Drugs that are permanently ionised contain groups which dissociate so strongly that they remain ionised over the range of the body pH. Such compounds are termed polar, for their groups are either negatively charged (acidic, e.g. heparin) or positively charged (basic, e.g. ipratropium, tubocurarine, suxamethonium) and all have a very limited capacity to cross cell membranes. This is a disadvantage in the case of heparin, which is not absorbed by the gut and must be given parenterally. Conversely, heparin is a useful anticoagulant in pregnancy because it does not cross the placenta (which the orally effective warfarin does and is liable to cause fetal haemorrhage as well as being teratogenic). The clinical relevance of drug passage across membranes may be illustrated with reference to the following:
Brain and cerebrospinal fluid (CSF). The capillaries of the cerebral circulation differ from those in most other parts of the body in that they lack the filtration channels between endothelial cells through which substances in the blood nominally gain access to the extracellular fluid. Tight junctions between adjacent capillary endothelial cells, together with their basement membrane and a thin covering from the processes of astrocytes, separate the blood from the brain tissue. This barrier places constraints on the passage of substances from the blood to the brain and CSF. Compounds that are lipid-insoluble do not cross it readily, e.g. atenolol, compared with propranolol (lipid-soluble), and CNS side-effects are more prominent with the latter. Therapy with methotrexate (lipid-insoluble) may fail to eliminate leukaemic deposits in the CNS. Conversely lipid-soluble substances enter brain tissue with ease; thus diazepam (lipid-soluble) given intravenously is effective within one minute for status epilepticus, and effects of alcohol (ethanol) by mouth are noted within minutes; the level of general anaesthesia can be controlled closely by altering the concentration of inhaled anaesthetic gas (lipid-soluble).
Placenta. Chorionic villi, consisting of a layer of trophoblastic cells that enclose fetal capillaries, are bathed in maternal blood. The large surface area and blood flow (500 ml/min) are essential for gas exchange, uptake of nutrients and elimination of waste products. A lipid barrier that allows the passage of lipid-soluble substances but excludes water-soluble compounds, especially those with molecular weight exceeding 600,6 therefore separates the fetal and maternal bloodstreams. This exclusion is of particular importance with short-term use, e.g. tubocurarine (mol. wt 772) (lipid-insoluble) or gallamine (mol. wt 891) used as a muscle relaxant during Caesarian section do not affect the infant; with prolonged use, however, all compounds will eventually enter the fetus to some extent (see: Drugs and the embryo and fetus).
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...