Distribution of drugs

Distribution of drug is the drugs taken throughout the body by bloodstream Once absorbed, it gets distributed to other tissues which had no drug.

Factors that govern distribution of drug

1. Lipid solubility, pH, pKa etc.
2. Blood flow to the organ
3. Binding and tissue affinity of drugs
4. Circulatory disorders, kidney diseases
5. Competition among drugs for binding sites

Blood flow rate limiting step in distribution – Highly perfused organs such as Liver, Kidney, GI tract, Brain, Lungs receive rapidly high levels of drug. Lesser levels are achieved in less perfused organs like muscle, fat tissue.

Plasma protein binding of drugs

Drugs tend to become associated with several blood constituents and become unavailable in active functions. Many drugs are bound to plasma proteins. It is only the unbound or free fraction of a drug that can diffuse out of capillaries into tissues.

Albumin and other plasma proteins are essentially contained within blood vessels and so the distribution of drugs that are bound is restricted. When more than 70 – 80 % of the drug is bound to plasma protein, it acts as a circulating reservoir for the drug.

When two or more drugs can bind to the same site of the plasma proteins, administration of a second drug may significantly affect the binding of the first drug.

At its therapeutic concentration warfarin is 97.4% bound. If a therapeutic dose of the non-steroidal anti-inflammatory drug phenylbutazone is administered, bound warfarin decreases to 92%. Thus free warfarin increases from 2.6 to 8%. This increases the anticoagulant effect of warfarin considerably. It also reduces its half-life from 18.4 to 9.6 hours since it is also more available for biotransformation and excretion.

Changes in binding have the greatest effect on the proportion of free drug when the percent bound is high. Reducing the binding from 98% to 96% will double the amount of free drug from 2% to 4% and thus the half-life of the drug would be reduced much.

The drug protein binding reaction is reversible and obeys the law of mass action.

Drug + protein => Drug-protein complex

Acidic drugs are bound primarily to albumin and basic drugs are bound primarily to α₁– acid glyco protein. Binding does not prevent a drug from reaching its site of action but it slows the rate at which a drug reaches a concentration sufficient to produce a pharmacologic effect.

Drug protein binding limits glomerular filtration or an elimination process, because bound drug cannot be filtered. However, binding does not limit the elimination of drugs by active secretion or metabolized by the liver, because the fraction of the drug that is free is transported and metabolized.

When free drug concentration is lowered, there is rapid dissociation of the drug – receptor complex to maintain the amount of drug in the free state.

Factors affecting plasma protein binding

1. Drug concentration
2. Number of drug binding sites on the protein
3. Protein concentration
4. Lipid solubility – there is a good correlation between this and the binding of penicillins and tetracyclines
5. Weak acids like penicillins are bound more extensively than weak bases
6. Competing molecules
7. Species variation
8. Disease

Tissue storage of drugs

Some drugs accumulate in specific tissues (accumulation of drug is not a proffered action of drug, good drugs should be excreted).

Examples of drug accumulation in tissues

1. Heart – Digoxin
2. Liver – Chloroquine, digoxin, cadmium
3. Kidney –  digoxin, chloroquine, cadmium
4. Iris – atropine
5. Bone and teeth  – tetracycline
6. Adipose tissue – thiopentone, ether, DDT
7. storage in fat long due to poor blood supply
8. Mercury – RBC
9. Arsenic – Nail and hair

Redistribution of drugs

Occurs in highly fat soluble drugs- Initially taken up by brain, heart, kidney but Later deposited in less vascular tissues – muscle, fat

On redistribution, plasma concentration falls leading to loss of drug action. On repeated doses, these sites fill up leading to longer action of the drug.

Barriers to drug distribution

Blood brain barrier or BBB

Blood brain barrier or BBB is a physical / functional barrier which does not permit ionized and non lipid soluble drugs to pass through into the Central Nervous System. It is mainly formed by the endothelial cells of the CNS blood vessels. Its purpose is to protect the brain from the chemical environment of the rest of the body due to the delicate balance between excitation and inhibition maintained within the CNS.

The brain capillaries do not contain fenestrations (holes). There are more tight junctions in brain capillaries decreasing the rate of diffusion through interstitial spaces. Glial cells ensheath the brain capillaries providing a second set of cell membranes which must be traversed as well as a second intracellular compartment where cellular metabolic processes can transform entering substances

Chemical or enzymatic barrier – MonoAmineOxidase, cholinesterase – This barrier prevents 5 HT, catecholamines, ACh from entry into CNS

Carrier mediated transport – to facilitate exit of drugs

Highly lipophilic drugs enter easily because they cross membranes. (Fig. 18) Unionized forms of drugs enter more easily than ionized forms. Penicillin, streptomycin, gentamicin – do not cross the BBB

Placenta

Placenta virtually not a barrier. Any drug taken by mother is likely to affect the fetus, hence care must be taken while administering drugs to pregnant animals. Only highly ionised drugs and drugs with low lipid solubility are excluded from passing through the placenta.

Placenta is important from the point of view of teratogenicity of drugs

Milk

Governed by rules of passage across membranes.

The mammary gland epithelium, like the other biological membranes act as a lipid barrier and many drugs readily diffuse from the plasma into the milk.

The pH of milk varies somewhat; but in goats and cows it is generally 6.5 – 6.8 if mastitis is not present. Weak bases tend to accumulate in milk because the fraction of ionized, nondiffusible drug is higher. Agents delivered by intramammary infusion can diffuse into the plasma to a greater or lesser degree based on pH differences and the pKa of the drug.

In cows Maximum Residue Levels (MRL) in milk has been  recommended for many drugs to minimize human exposure risk. In case of drug administration, milk to be discarded up to withdrawal time.