugs with a narrow therapeutic index—digoxin, lithium,
phenytoin.
• Care with drugs which produce active metabolites—Benzodiazepines
(diazepthioridazine); opioids (morphine, pethidine,
dextropropoxyphene).
• Care with drugs that may further reduce renal function—NSAIDs.

45. • Lungs
 alcohol breath
• Breast milk
 acidic ---> ion traps alkaloids
 alcohol: same concentration as blood
 antibiotics
• Also bile, skin, saliva
Excretion: Other routes

46. Drugs may follow Zero order or first order kinetics .
Depends on
Rate of Elimination ∝ [Plasma concentration]order
First order kinetics
• A constant fraction of drug is eliminated per unit
of time.
• When drug concentration is high, rate of
disappearance is high. Example: Most of the
drugs follow first order kinetics.
Zero order kinetics
• Rate of elimination is constant.
• Rate of elimination is independent of drug concentration.
• Constant amount eliminated per unit of time. Example: Alcohol, warfarin,
theophylline, aspirin, phenytoin
Kinetics of Elimination

47. • Maintenance of drug therapy is by
repeated administration
• Accumulation occurs when the drug
is administered before the previous
dose is completely eliminated.
• Steady state means that the drug
has reached a stable concentration:
 At steady state, the drug is
being eliminated at the same
rate as it is being administered.
 Once steady state is achieved,
consistent amount of drug is
maintained in the body.
Steady State Plasma Concentration

49. • Dose-response (DR) curve
 Depicts the relation between drug dose
and magnitude of drug effect
• Drugs can have more than one effect
• Drugs vary in effectiveness
 Different sites of action
 Different affinities for receptors
• The effectiveness of a drug is considered
relative to its safety (therapeutic index)
Drug Effectiveness

50. • Effective dose (ED50) = dose at
which 50% population shows
response
• Lethal dose (LD50) =dose at which
50% population dies
• TI = LD50/ED50, an indication of
safety of a drug (higher is better)
Therapeutic Index

51. • Relative strength of response
for a given dose
 Effective concentration
(EC50) is the concentration
of an agonist needed to
elicit half of the maximum
biological response of the
agonist
 The potency of an agonist
is inversely related to its
EC50 value
• D-R curve shifts left with
greater potency
Potency

52. • Maximum possible effect relative to other
agents
• Indicated by peak of D-R curve
• Full agonist = 100% efficacy
• Partial agonist = 50% efficacy
• Antagonist = 0% efficacy
• Inverse agonist = -100% efficacy
Efficacy

53. • Decreased response to same dose with
repeated (constant) exposure or more
drug needed to achieve same effect
• Right-ward shift of D-R curve
• Sometimes occurs in an acute dose
(e.g. alcohol)
• Can develop across drugs (cross
tolerance)
• Caused by compensatory mechanisms
that oppose the effects of the drug
Tolerance (desensitization)

54. • Increased response to same dose with
repeated (binge-like) exposure or less
drug needed to achieve same effect
• Left-ward shift in D-R curve
• Sometimes occurs in an acute dose (e.g.
amphetamine)
• Can develop across drugs (cross
sensitization)
Sensitization

55. • Pharmacokinetic - changes in drug availability at
site of action (decreased bioavailability)
 Decreased absorption
 Increased binding to depot sites
• Pharmacodynamic - changes in drug-receptor
interaction
 G-protein uncoupling
 Down regulation of receptors
Mechanisms of Tolerance and Sensitization

56. • Psychological - As the user becomes familiar with the drug’s
effects, s/he learns tricks to hide or counteract the effects. Set
(expectations) and setting (environment)
 Motivational
 Habituation
 Classical and instrumental conditioning (automatic physiological
change in response to cues
• Metabolic - The user is able to break down and/or excrete the drug
more quickly due to repeated exposure.
 Increased excretion
Other Mechanisms of Tolerance and Sensitization

57. • Pharmacokinetic and pharmacodynamic
 With pharmacokinetic drug interactions, one drug affects
the absorption, distribution, metabolism, or excretion of
another.
 With pharmacodynamic drug interactions, two drugs have
interactive effects in the brain.
 Either type of drug interaction can result in adverse effects
in some individuals.
 In terms of efficacy, there can be several types of
interactions between medications: cumulative, additive,
synergistic, and antagonistic.
Drug-drug Interactions

58. Drug-drug Interactions
A drug interaction occurs when one drug given with or
shortly after another drug alters
the effect of one drug or both drugs. Usually, the effect
of one of the drugs is either increased or decreased or
cause unexpected side effects.
The drugs involved can be prescription medications,
over-the-counter medicines and even vitamins and
herbal products.

59. Types of drug interactions
1. Drug-drug interactions
2. Drug-food interactions
3. Chemical-drug interactions
4. Drug-laboratory test interactions
5. Drug-disease interactions

60. The consequences of drug-drug
interactions
Antagonism 1+1 = -1
Additive 1+1 = 2
Synergism 1+1 = 4
Potentiation 1+ 0= 2

61. Outcome Of Drug Interactions
• Beneficial
• Probenecid with penicillin reduces the dose of penicillin by
decreasing excretion of penicillin.
• Hydrochlorothiazide and spironolactone
• Harmful
• Aspirin and blood-thinners like warfarin – increased bleeding
• Lack of efficacy
• antacids can prevent absorption of many medicines (such as
antibiotics, blood thinners and heart medications)

62. In Vitro Interactions
• Interactions occurring outside an organism before administration of the drugs;
also called incompatibility.
• Two or more drugs delivered simultaneously through the same line - risk of
physicochemical incompatibilities.
• Physical or visual incompatibilities present in the form of precipitation,
effervescence, colour change, and related visual changes.
• Do not draw in same syringe
• Thiopentone and suxamethonium
• Penicillin and aminoglycosides –
• Phenytoin precipitates in dextrose solutions, e.g. D5W. Always give phenytoin
with normal saline.
• On the other hand valproic acid and amphotericin precipitates in saline, therefore,
should always be given with dextrose solution.
• Ampicillin, chlorpromazine and barbiturates interact with dextran in solutions and
are broken down or form chemical compounds