Pharmacology

Abstract

Headache treatment has been based primarily on experiences with non-specific drugs such as analgesics, non-steroidal anti-inflammatory drugs, or drugs that were originally developed to treat other diseases, such as beta-blockers and anticonvulsant medications. A better understanding of the basic pathophysiological mechanisms of migraine and other types of headache has led to the development over the past two decades of more target-specific drugs. Since activation of the trigeminovascular system and neurogenic inflammation are thought to play important roles in migraine pathophysiology, experimental studies modeling those events successfully predicted targets for selective development of pharmacological agents to treat migraine. Basically, there are two fundamental strategies for the treatment of migraine, abortive or preventive, based to a large degree on the frequency of attacks. The triptans, which exhibit potency towards selective serotonin (5-hydroxytryptamine, 5-HT) receptors expressed on trigeminal nerves, remain the most effective drugs for the abortive treatment of migraine. However, numerous preventive medications are currently available that modulate the excitability of the nervous system, particularly the cerebral cortex. In this chapter, the pharmacology of commercially available medications as well as drugs in development that prevent or abort headache attacks will be discussed.

Figure 1

Schematic representation of prostanoid formation and peripheral sensitization. Arachidonic acid released from membrane phospholipids by phospholipases A2 is as substrate for COX-2, generating PGG2 and then PGH2. PGH2 is the substrate for most terminal prostaglandin synthases including mPGES-1 and PGIS. Inflammatory cytokines induce both COX-2 and mPGES-1 in the periphery and in the CNS. Although prostaglandins do not directly activate nociceptors, PGE₂ binds to prostaglandin E (EP) receptors, and activates phosphokinases intracellularly and increases sodium channel permeability through postreceptor events that sensitize nociceptive sensory nerve endings to other mediators (like histamine and bradykinin) and by sensitizing nociceptors to respond to non-nociceptive stimuli (allodynia). Prostanoids mediate pain sensitization through mainly EP₁, EP₂ and IP. PGE₂ and PGI₂ also indirectly potentiate TRPV1 channel and NaV1.8 sodium channel activation by phosphorylation via PKA and PKC. Those events lead to an elevation of the resting membrane potential and a reduction in the firing threshold of trigeminal nerves. In the spinal cord, PGE2 acts on EP₂ receptors on the second order nociceptive neurons resulting in inhibition of glycine receptors through PKA-dependent phosphorylation. Glucocorticoids and NSAIDs have the ability to block phospholipase A and COX enzymes.