2. Pharmacokinetics
Absorption, distribution, metabolism and elimination of a drug
Involves passage across numerous cell membranes
Plasma membrane is the basic barrier
Characteristics of drugs that predict the availability and movement are
1. Molecular size
2. Degree of ionisation
3. Relative lipid solubility
4. Its binding to serum and tissue proteins
4. Passive diffusion
Diffusion along a concentration gradient by virtue of its solubility in the lipid
bilayer
Non electrolyte – steady state concentration same on both sides of the membrane
Ionic compounds – steady state concentration depends on the electrochemical
gradient and difference in pH across the membrane
Ratio of non ionised to ionised at any pH is calculated by Henderson - Hasselbalch
equation
5. Henderson–Hasselbalch equation
𝑝𝑘𝑎 = 𝑝ℎ + 𝑙𝑜𝑔
𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 𝑓𝑜𝑟𝑚
𝑢𝑛𝑝𝑟𝑜𝑡𝑜𝑛𝑎𝑡𝑒𝑑 𝑓𝑜𝑟𝑚
pka – dissociation constant
Acidic drug accumulates more on the basic side of the membrane and vice versa
This phenomenon is called ion trapping
6. 𝒑𝒌𝒂 𝒂𝒄𝒊𝒅 = 𝒑𝑯 + 𝐥𝐨𝐠
𝒏𝒐𝒏𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒂𝒄𝒊𝒅
𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒂𝒄𝒊𝒅
𝒑𝒌𝒂 𝒃𝒂𝒔𝒆 = 𝒑𝒉 + 𝐥𝐨𝐠
𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒃𝒂𝒔𝒆
𝒏𝒐𝒏𝒊𝒐𝒏𝒊𝒔𝒆𝒅 𝒃𝒂𝒔𝒆
Stronger the acid / weaker the base lower will be the pka value
Weakly basic drugs are non ionised in basic media and weakly acidic drugs non ionised in acidic media
If 𝑝𝑘𝑎 = 𝑝𝐻 it would remain 50% ionised and 50% non ionised
If pH increases or decreases by 1 unit there is a 10 fold increase or decrease in the ratio of the ionised
and non ionised fraction of the drug
Strongly acidic / basic drugs remain predominantly ionised at all pH therefore poorly absorbed
8. Facilitated diffusion
Carrier can move a drug substrate along its concentration gradient only
No energy required
Rate of diffusion depends on the binding ability of the drugs to its carrier
Two drugs having similar physico-chemical characteristics can compete for the
same transfer mechanism thus interfere with each other
E.g. amino acids in brain, antimetabolite anticancer drugs, antiviral drugs
9. Active transport
Energy dependent carrier mediated transport taking place against the
electrochemical gradient
Energy generated by membrane ATPase
Process can be blocked by inhibiting cell metabolism or by reducing ATP levels
Drugs having same characteristics can compete
10. Primary active transport
Bio transportation of drugs directly coupled with ATP hydrolysis
ATP binding cassette (ABC) carry out the process
E.g. antibiotics, anticancer drugs
11. Secondary active transport
One ion/solute supplies driving force for the transport of other ion/solute
Symporter/co-transporter – in the same direction. Na+/K+/2Cl- symporter
Antiporter/counter-transporter – in opposite direction. Na+-H+ exchanger
Not directly linked with ATP hydrolysis
12. ABC family of super transporters
7 subclasses (ABC A to ABC G)
Encoded by 49 genes
Most important example is P–glycoprotein (ABCB1 or MDR-1)
13. Solute linked carrier(SLC)
Facilitated diffusion or secondary active transport
43 SLC families encoded by different genes
Neuronal – serotonin, NE, dopamine
Non neuronal – GLUT, cholesterol
14. Pinocytosis
Pinocytosis – process where a cell engulfs a fluid or a drug in solution
This is applicable to proteins and other big molecules, and contributes little to
transport of most drugs
15. Filtration
Free or unbound drug of small molecular size pass through pore or spaces
between cells
E.g. urea, alcohol, glucose
18. From GIT
Mainly by passive diffusion
Sugar and other nutrients by active transport
Gut is more permeable to non-ionised lipid soluble form of drug
Ability of a drug to be absorbed is compromised by
P-glycoprotein efflux by enterocytes
Metabolism in these cells and liver
Diseases that may affect absorption
19. From mouth
Saliva pH is slightly acidic
When stimulated by sublingual drugs it becomes alkaline (~7.4)
Lipid soluble non-ionised basic drugs are absorbed
Drug goes directly into circulation bypassing the first pass metabolism
E.g. isosorbide dinitrate
20. From stomach
pH is acidic
Lipid soluble acidic or neutral drugs are absorbed
Undergoes first pass metabolism
21. From intestine
Alkaline pH
Lipid soluble non-ionised basic or neutral drugs are absorbed
Chances of first pass metabolism
Enterohepatic circulation maybe seen
22. From large intestine to colon
Alkaline pH
Absorption through external haemorrhoidal vein
Minimal first pass effect
23. Absorption via parenteral sites
Intravenous – completely absorbed and rapidly distributed
reach the blood stream directly without crossing any membrane
Intramuscular and subcutaneous – absorbed mainly by passive diffusion
from the injection site to the plasma or lymph
IM absorption more rapid than SC because of high vascularity of
muscles
24. Absorption via lungs
Lipid soluble drugs are absorbed
Vaporised form – general anaesthetics
Aqueous solution – salbutamol
Spray of suspended micro fined particles – disodium cromoglycate
Absorbed by simple diffusion
From pulmonary epithelium and mucous membrane of trachea and lungs
Absorption rapid – large surface area and high vascularity
First pass metabolism avoided
25. Absorption via topical sites
Poor absorption through intact skin
Underlying dermis permeable to lipid soluble drugs
Transdermal application – nitro-glycerine, scopolamine, clonidine
Mucous membrane application - thin and highly vascular absorbing surface.
Oxytocin and vasopressin as nasal spray
Eye drops and ointments absorbed through cornea
26. Bioavailability
Fractional extent to which an administered dose of drug reaches its site of action or a biological
fluid (usually the systemic circulation) from which the drug has access to its site of action
It is an absolute term which requires measurement of both true rate and total amount of drug
that reaches the general circulation from an administered dosage form
Equivalence – comparison of two different brand products of the same drug with a set of
established standards
Different brands of the same drug can be chemically equivalent but may not be biologically or
therapeutically equivalent
27. Bioequivalence
Two or more similar dosage forms of the same drug reach the blood circulation at
the same relative rate and to the same relative extent
Difference in bioavailability are primarily seen with oral dosage forms
Differences of less than 25% will not have a significant effect on clinical outcome –
bioequivalent
Differences of bioavailability assume much greater concern with drugs having
narrow margin of safety
28. Measurement of bioavailability
The absorption pattern of two brand products is plotted against time
Peak plasma concentration{C max}
Time to attain peak plasma concentration{t max}
Area under the curve{AUC}
The first 2 parameters are simple indicators for the rate of absorption
AUC reflects the extent of absorption
For the product to be considered bio equivalent C max, t max and AUC should not
be significantly different
AUC is a better indicator for bioavailability of drugs to be given for longer period
32. Pharmaceutical factors
Particle size – dissolves more rapidly when surface area is increased by decreasing particle
size. e.g. micro-fined aspirin, spironolactone
Salt form – salt dissolves better than their parent compounds. E.g. phenytoin sodium
Crystal form – e.g. amorphous novobiocin have better bioavailability compared to their
crystalline form
Water of hydration – many drugs associates with water to form hydrates. E.g. anhydrous
forms of ampicillin have better bioavailability than their hydrous forms
Nature of excipients and adjuvants – these are pharmacologically inert substances used as
filling material or binding agent. With a drug which obeys zero or mixed order kinetics
change from one brand to other may lead to therapeutic failure or drug intoxication due to
different excipients/adjuvants
Degree of ionisation – non ionised lipid soluble drugs are better absorbed
33. Pharmacological factors
Gastric emptying and gastrointestinal motility – gastric emptying increases absorption as it reaches
larger surface area. Promoted by fasting, anxiety, lying on right side, hypothyroidism and gastro-
kinetic drugs
Gastro-intestinal disease – in coeliac disease amoxicillin shows decreased absorption while
cephalexin shows increased absorption ampicillin shows no change.
Food and other substances – empty stomach increases absorption
First-pass effect – drug degradation occurring before drug entering the systemic circulation for drugs
taken orally therefore there is decreased bioavailability and diminished therapeutic response
34. Cont.
Drug-drug interactions – e.g. paraffin decreases bioavailability of fat soluble
vitamins as it emulsifies fats
Pharmacogenetic factors – e.g. slow acetylators of isoniazid show increased
bioavailability in American whites leading to isoniazid toxicity
Miscellaneous factors – route of administration, area of absorbing surface, state
of circulation at the site of absorption
35. Drug distribution
Pattern of scattering of the specific amount of drug among various locations
within the body
Distributed into all organs including non relevant to its pharmacological effect
After absorption the drugs may not only get reversibly associated with its site of
action but may bind to plasma proteins and may accumulate in various storage
sites
Distribution, metabolism and excretion termed as drug disposition
36. Factors affecting drug distribution
Lipid solubility
Ionisation at physiological pH ( a function of pKa)
Extent of binding to plasma and tissue proteins
Presence of tissue specific transporters
Differences in regional blood flow
37.
38. Volume of distribution
Volume of the plasma that would accommodate all the drug in the body, if the
concentration throughout was the same as in plasma
𝒂𝑽𝒅 =
𝒕𝒐𝒕𝒂𝒍 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈 𝒊𝒏 𝒕𝒉𝒆 𝒃𝒐𝒅𝒚
𝒎𝒈
𝒌𝒈
𝒄𝒐𝒏𝒄 𝒐𝒇 𝒕𝒉𝒆 𝒅𝒓𝒖𝒈 𝒊𝒏 𝒕𝒉𝒆 𝒑𝒍𝒂𝒔𝒎𝒂(
𝒎𝒈
𝑳
)
aVd = apparent volume of distribution
Expressed in L/kg
39. If the drug does not cross capillary walls aVd = plasma water i.e. 3L. Seen in
drugs with high molecular weight or lesser lipid soluble drugs
Drugs highly bound to plasma proteins have a low aVd value and vice versa
aVd for many drugs may be much more than the actual body volume which
means that they are widely distributed and are difficult to be removed by
haemodialysis.
If a drug is having smaller aVd have less protein binding also , it is easier to be
removed by haemodialysis
aVd<5L – drug is retained within the vascular compartment. e.g.
heparin, insulin
aVd~15L – drug is restricted to the extracellular fluid. e.g. aspirin, amoxycillin
aVd>20l – indicates distribution throughout the total body water.
e.g. phenytoin, methyldopa
40. Redistribution
Highly lipid soluble drugs get initially distributed to organs with high blood flow
Then to less vascular but more bulky tissues
Plasma concentration falls and the drug is withdrawn from the highly perfused
sites
If the site of action was in one of the highly perfused organs , redistribution results
in termination of drug action
E.g. anaesthetic action of thiopentone sodium injected IV is terminated in few
minutes due to redistribution
43. Blood-brain barrier(BBB)
Endothelial cells of brain capillaries are tightly joined and lack intercellular pores
Glial cells envelope these capillaries which are less permeable
Anatomically there exists a dual barrier in CNS ; blood-brain barrier and the blood- CSF
barrier(located in the choroid plexus)
Efflux transporters – molecular barrier. P-glycoprotein and ABCC1
Protects brain tissue from toxic substances and some neurotransmitters
Only lipid soluble non-ionised form of drugs penetrate
Inflammatory conditions like meningitis increases penetration to penicillins
44.
45. Regions of the brain which are relatively
permeable
1. Pituitary gland
2. Pineal body
3. Median eminence
4. Choroid plexus
5. Area postrema near floor of fourth ventricle
46. Blood-CSF and CSF-brain barrier
CSF is secreted by epithelial cells of choroid plexus which are lined by occluding
zonulae
CSF-brain barrier there is no occluding zonulae. CSF brain barrier is extremely
permeable toto drug molecules.
In cases of brain abscess drugs can be given intrathecally which easily cross CSF-
brain barrier
47. Placental barrier
Placental membrane lipid in nature – passive diffusion of non-ionised lipid soluble
substances
Active transport and pinocytosis are also operative
Drug administration during pregnancy severely restricted
Hypoxia increases permeability of drugs
48. Reservoirs
Cellular reservoir - tissue affinity could be due to binding to tissue proteins or
nucleoproteins. E.g. digoxin and emetine in skeletal muscles, heart, kidney
Fat as reservoir – highly lipid soluble drugs get selectively accumulated in fat and
adipose tissue. E.g. thiopentone
Transcellular reservoir – aqueous humour, CSF, endolymph, joint fluid, pleural,
pericardial and peritoneal sacs
Bones and connective tissue as reservoir – e.g. tetracyclines, cisplatin, lead
49. Important proteins that contribute to drug
binding
1. Plasma proteins – albumin. Most of the acidic drugs bind. E.g. warfarin
2. α1-Acid glycoprotein - lipophilic basic drugs bind. E.g. quinidine . It is an acute
phase reactant protein, its plasma concentration increases in physiological and
pathological stress
3. Tissue proteins and nucleoproteins – drugs having high apparent volume of
distribution bind. E.g. digoxin
4. Miscellaneous binding proteins – steroids bind to corticosteroid binding
globulin, thyroxine to α-globulins, antigens to gamma globulins
50. Plasma protein binding
Drugs usually bind to plasma and cellular proteins in a reversible manner and in
dynamic equilibrium
𝑭𝒓𝒆𝒆 𝒅𝒓𝒖𝒈 + 𝑷𝒓𝒐𝒕𝒆𝒊𝒏 ↔ 𝑫𝒓𝒖𝒈𝑷𝒓𝒐𝒕𝒆𝒊𝒏 𝒄𝒐𝒎𝒑𝒍𝒆𝒙
As the free or unbound drug is eliminated from the body more drug dissociates
from the drug plasma protein complex
Extensive protein binding does not prevent the drug from reaching its site of
action but only prolongs the drug availability and duration of action
51. Clinically important aspects of plasma
protein binding
High plasma protein bound drugs remain largely restricted to the vascular
compartment and have lower volumes of distribution
Bound fraction is not available for action
High degree of binding makes the drug long action
High protein bound drugs are difficult to be removed by dialysis
Binding of drugs to plasma proteins is a capacity-limited and saturable process
More than one drug can bind to the same site of albumin leads to displacement
interaction. Drug with high affinity displaces that with low affinity. If just 1% of a drug
which is 99% bound is displaced the concentration of free form will be doubled
52. Displacement reactions
Phenylbutazone displaces tolbutamide from its binding sites leading to
hypoglycaemia
Tolbutamide displaces warfarin resulting in increased risk of haemorrhage
Sulphonamides displaces bilirubin leading to kernicterus in neonates
Salicylates displaces methotrexate
Curves depict the distribution of the barbiturate anesthetic thiopental into different body compartments following a single rapid
intravenous dose. Note breaks and changes of scale on both axes. The drug level at thiopental’s site of action in the brain closely mirrors the plasma level of the
drug. The rate of accumulation in the various body compartments depends on regional blood flow; the extent of accumulation reflects the differing capacities of
the compartments and the steady but slow effect of elimination to reduce the amount of drug available. Emergence from the anesthetic influence of this single dose
of thiopental relies on redistribution, not on metabolism. The drug will partition out of tissue depots as metabolism and elimination take their course. Depletion
of compartments will follow the same order as accumulation, as a function of their perfusion.