An insight into drug distribution and interactions at different pharamacokinetic levels

1. Drug distribution and its
clinical significance
Presented by- Deepak Pandey

2. Introduction
• After absorption of drug into
systemic circulation drug is
distributed to various tissues
leading to decline in plasma
concentration and subsequent
increase in drug concentration
in different tissues. The
distribution of drug leads to
• Therapeutic action of drug at the
target site
• Elimination of drug through liver,
kidneys

3. One-compartment open model
• Pharmacokinetic models that simulate the kinetic process of drug absorption,
distribution and elimination.
• Assumed that the body acts as a single homogenous compartment into which
drugs can enter and leave easily

4. One-compartment open model
• On a semi-log plot, the plasma drug
concentration declines linearly with time
• Ka and Ke are absorption constant and
elimination constant respectively
• Significance- Volume of distribution, clearance
and elimination half life can be calculated
based on kinetic order of elimination.
• Aminoglycosides being polar aren’t
extensively absorbed into tissues and remain
mostly in plasma thereby following a one
compartment open model

5. Steady-state concentration
• When the drug is administered at a constant
rate or at regular intervals, the cumulative
accumulation of drug and simultaneous
elimination are balanced and a steady
concentration is reached
• For maintenance of steady state
concentration, the vol of drug that is cleared
of drug must be replenished continuously.
• Significance- To calculate maintenance dose of
drug as under-
where, Cp is the plasma concentration of drug,
CL is clearance and F is bioavailability of drug

6. Volume of distribution (Vd)
• It is an apparent volume available for
administered amount of drug to
disperse considering the whole human
body as a homogenous solution
• Volume of distribution = Quantity of
drug administered/ Plasma
concentration (C)
• It shows the extent of distribution or
accumulation of drug in tissues
• Eg- Warfarin has low (Vd) owing to its
high plasma protein binding while
Chloroquine has high (Vd) because of
its accumulation into peripheral fat.

7. Volume of distribution

8. Volume of distribution (Vd)
• Factors affecting volume of distribution
• Lipid solubility of the drug
• Ionization of the drug at physiological pH
• Plasma protein binding of the drug
• Limitation- It is assumed that the concentration of drug in different
tissues corresponds to the plasma concentration and that the
response of drug varies in accordance with the plasma concentration
which may not be true in each case.

9. Volume of distribution (Vd)
• It is used to determine the loading dose of a drug
• Loading dose = Target concentration X Volume of distribution
Suppose the target concentration of a drug is 15mg/ml and Volume of
distribution of the same drug is 30 L.
• Since, the Volume of distribution of a drug in a patient doesn’t depend on the
amount of drug administered or the route of administration, it will remain
same
Then, the loading dose will be 15mg/ml X 30L = 1.5g/L X 30L i.e, 45 g

10. Two compartment open model
• Most drugs after entering systemic circulation are
in different equilibrium with tissues and elimination
through clearance depending on
• Rate constant of drug absorption into tissues
(K12 in diagram)
• Rate constant of drug removal from tissue back
into plasma (K21 in diagram)
• Elimination rate constant of drug (K10 in
diagram)
• These rate constants are determined by properties
of drug (mol weight, mol size, pKa of drug, lipid
solubility of drug) and tissue ( tissue selectivity for
drug, presence of transporters at tissue level,
physiological pH)

11. Two compartment open model
• The plasma concentration of drug declines
rapidly after IV bolus injection due to
distribution into tissues (Distribution
phase)
• A prolonged elimination phase when
tissues are in equilibrium with plasma drug
concentration and the rate of decline of
plasma concentration of drug depends on
clearance of drug.
• The peak tissue concentration of drug
represent equilibrium between tissue and
plasma.

12. Two compartment open model
• Concentration time graph represents the ongoing
process of drug redistribution and drug elimination
simultaneously
• Lipid soluble drugs like benzodiazepines or drugs
with high tissue affinity follow this pattern of
distribution.
• Significance- In drugs with narrow therapeutic
index, if the minimum toxic concentration lies
within the range of distributive phase, frequent
dosing can overshoot the plasma concentration.
• Thus, choice of dose and interval or the rate of
infusion should be relative to the distribution half
life of drug.

13. Factors affecting distribution
• Physiochemical properties of drug- Lipid
solubility of drug (based on oil-water
partition coefficient), size of drug
molecule, pKa of drug
• Amount of drug delivered to an organ
depends on the regional blood flow to
that organ-
• Physical exercise increase blood flow-
increased action of IM insulin after exercise.

14. Factors affecting distribution
• Capillary permeability of tissue-
• Hepatic and renal capillaries permeable in comparison to brain capillaries- Allow
large molecules to pass easily
• Can be affected in disease conditions- Meningitis- Increased drug uptake in brain
• Plasma protein binding of drug
• Presence of barriers- Blood brain barrier, Placental barrier
• Tissue selectivity of drug (Incorporation of bisphosphonates into bone)-
Accumulation of drug into tissues
• Presence of specific transporters in tissues
• Pathophysiological conditions

15. Drug uptake into tissues
• Entry of drug from systemic circulation
into different tissues can occur
through-
• Passive diffusion-
• Spontaneous
• Depends on membrane thickness, capillary
permeability and concentration gradient of
drug
• Hydrostatic/Filtration pressure-
• Arterial end- Hydrostatic pressure higher
than mean tissue pressure by around 8mm
Hg- Drug absorption,
• Venous end- Hydrostatic pressure is less-
Absorptive pressure- Remaining drug is
absorbed back into systemic circulation

16. Drug uptake by organs
• First order kinetics at tissue systemic circulation partition

17. Drug uptake by organs
• R– Ratio of drug concentration in tissue vs
systemic circulation.
• Also estimated from partition coefficient of a
drug. R value- 20 in flutamide in prostate,
digoxin 60 in myocardial tissues
• High R value- Long distribution phase and
accumulation of drug in tissues
• Drug accumulation-
• DDT in adipose tissue- high lipid solubility
• Digoxin- specific proteins in myocardial tissue
• Phenothiazines- to melanin of skin and eye
• Tetracycline- insoluble chelate with calcium
• Specific transporters- amphetamine into
adrenergic tissues

18. Drug uptake by organs
• Perfusion/Flow limited uptake of
drug- Drug diffuses rapidly across
membrane (hepatic and renal
vessels)- a person with CHF- reduced
filtration and reduced clearance
• Diffusion/Permeability limited-
Across Blood brain barrier-
Increased absorption in
inflammatory states that promote
increased capillary permeability

19. Plasma protein binding

20. Plasma protein binding
• Protein bound drug- Reversibly
bound but unable to diffuse and
therapeutically inactive
• Albumin- Binds acidic drugs like
salicylates, phenylbutazone and
penicilins
• Alpha-1 acid glycoprotein-Binds
basic drugs like- Imipramine, &
lidocaine

21. Plasma protein binding
• Factors affecting plasma protein binding
• Drug-
• Physiochemical properties of drug
• Total concentration of drug in body
• Protein-
• Physicochemical nature of protein to which drug is bound
• Quantity of protein available to be bound to drug
• Affinity between drug and protein i.e, magnitude of association constants
• Drug interactions-
• Competition by other substances at the protein binding site- Phenylbutazone and warfarin
• Alteration of protein that modifies affinity of protein for drug. Eg- Aspirin acetylates lysine
residues of albumin
• Pathophysiologic condition of patient- Plasma protein binding reduced in uremia or
hepatic diseases

24. Plasma protein binding
• Drugs highly bound to plasma protein like ceftriaxone, cefoperazone,
warfarin, - Low Volume of distribution, Low clearance
• Disease states decreasing plasma protein binding- Increased free
fraction available for interaction with receptors- increased chances of
toxicity of highly plasma protein bound drugs
• Disease states increasing plasma protein binding (acute phase
response leads to increase in alpha-1 acid glycoprotein)- Reduced
therapeutic effect of drug

25. Blood brain barrier
• Brain vasculature has specialized endothelium (tight intercellular
junctions, paucity of intracellular vesicles, abundant mitochondria)
surrounded by pericytes and astroglial process.
• Drugs with high lipophilicity or those with specific transporters can
enter through blood brain barrier- Gabapentin and L-Dopa via LAT1
Neutral amino acid carrier
• Blood brain barrier permeability may be altered in disease states and
aging.

26. Placental barrier
• Physiological barrier between maternal
circulation and fetal circulation at placenta
• Passage of drug through placenta depends
on-
• Drug factors- Molecular weight, lipophilicity,
Unionized fraction, protein binding of drug
• Maternal factors- Drug concentration in
maternal circulation, Uterine blood flow,
functional integrity and thickness of placental
barrie

27. Therapeutic drug monitoring
• Purpose- To adjust plasma concentration and maintain it within a specified
range.
• Measurement of both values of minimum and maximum concentrations
are to be recorded.
• The necessary dose adjustment is done considering the clearance of drug
to remain constant.
• Applied when-
• The drug has a low therapeutic index
• There is a good plasma concentration- biological response relationship
• There are no other easily measurable physiological parameters
• Or, to monitor adherence or adverse drug reactions

28. Therapeutic drug monitoring
• Sampling of blood is to be done only
after steady state of plasma
concentration is reached, ie, after five
half lives except in case of toxicity
• After the steady state is reached,
sampling to be done after proper time
for distribution of drug to finish.
• A therapeutic range of plasma
concentration is used to guide the
desired concentration of drug
• The subsequent dosing and intervals are
titrated accordingly

29. THANK YOU