What medication does not cross the blood-brain barrier?: Examples and pharmacological reasons

October 12, 2025 •

3 min read

Approximately 98% of small-molecule drugs and virtually all large-molecule drugs do not effectively cross the blood-brain barrier (BBB), presenting a significant pharmacological challenge for central nervous system therapies. The BBB is a highly selective barrier designed to protect the brain, and understanding what medication does not cross the blood-brain barrier is critical for both patient safety and therapeutic efficacy.

Quick Summary

The blood-brain barrier protects the CNS by limiting drug access, with many medications like second-generation antihistamines, some cardiovascular drugs, and large molecules being unable to cross. This is determined by a drug's size, lipid solubility, and the action of efflux pumps.

Key Points

BBB Protects the Brain: The blood-brain barrier (BBB) is a selective defense mechanism that prevents most drugs and toxins from entering the central nervous system.
Antihistamines Vary: Second-generation antihistamines like fexofenadine and loratadine are less lipophilic and generally do not cross the BBB, minimizing sedative effects.
Some Blood Pressure Drugs are Restricted: Specific ACE inhibitors (e.g., benazepril) and ARBs (e.g., olmesartan) are designed not to cross the BBB to avoid CNS side effects.
Dopamine is Barred, its Precursor is Not: Dopamine cannot cross the BBB, which is why its precursor, L-DOPA, is used to treat conditions like Parkinson's disease.
Large Molecules are Excluded: Nearly all large molecule drugs, including proteins and peptides, are blocked by the BBB, presenting a major challenge for CNS drug development.
Efflux Pumps Add a Layer of Defense: Active efflux transporters like P-glycoprotein can actively pump certain small-molecule drugs out of the brain, further restricting entry.

The Blood-Brain Barrier (BBB): An Overview

The blood-brain barrier (BBB) is a dynamic, highly selective membrane in the central nervous system (CNS) that separates the circulating blood from the brain's extracellular fluid. It protects the brain from foreign substances, toxins, and pathogens while allowing essential nutrients like glucose to enter. The BBB is formed by specialized endothelial cells lining brain capillaries, creating a continuous wall with tight junctions. These capillaries differ from others in the body by lacking fenestrations (pores). Pericytes and astrocytic endfeet surround the endothelial cells, providing support and regulating barrier function.

Pharmacological Principles of BBB Penetration

Several physicochemical properties determine a drug's ability to cross the BBB:

Molecular Weight: Molecules smaller than 400-500 Daltons are more likely to cross via passive diffusion. Large molecules like proteins are typically blocked unless specifically modified for transport.
Lipid Solubility (Lipophilicity): Lipid-soluble drugs can more easily pass through the BBB's lipid-based cell membranes, unlike water-soluble molecules which are generally repelled.
Charge: Ionized or highly charged molecules are less likely to cross the BBB due to reduced lipid solubility.
Efflux Transporters: The BBB contains active efflux transporters, such as P-glycoprotein (P-gp), which pump drugs back into the bloodstream, limiting their concentration in the brain. This is a significant factor in why many drugs fail to enter the CNS.

Key Medications That Do Not Cross the BBB

Certain medications are designed not to cross the BBB to minimize side effects or target effects outside the CNS. Key examples include:

Second-Generation Antihistamines

Unlike first-generation antihistamines that cause drowsiness by crossing the BBB, second-generation antihistamines are less lipophilic and more easily ionized. This restricts their action to peripheral histamine receptors, reducing CNS effects.

Examples include:

Fexofenadine (Allegra).
Loratadine (Claritin).
Cetirizine (Zyrtec).

Certain Cardiovascular Drugs

Many hypertension medications are formulated to act peripherally without affecting the CNS, avoiding neurological side effects like dizziness. Examples include:

Angiotensin II Receptor Blockers (ARBs): Non-crossing examples include Olmesartan, Eprosartan, Irbesartan, and Losartan.
Angiotensin-Converting Enzyme (ACE) Inhibitors: Non-crossing examples include Benazepril, Enalapril, and Quinapril.

Neurotransmitters and Large Molecules

Some neurotransmitters, like dopamine, are too large and polar to cross the BBB when administered systemically. For Parkinson's disease, the precursor L-DOPA is used as it is transported across the BBB and then converted to dopamine in the brain. Additionally, large molecules such as peptides, proteins (like monoclonal antibodies), and gene therapies generally cannot cross the BBB due to their size.

Comparison of BBB Penetration by Drug Type


Drug Class	Non-BBB Crossing Examples	BBB Crossing Examples	Key Reason for Difference
Antihistamines	Fexofenadine, Loratadine	Diphenhydramine	Second-gen are less lipophilic and more easily ionized.
ACE Inhibitors	Benazepril, Enalapril, Quinapril	Captopril, Lisinopril, Ramipril	Differing lipophilicity and molecular structure.
Angiotensin II Receptor Blockers (ARBs)	Olmesartan, Losartan, Irbesartan	Telmisartan, Candesartan	Molecular structure influences lipid solubility.
Neurotransmitters	Dopamine	L-DOPA (Precursor)	Dopamine is too polar, while L-DOPA has an active transporter.
Large Molecules	Vancomycin, Antibodies, Peptides	-	High molecular weight (>400-500 Da).

Clinical Implications of Non-BBB Crossing Drugs

The fact that certain drugs do not cross the BBB has several clinical implications:

Reduced Side Effects: Avoiding CNS penetration reduces side effects like the sedation from older antihistamines or dizziness from some blood pressure medications.
Challenges for CNS Therapy: The BBB is a major hurdle for developing treatments for neurological disorders as most drugs struggle to reach their target in the brain.
Innovative Delivery Strategies: This challenge drives research into new methods to deliver drugs past the BBB, including nanoparticles, focused ultrasound, and modified drug structures.

For further reading on drug transport across the blood-brain barrier, consult resources like those provided by the National Institutes of Health.

Conclusion

The blood-brain barrier is a crucial defense mechanism impacting the pharmacology and clinical use of many medications. Identifying what medication does not cross the blood-brain barrier highlights drugs like second-generation antihistamines, specific cardiovascular agents, and neurotransmitters like dopamine. These drugs are vital for targeted treatments and minimizing CNS side effects. However, the BBB also complicates the treatment of brain diseases, stimulating innovative research to overcome this barrier for future therapies.

Frequently Asked Questions

Second-generation antihistamines, such as fexofenadine (Allegra), are designed to be more water-soluble and have larger, more polar molecular structures than older antihistamines. This makes it difficult for them to pass through the lipid-based cell membranes of the BBB, ensuring they primarily target H1 receptors in the body rather than the brain.

Yes, some cardiovascular drugs can cross the blood-brain barrier, while others are specifically designed not to. For example, the ACE inhibitor captopril is known to cross, while benazepril does not significantly penetrate the BBB. This difference affects whether they may produce central nervous system side effects.

Parkinson's disease is caused by low dopamine levels in the brain. Since dopamine cannot cross the BBB, systemic dopamine treatments are ineffective. L-DOPA, the precursor to dopamine, can cross the barrier and is then converted into dopamine by an enzyme in the brain, restoring levels of the neurotransmitter.

P-glycoprotein and other efflux pumps are transmembrane proteins that act as a crucial defense mechanism in the BBB. They recognize and transport many drugs and toxins out of the brain endothelial cells and back into the bloodstream, preventing them from accumulating in the brain and causing damage.

Yes, larger molecular antibiotics generally do not cross the BBB. A well-known example is vancomycin, a large glycopeptide antibiotic. Due to its size, it does not penetrate the BBB under normal physiological conditions.

Drug size is a primary determinant of BBB penetration. Molecules with a molecular weight less than 400-500 Daltons have a higher chance of passive diffusion, provided they also have sufficient lipid solubility. All large molecules, including many peptides and proteins, are effectively blocked by the barrier's tight junctions.

To overcome the BBB, researchers are developing strategies like using nanoparticles to encapsulate drugs, or utilizing focused ultrasound to temporarily and locally open the barrier. These methods aim to deliver targeted therapies to the brain while bypassing the natural barrier.