Drug application and uptake - Pharmacokinetics

Drug application and uptake

You are certainly aware that drugs are applied by various routes; the choice depends largely on the pharmacokinetic properties of the drug in question. Table 2.1 lists some characteristics of the major routes.

We will look at the various routes of application in turn. Oral uptake is the most common one, so let's start with this one.

Oral drug application

Inside the digestive tract, drug molecules encounter a quite aggressive chemical milieu. E.g., the acidic pH in the stom-ach (pH ~2) and the presence of proteases and nucleases in the gut preclude the application of proteins, nucleic acids, and other labile molecules. The gut mucous membrane presents a barrier to uptake; many drugs are not able to ef-ficiently cross it by way of diffusion.

For those drugs that make it from the gut lumen into the blood, the liver presents another formidable barrier. All blood drained from the intestines (as well as the spleen and the pancreas) is first passed through the liver before being released into the general circulation. This is schematically depicted in figure 2.1.

Inside the liver, the blood leaves the terminal branches of the portal vein and the liver artery and is filtered through the liver tissue (Figure 2.3a).

The liver tissue has a characteristic honey-comb structure (Figure 2.3b). The individual hexagons of the honeycomb are referred to as lobuli. The portal vein and liver artery branches spread along the boundaries of the lobuli. The blood that leaves them is filtered through the tissue towards the center of the lobulus, where it reaches the central vein. The central veins then siphon the blood toward the systemic circulation.

A notable feature of the liver tissue is its lack of real blood vessel walls along the way from the portal vein branches to the central veins. Therefore, the blood gets into intimate contact with the liver epithelial cells, which therefore can very efficiently extract from the blood any compound they see fit (Figure 2.3c).

The liver is a metabolically very versatile organ and is ca-pable of chemically modifying a great many substrates – including drugs – in a variety of ways and with great effi-ciency. In fact, many drugs cannot be orally applied at all because even during the initial passage the liver extracts them quantitatively from the portal venous blood. This phe-nomenon is called the `first pass effect'. An example of a drug that undergoes a substantial first-pass effect is propra-nolol (Figure 2.2).

Propranolol, which blocks β-adrenergic receptors, is com-monly used in patients with cardiovascular disease. Shown below are two metabolites. The left one (4-hydroxypropra-nolol) is still active but not quantitatively very important. The right one (naphthyloxymethyllactate) is entirely inac tive. Only about 30% of the propranolol ingested actually shows up in the systemic circulation – the rest is either not absorbed or metabolized in the liver during the first pas-sage. The extent of this first pass effect shows considerable inter-individual variation – which means that the required dosage may vary considerably and has to be empirically determined with each patient. The fraction that reaches the systemic circulation (~30% in our example) is designated as the `bioavailability' of the drug.

To sum up: Oral application has

•     Advantages: Convenience – route of choice if possible

•     Disadvantages:

1.                 Aggressive chemical milieu in the digestive tract – precludes application of proteins, nucleic acids..

2.                 Gut mucous membrane presents a barrier

3.                 Blood from the intestine is passed through the liver

– liver may immediately extract and metabolize the drug (`first pass effect')

4.                 Absorption is slow (not suitable for emergency treat-ment) and variable

Intravenous drug application

With intravenous application, we have the following advan-tages:

•     `Absorption', even of large molecules, is quantitative and instantaneous. This is essential if drug action is needed immediately.

•     Short-lived drugs can be continuously applied by in-fusion, and the infusion rate can be controlled so as to `titrate'the clinical effect. Examples: Muscle relaxation with succinylcholine during narcosis, control of blood pressure in hypertonic crisis with sodium nitroprusside (both drugs will be discussed later in this class).

•     No exposure of drug to harsh conditions – proteins can be applied this way

Disadvantages:

•     Involved (needs trained professional for each applica-tion – dangerous if not performed properly)

•     Adverse reactions to drugs will be more instantaneous and serious, too (example: penicillin allergy)

Other routes of drug applicaton

Dermal application has two cases:

Topical application (treatment of skin disease). No critical issues here; often preferable to systemic therapy (high local drug concentrations, minimal side effects on the rest of the body).

•     Dermal application for systemic use.

– Uptake typically slow and inefficient (Mother Nature gave us skin as a barrier, not as a conductor). Notable exception: very hydrophobic compounds (organic solvents, nerve gases).

– Retarded uptake can be utilized for sustaining pro-longed, slow delivery (example: Nicotine for wean-ing smokers)

Mucosal application exploits the fact that, compared to the skin, the barrier is much thinner. Moreover, the veins un-derlying the mucous membranes in the two favorite places (nose and rectum) are not drained into the liver – i.e., the first pass effect can be circumvented. Examples:

1.  Nose: Cocaine, antidiuretic hormone (ADH). ADH is a peptide – so even peptides can make it across the mucosa

2.  Rectum:  Acetaminophen.  Rectal application will in-

crease the bioavailability of this drug as compared to oral uptake, because the first pass effect is absent. ¹

Pulmonal application (Figure 2.4) has two modes:

•     Gaseous drugs reach the alveoli. This mainly applies to inhalation anesthetics (chloroform, ether, N₂O, and their more modern replacements). Very rapid transition into the bloodstream – very rapid onset of action.

•     Non-gaseous drugs can be conveyed by aerosols. The droplets are actually deposited in the bronchi but do not reach the alveoli (topical / mucosal application). Exam ple: Steroids for asthma therapy (asthma is an affliction of the bronchi).