- Drug entry to the brain
- Blood-brain barrier
- Factors affecting drug entry into the brain
- Differences between blood-brain barrier and CSF transport
- Drug therapy for diseases of the CNS: Antimicrobial drug therapy
- Drug therapy for diseases of the CNS: Anti-inflammatory therapy
- Anticancer chemotherapy of the nervous system
- Adverse CNS reactions caused by drugs
Drug therapy for diseases of the central nervous system (CNS) involves the complicating factors of drug penetration across the blood-brain barrier (BBB), the therapeutic effect on the CNS, and the potential for adverse effects. Drug efficacy for central nervous system disorders depends on the extent of penetration across the blood-brain barrier after systemic administration. However, once a drug penetrates the blood-brain barrier it may cause an undesirable effect unrelated to the drug’s therapeutic effect. For example, antibiotics and antiparasitic drugs can produce adverse central nervous system effects that are not relevant to the drug’s therapeutic action. This chapter will not review all aspects of central nervous system drug therapy or toxicity but will focus on important issues of drug penetration, antimicrobial therapy, anti-inflammatory therapy, anticancer therapy and adverse drug reactions. Readers are referred to specific chapters on anticonvulsant therapy and treatment of traumatic central nervous system injury.
Drug entry to the brain
For a drug to elicit an effect on the CNS, either the drug or a metabolite of the drug must penetrate the BBB. An exception to this is drug-induced vomiting. The area of the brain that stimulates vomiting, the chemoreceptor trigger zone (CRTZ), is in the brain’s fourth ventricle, which is outside the blood-brain barrier and thus exposed to circulating toxins and drugs.
There is free drug movement from the plasma into most tissues as fenestrations between capillary endothelial cells allow easy drug diffusion. However, the blood-brain barrier is more restrictive; here, capillary endothelial cells have tight junctions and a continuous basement membrane. In a recent review of 7000 drugs only 5% were able to affect the central nervous system. These drugs were primarily compounds used to treat depression, schizophrenia and insomnia. Most of these drugs were either of very small molecular weight or drugs with high lipophilicity that facilitated penetration across the BBB.
Drug penetration of the central nervous system may be possible via simple diffusion through endothelial cells or carrier-mediated transport. Small unbound lipid-soluble compounds can penetrate endothelial cells via simple diffusion. Passive diffusion correlates with the blood-brain drug concentration gradient and the lipid solubility of the drug, but is inversely correlated with the drug’s extent of ionization and molecular weight). In other words, if the drug has a large blood to brain concentration gradient, is lipophilic or non-ionized, it will tend to cross the BBB. For less lipophilic drugs, entry into the brain is possible if the concentration gradient between plasma and brain is high enough. Therefore, large doses or high plasma concentrations of drugs (e.g. penicillin antibiotics) can reach sufficient levels in the central nervous system to produce therapeutic or toxic effects. Carrier-mediated transport (CMT), which can occur via facilitated diffusion oractive transport, allows carrier systems to transport glucose, fatty acids and other nutrients from the blood to the brain. The role of carrier-mediated diffusion for drug transport into the brain is minor except for a few basic drugs, such as antihistamines.
Factors affecting drug entry into the brain
Drug ionization affects the lipophilicity of a drug and its ability to enter the CNS. Only neutral (uncharged) drugs enter the central nervous system to a high enough extent to produce therapeutic or adverse effects. There are several examples of drugs for which the degree of ionization influences central nervous system effects. Of the antimuscarinic drugsthe tertiary amines atropine and butylscopolamine can produce central nervous system changes, such as excitement. These drugs are uncharged and cross the blood-brain barrier readily. Whereas, the quaternary amines have a charged nitrogen atom, which limits their ability to diffuse across the BBB. The quaternary amines, such as methylscopolamine, isopropamide, propantheline bromide and glycopyrronium bromide, are not associated with the same risk of central nervous system effects observed with tertiary amines.
Small lipophilic drugs cross the blood-brain barrier more easily than larger or more hydrophilic drugs. Minor changes in structure can drastically change the drug’s lipophilicity and ability to cross the BBB.
• Heroin, which has one additional hydroxyl group compared with morphine, crosses the blood-brain barrier quickly after injection, producing a pronounced euphoric effect.
• In comparison, morphine has only one hydroxyl group and thus a slightly slower onset of effect.
• Diazepam has an additional methyl group compared with other benzodiazepines, which causes it to cross the blood-brain barrier more rapidly and makes it the preferred drug for treating status epilepticus.
• Enrofloxacin appears to cross the blood-brain barrier more easily than ciprofloxacin because the addition of an ethyl group makes it more lipophilic.
The molecular size of the drug affects penetration across the BBB. The molecular mass threshold for drugs active in the central nervous system appears to be <400-500 daltons. Most therapeutic drugs have a molecular weight below this threshold. In order to inhibit penetration across the BBB, drug molecules can be conjugated with larger molecules, such as proteins.
Drugs can enter the brain via carrier-mediated transport (CMT). These transport systems carry nutrients to the brain from the blood. Such transport systems include the glucose transporter, the lactate transporter, the cationic amino acid transporter and the large amino acid transporter (LAT). An example of a drug that utilizes CMT is dopamine. Dopamine as the parent drug does not penetrate the blood-brain barrier after systemic administration. However, when converted to an alpha-amino acid derivative, levodopa (L-dopa), it utilizes the LAT to be transported across the BBB. Once in the brain, levodopa is metabolized to dopamine where it is helpful for treatment of Parkinson’s disease.
CMT can also transport anticonvulsant drugs. Gabapentin is a gamma-amino acid used to treat epilepsy. It mimics an alpha-amino acid and utilizes the LAT to penetrate the brain. It has been observed that gabapentin is effective in some patients who were refractory to other epileptic drugs. Perhaps an explanation is that if refractoriness to anticonvulsant drugs is mediated by over-expression of P-glycoprotein in some patients, a drug that utilizes another transport system may be more effective.
A transmembrane protein coded by the multi-drug resistance (MDR) gene is present in the blood-brain barrier to ‘pump’ drugs out of the CNS. This protein is called P-glycoprotein (P-gp) and has also been known as MDR1 and the ATP-binding cassette subfamily B member 1, or ABCB1. P-gp is also located in the gastrointestinal tract, placenta and kidneys, and other organs. Thorough reviews have been presented recently to discuss the role of P-gp in the functional blood-brain barrier. P-gp is now regarded as an integral part of the functional blood-brain barrier and an important determinant of drug penetration into the CNS. P-gp may exclude important drugs, such as dexamethasone, anti-viral (anti-HIV) drugs, anticancer drugs (used for treating brain tumours) and anticonvulsants. For example, it has been shown that resistance to anticonvulsant drugs may be related to polymorphism of the gene that codes for P-gp. In some clinical cases refractory to anticonvulsant drugs, the membrane pump is up-regulated, thus impairing drug penetration to an epileptogenic region of the brain.
P-gp participates in neuroprotection of the brain by regulating drug entry and acting asa ‘guardian’ of theCNS by preventing the accumulation of drugs in the brain. Deficiency in blood-brain barrier P-gp explains why some Collies and related breeds are susceptible to therapeutic doses of ivermectin and similar drugs (discussed in more detail below). Inhibitors of P-gp that are of veterinary importance include ketoconazole, ciclosporin, calcium-channel blockers (diltiazem), erythromycin and antiarrhythmics (lidocaine and quinidine). Drug interactions caused by these inhibitors have allowed increased penetration of drugs that are normally excluded from the brain. For example, quinidine can increase the central nervous system effects of loperamide and of digoxin, which are ordinarily excluded from the brain.
Differences between blood-brain barrier and CSF transport
Some investigators have made the mistake of equating blood-brain barrier transport to blood-CSF transport. It is not legitimate to evaluate drug brain penetration on the basis of penetration into the CSF. Drug entry into the CSF is not an index of blood-brain barrier transport. Drugs that enter the CSF may be transported out quickly via absorption by the arachnoid villi. The endothelial cells of the brain represent a surface area of exchange that is 5000 times greater than the blood-CSF barrier. Therefore, the blood-CSF barrier is insignificant for determining drug penetration to the brain.
Table summarizes the drugs used to treat central nervous system disorders in dogs and cats.
|Drug||Clinical use and comments||Recommended dose|
|Azathioprine||Used to treat immune-mediated diseases. Use cautiously and at much lower doses in cats||Dogs: 2 mg/kg orally q24h, followed by long-term therapy with 0.5-1.0 mg/kg orally q48h|
|Cefotaxime||Used for infections caused by Enterobacteriaceae are resistant to other drugs and Streptococcus spp. Penetrates the central nervous system better than other cephalosporins||Dogs and cats: 30 mg/kg i.v., i.m. or s.c. q8h|
|Ceftazidime||Used for infections caused by Enterobacteriaceae or Pseudomonas spp. that are resistant to other drugs and Streptococcus spp. Penetrates the central nervous system better than other cephalosporins||Dogs and cats: 20-30 mg/kg i.v. q12h|
|Chloramphenicol||Used for some infections of the CNS. However, the activity against Gram-negative bacilli not good enough for treatment of infections caused by these bacteria||Dogs: 50 mg/kg orally q8h Cats: 50 mg/cat orally q8h|
|Clindamycin||Used to treat protozoal infections. However, efficacy has not been established||Dogs and cats: 11 mg/kg q12h or 22 mg/kg orally q24h|
|Used to treat central nervous system lymphoma||Dogs and cats: 50 mg/m2 s.c. q12h for 2 days. Repeat every 3 weeks|
|Dexamethasone sodium phosphate||Used to treat central nervous system oedema and inflammation||Dogs and cats: 0,15 mg/kg i.v. q6h for 2-4 days|
|Fluconazole||Used to treat fungal infections of the CNS||Dogs: 10-12 mg/kg orally q24h Cats: 50 mg/cat orally q12h or q24h|
|Itraconazole||Used to treat opportunistic and invasive fungal infections of the CNS||Dogs and cats: 5-10 mg/kg orally q24h|
|Lomustine||Used to treat tumours of the CNS, particularly gliomas||Dogs and cats: 60-80 mg/m2 orally q6-8 weeks|
|Meropenem||Used for infections of the CNS. Use for cases in which resistant bacteria may be suspected. Does not have the risk of central nervous system toxicity compared with imipenem||Dogs and cats: 5.5-11 mg/kg i.v. q12h|
|Methylprednisolone sodium succinate||Used to treat acute spinal cord trauma||Dogs and cats: <3h since injury: 30 mg/kg i.v. injection followed by 5.4 mg/kg/h CRI for 24 hours. If a CRI is not available then treat initially with 30 mg/kg i.v. within the first 8 hours of trauma, followed by 15 mg/kg i.v. at 2 and 6 hours after the initial injection. Thereafter 15 mg/kg i.v. q6h for 48 hours|
|Metronidazole||Treatment of central nervous system infections caused by Bacteroides (anaerobe). Caution that metronidazole can cause adverse central nervous system effects||Dogs and cats: 10-20 mg/kg orally q8h (most common is 15 mg/kg q12h)|
|Prednisolone||Used to treat inflammation of the CNS||Start with 2 mg/kg orally q12h. Gradually taper to lower doses until goal of 0.5 mg/kg orally q48h is achieved|
|Pyrimethamine||Treatment of protozoal infections of the CNS. Usually used in combination with sulfadiazine or other sulphonamide||Dogs and cats: 1 mg/kg orally q24h. Used with sulphonamide concurrently at a dose of 25 mg/kg orally q12-24h|
|Trimethoprim-sulphonamide||Used to treat protozoal infections||Dogs and cats: 15-30 mg/kg orally q12h|