Short and sweet powerpoint presentaion on Pharmacokinetics

1. • PHARMACOKINETICS
• Dr Sandeep

2. • Pharmocokinetics
- Refers on how the body acts on the drug
- Pharmacokinetics is the quantitative study of drug
movement in, through and out of the body.
• Pharmacodynamics
o Refers on how the drug acts on the body
o It attempts to elucidate the complete action-effect
sequence and the dose-effect relationship.
o Modification of the action of one drug by another
drug is also an aspect of pharmacodynamics.

3. • drug in tissues
metabolites in tissues
Drug at the site of Administration
1 . ABSORPTION
(INPUT)
Drug in plasma
2. DISTRIBUTION
3. METABOLISM
4. ELIMINATION
(OUTPUT)
Drug & metabolites in urine, feces, or bile

4. II. Routes of Drug
Administration
- Determined primarily
by the properties of the
drug
2 MAJOR ROUTES OF
DRUG
ADMINISTRATION
1. Enteral
2. Parenteral

5. ENTERAL routes
A. ORAL
B. SUBLINGUAL
C. RECTAL

6. PARENTERAL
SC / subcutaneous
IM /
intramuscular
IV / intravascular

7. ENTERAL
A. ORAL
- Most common route of administration
- Most variable
- Cheapest
- Non – invasive
- Both solid and liquid forms can be given

8. disadavantages

9. B. SUBLINGUAL
- Placement under the tongue
- Allows the drug to diffuse into the capillaries & therefore to
enter the systemic circulation
Advantage: the drug bypasses the intestine & liver & thus avoids
1st pass metabolism
Only lipid soluble and non irritating drugs can be used
Drug can be spit once effect is achieved
examples: GTN, Buprenorphine

10. C. RECTAL
- Useful if the drug induces vomiting if given orally or if the
patient is already vomiting
- Drainage of the rectal region bypasses the portal circulation
- Similar to the sublingual route, it prevents the destruction of
the drug by intestinal enzymes or by the low pH in the
stomach
- Its embarrassing and rather inconvenient
- Absorption is rather unpredictable
- Rectal inflammation seen in some patients due to drugs
- Examples : paraldehyde, ergotamine, diazepam

11. Parenteral
• Advantages
• Fast: 15–30 seconds for IV,
3–5 minutes for IM and
subcutaneous (SC)
• 100% bioavailability
• suitable for drugs not
absorbed by the gut or
those that are too irritant
(anti-cancer)
• IV can deliver continuous
medication, e.g., morphine
for patients in continuous
pain, or saline drip for
people needing fluids
• Disadvantages
• more risk of addiction when
it comes to injecting drugs
of abuse
• Belonephobia, the fear of
needles and injection.
• If needles are shared, there
is risk of HIV and other
infectious diseases
• If not done properly,
potentially fatal air boluses
(bubbles) can occur.
• Need for strict asepsis

12. Parenteral
• Used for drugs which are
poorly absorbed in the
GIT
• For unconscious patients
• Circumstances that
require a rapid onset of
action
• Provides the most control
over the actual dose
delivered to the body

13. Parenteral
A. Intravenous
- IV injection is the most common route
- For drugs which are not absorbed orally
- Bypasses the liver
- Permits a rapid effect and a maximal degree of control over the
circulating levels of the drug
- 100% bioavailability
- We can accurately measure the response to drug given
- Can cause thrombophlebitis
- Risky route
- Can introduce bacterial contamination at the site
- Only aqueous forms can be used

14. B. INTRAMUSCULAR
• The drug is injected in one of the large skeletal muscles—deltoid,
triceps, gluteus maximus, rectus femoris, etc.
• Muscle is less richly supplied with sensory nerves (mild irritants
can be injected) and is more vascular (absorption of drugs in
aqueous solution is faster)
• It is less painful, but self injection is often impracticable because
deep penetration is needed.
• Depot preparations (oily solutions, aqueous suspensions) can be
injected by this route.
• Local hematoma seen in pts on anticoagulants

15. c. SC / SUBCUTANEOUS
• The drug is deposited in the loose subcutaneous tissue
which is richly supplied by nerves (irritant drugs cannot
be injected) but is less vascular.
• Only small volumes can be injected s.c.
• Self-injection is possible because deep penetration is not
needed
• Avoided in shock patients
• Some special forms:
• DERMOJET
• PELLET IMPLANTATION

16. D. Intradermal
• The drug is injected into the skin raising a bleb
(e.g. BCG vaccine, sensitivity testing)
• This route is employed for specific purposes
only.

17. E. TRANSDERMAL
• Drugs may be applied to the skin either for local topical efect,
such as steroids, but also may be used to avoid first-pass
metabolism and improve bioavailability.
• Factors favouring transdermal absorption are high lipid
solubility and a good regional blood supply to the site of
application- thorax and abdomen
• Special transdermal formulations (patches) are used to ensure
slow, constant release of drug for absorption and provide a
smoother pharmacokinetic profile.
• examples;: Fentanyl patch, LA patch for veinupuncture

18. 3. Others
a. Inhalation
- Provides a rapid delivery
of a drug across a large
surface area of the
mucus membranes of
the respiratory and the
pulmonary epithelium
- Effect is as rapid as IV
injection
- For gaseous drugs
- Droplets less than
1micron reach alvelous
and hence Systemic
ciculation

19. • Advantages
• Fastest method, 7–10
seconds for the drug to
reach the brain
• Disadvantages
• Typically a more addictive
route of administration
because it is the fastest,
leading to instant
gratification.
• Difficulties in regulating the
exact amount of dosage
• Patient having difficulties
administering a drug via
inhaler

20. Routes of Drug Administration-contd
3. Others
b. Intranasal
- Through the nose
eg. : desmopressin,
salmon calcitonin,
cocaine

21. . Others
c. Intrathecal, intraventricular
- Introducing drugs directly into
the cerebrospinal fluid / CSF
Eg., amphotericin B

22. • TOPICAL
• used when a local effect of
a drug is required
- Eg., clotrimazole, atropine

23. Others
• Epidural
• The epidural route is used to provide regional analgesia
and anaesthesia.
• Epidural local anaesthetics, opioids, ketamine and
clonidine have all been used to treat acute pain, whereas
steroids are used for diagnostic and therapeutic purposes
in patients with chronic pain.
• Drug may be given as a single-shot bolus or through a
catheter placed in the epidural space as a series of
boluses or by infusion.

24. I. ABSORPTION OF DRUGS
• Is the transfer of a drug
from its site of
administration to the
bloodstream
• IV delivery – absorption
is complete

25. Methods of crossing Cell membrane
• Passive Diffusion
• Facilitated Diffusion
• Active Transport
• Pinocytosis

26. Biological membrane

27. Passive transport (down hill movement)
• Most important Mechanism for most of the Drugs
• Majority of drugs diffuses across the membrane in the direction of
concentration gradient
• No active role of the membrane
• Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the
membrane
• Characteristics
– Not requiring energy
– Having no saturation
– Having no carriers
– Not resisting competitive inhibition

28. Passive transport
Affecting factors :
the size of molecule
lipid solubility
polarity
degree of ionization
the PH of the environment

29. Influence of pH
• Most drugs are weak electrolytes, i.e. their ionization is pH
dependent
• The ionization of a weak acid HA is given by the equation:
• Henderson-hesselback equation
pKa = negative logarithm of acid dissociation constant
[A-] = ionized Drug
[HA] = unionized drug
• At a pH below their pKa weak acids will be more unionized; at a pH
above their pKa they will be more ionized. The reverse is true for
weak bases, which are more ionized at a pH below their pKa and
more unionized at a pH above their pKa.

30. IMPLICATIONS
• Acidic drugs, e.g. aspirin (pKa 3.5) are largely unionized at acid
gastric pH and are absorbed from stomach, while bases, e.g.
atropine (pKa 10) are largely ionized and are absorbed only
when they reach the intestines.
• Ion trapping: The unionized form of acidic drugs which
crosses the surface membrane of gastric mucosal cell, reverts
to the ionized form within the cell (pH 7.0) and then only
slowly passes to the extracellular fluid.

31. • The drugs which are Unionized, low polarity
and higher lipid solubility are easy to
permeate membrane.
• The drugs which are ionized, high polarity and
lower lipid solubility are difficult to permeate
membrane.

32. Facilitative transport
• Move substrate of a single
class (uniporters) down a
concentration gradient
• No energy dependent
• Similar to entry of glucose
into muscle (GLUT 4)
• Nurotransmitter entry via
SLC family
• Faster than passive
diffusion

33. Active Transport –
energy dependent
• Active (concentrative) transporters
– can move solutes against a concentration gradient
– energy dependent
• Primary active transporters - generate energy
themselves (e.g. ATP hydrolysis)
• Secondary transporters - utilize energy stored in
voltage and ion gradients generated by a primary
active transporter (e.g. Na+/K+-ATPase)
• Symporters (Co-transporters)
• Antiporters (Exchangers)

34. ACTIVE TRANSPORT

35. Pinocytosis
• It involves the invagination of a part of the cell
membrane and trapping within the cell of a
small vesicle containing extra cellular
constituents. Too large molecules access
inside cell via this pathway.

36. ABSORPTION-contd
• Absorption is movement of the drug from its site of
administration into the circulation.
• Aqueous solubility : a drug given as watery solution is absorbed
faster than when the same is given in solid form or as oily
solution.
• Concentration : Passive diffusion depends on concentration
gradient; drug given as concentrated solution is absorbed faster
than from dilute solution.
• Area of absorbing surface: Larger it is, faster is the absorption.
• Vascularity of the absorbing surface

37. Bioavailability
• Fraction of a drug dose reaching the systematic circulation
compared with same dose given intravenously.

38. Factors affecting Bioavailabilty
• Pharmaceauticals: The way in which a drug is
formulated affects its rate of absorption.
• Physicochemical: Food in stomach delays
absorption
• Patient factors: The presence of coeliac
disease, malabsorption syndromes
• First Pass Metabolism

40. First Pass Metabolism
• The first pass effect (also known as first-pass metabolism or
presystemic metabolism) is a phenomenon of drug metabolism
whereby the concentration of a drug is greatly reduced before it
reaches the systemic circulation.
• It is the fraction of drug lost during the process of absorption which
is generally related to the liver and gut wall.
• After a drug is swallowed, it is absorbed by the digestive system and
enters the hepatic portal system. It is carried through the portal
vein into the liver before it reaches the rest of the body. The liver
metabolizes many drugs, sometimes to such an extent that only a
small amount of active drug emerges from the liver to the rest of
the circulatory system. This first pass through the liver thus greatly
reduces the bioavailability of the drug.

41. First Pass Metabolism

42. • An orally administered drug, the bioavailable
fraction (FB) is given by:
• FB = FA × FG × FH
• FA is the fraction absorbed
• FG the fraction remaining after metabolism in the gut
mucosa
• FH the fraction remaining after hepatic metabolism.
• High/better oral bioavailability drugs are those which
are stable in the gastrointestinal tract, are well absorbed
and undergo minimal first-pass metabolism.

43. Extraction ratio
• The extraction ratio (ER) is that fraction of
drug removed from blood by the liver.
• ER depends on hepatic blood low, uptake into
the hepatocyte and enzyme metabolic
capacity within the hepatocyte.

44. 2. DISTRIBUTION
• Once a drug has gained access to the bloodstream, it gets
distributed to other tissues that initially had no drug,
concentration gradient being in the direction of plasma to
tissues.
• Apparent volume of distribution (V) Presuming that the body
behaves as a single homogeneous compartment with volume
V into which drug gets immediately and uniformly distributed.
• Vd = Iv dose of drug/plasma conc

47. Blood–brain barrier
• The blood–brain barrier (BBB) is an anatomical
and functional barrier between the circulation
and the central nervous system .
• Active transport and facilitated diffusion are
the predominant methods of molecular
transfer
• Only lipid soluble and low molecular weight
drugs cross BBB by simple diffusion

49. 3.METABOLISM
• Metabolism produces a more polar (water soluble) molecule that
can be excreted in the bile or urine – the chief routes of drug
excretion. here are two phases of metabolism, I and II.
 Phase I (functionalization or non-synthetic)
• Oxidation
• Reduction
• Hydrolysis
 Phase II (conjugation or synthetic)
• Glucuronidation (e.g. morphine, propofol)
• Sulfation (e.g. quinol metabolite of propofol)
• Acetylation (e.g. isoniazid, sulfonamides)
• Methylation (e.g. catechols, such as noradrenaline

51. 4.Excretion
• URINE : Major route for Water Soluble drugs and Renal excretion
depends on GFR, Tubular Secretion and Tubular Reabsorption
• Faeces: Apart from the unabsorbed fraction, most of the drug
present in faeces is derived from bile. Relatively larger molecules
(MW > 300) are preferentially eliminated in the bile.
• Examples : Erythromycin, Rifampicin
• Exhaled Air: Gases and volatile liquids(alcohol, inhaled
anaesthetics)
• Milk: The suckling infant inadvertently receives drug excreted in
milk. The transport mechanism here being Passive Diffusion.
Lactating women should be prescribed only essential drugs.

52. Kinetics Of Elimination
• Clearance (CL) The clearance of a drug is the theoretical
volume of plasma from which the drug is completely removed
in unit time.
• CL= Rate Of Elimination/Plasma conc.(C)
 First order (exponential) kinetics
The rate of elimination is directly proportional to the drug
concentration, CL remains constant.
 Zero order (linear) kinetics
• The rate of elimination remains constant irrespective of drug
concentration, CL decreases with increase in concentration.
• Constant amount of the drug is eliminated in unit time, e.g.
ethyl alcohol

54. Half Life
• The Plasma half-life (t½) of a drug is the time
taken for its plasma concentration to be reduced
to half of its original value.
• t½ =0.7*V/CL
• 1 t½ – 50% drug is eliminated
• 2 t½ – 75% (50 + 25) drug is eliminated.
• 3 t½ – 87.5% (50 + 25 + 12.5) drug is eliminated.
• 4 t½ – 93.75% (50 + 25 + 12.5 + 6.25) drug is
• eliminated.

55. • Loading dose This is a single or few quickly
repeated doses given in the beginning to
attain target concentration rapidly.
• Loading Dose = Target Cp*V/F
• Maintenance dose This dose is one that is to
be repeated at specified intervals after the
attainment of target Cpss so as to maintain
the same by balancing elimination.

56. Implications of study
• Renal disease: the drugs that are normally excreted via the
renal tract may accumulate.
• If it is essential to give a drug that is highly dependent on
renal excretion in the presence of renal impairment, a
reduction in dose must be made.
• Knowledge of a patient’s creatinine clearance is very helpful in
estimating the dose reduction required for a given degree of
renal impairment
• D = Usual dose × (impaired clearance/normal clearance).

57. Liver Failure
• Hepatic impairment alters many aspects of the
pharmacokinetic profile of a drug. Protein synthesis is
decreased (hence decreased plasma protein levels and
reduced protein binding).
• In conditions of severe hypoalbuminaemia (e.g. in end-
stage liver cirrhosis or burns), the proportion of unbound
drug increases markedly such that the same dose will have
a greatly exaggerated pharmacological effect. The
magnitude of these effects may be hard to estimate and
drug dose should be titrated against clinical effect.
• Both phase I and II reactions are affected, and thus the
metabolism of drugs is reduced.

58. References
• PECK AND HILL 4TH Edin
• KD Tripathi 6th Edition

59. • THANK YOU