Medical brain Notes 3

  Some aspects of neurophysiology relevant to pharmacology This chapter presents some basic facts from neurophysiol-ogy that will be needed in subsequent chapters on the phar-macology of the nervous system. The nervous system can be divided according to different categories:   1.    Central versus peripheral. The central nervous system comprises the brain and the spinal cord, which together are protected from the periphery by the blood brain bar-rier.   2.    Somatic versus autonomic. The somatic nervous system comprises functions that are conscious – conscious sen-sations such as touch, temperature, pain etc., and vol-untary movements. Conversely, the autonomic nervous system deals with unconscious sensory input such as blood pressure, blood oxygen and carbon dioxide lev-els 1 , and the likewise unconscious regulatory responses to it. The two above distinctions are `orthogonal', which means that we find autonomic and somatic parts in both the cen-tral...

  Structure and function of synapses As we have seen, the presynaptic action potential will open voltage-gated calcium channels and thereby trigger exocytosis of the neurotransmitter that is stored in vesicles. The transmitter will then bind to a postsynaptic receptor. This will typically result in a local change to the postsynaptic membrane potential, which may or may not trigger a com-plete action potential (Figure 7.3). While a great many dif-ferent transmitters exist, individual neurons only seem to be using very few different ones. Although the time-honoured textbook dogma of one transmitter per neuron only is no longer valid, we will, for the purpose of this class, pretend it to be.   Calcium promotes transmitter exocytosis at multiple stages. There are several pools of neurotransmitter vesicles in the nerve ending, which differ by their maturity (e.g., amount of transmitter stored) and their availability for immediate exocytosis. One effect of calcium consists in the re...

  Mechanisms of drug action on synapses   Drugs may influence synaptic transmission by different mechanisms:   1.    Direct agonists and antagonists will directly bind to the postsynaptic receptor and either activate or competitive-ly block it.   2.    In many synapses, there are both post- and presynaptic receptors for the transmitter. The transmitter will act in an inhibitory fashion at the presynaptic membrane, thus providing for feedback control of release (Figure 7.4a). If its action is excitatory at the postsynaptic membrane, it is easy to see that the two receptors should be differ-ent. In this case, drugs may be developed that act solely on the presynaptic receptor. Such presynaptic agonists will then reduce the amount of transmitter available at the postsynaptic membrane, whereas presynaptic antag-onists will increase it.   3.    Drugs may augment the effect of the endogenous neuro-transmitter by inhibiting its usually very...

  Pharmacologically important neurotransmitters and their receptors Some examples of important neurotransmitters are shown in Figure 7.5. The first one to be recognized – and still one of those most important for pharmacotherapy – is acetylcholine. Its enzymatic cleavage by cholinesterase enables its extremely fast inactivation, which is necessary in a synapse with very high repetition rates such as the neuro-muscular junction in skeletal muscle. However, it is also used in slower synapses in the peripheral autonomic nervous system, as well as in the central nervous system; we will see later that these different types of cholinergic synapses may be targeted by specific drugs. Norepinephrine occurs in the peripheral and central au-tonomic system. The most important problem that is ad-dressed by drugs acting on adrenergic synapses is high blood pressure. Many of these drugs act as postsynap-tic antagonists or as presynaptic agonists, respectively. Dopamine differs from norepinephrine...

  Neurotransmitter receptors The receptors for neurotransmitters fall into two broad classes:   •       Ligand-gated ion channels, and   •       G protein-coupled receptors (GPCR).   Ligand-gated channels will respond to the binding of a spe-cific ligand with either opening or closing. We have seen an example of a ligand-gated channel before – the K  ir /sulfony-lurea system. There, the physiological agonist (ATP) act-ed from within the cell and effected channel closure. With neurotransmitter receptor channels, the agonists act from outside the cell and will cause channel opening.   Ligand-gated channels (and their ion selectivities) include:   •       Nicotinic acetylcholine receptor (Na  + , K + , Ca ++ )   •       NMDA glutamate receptor (Na  + , K + , Ca ++ )   •       ADP (Purine) receptor P2X (Na  +...

  Overview of the autonomic nervous system It was stated at the beginning that the peripheral autonomic system has a prominent place as a site of drug action. We will now look at the organization of this system, and at the distribution of transmitter receptors within it. This will enable us to understand the effects of drugs acting upon this system and rationales behind their usage.   The autonomic nervous system consists of two function-ally distinct parts that frequently exert antagonistic effects on their target organs. These are referred to as the sympa-thetic and the parasympathetic system, respectively. Figure 7.6 depicts some essential features. The parasympathet-ic system, for the most part, emerges from the central ner-vous system at the level of the  medulla oblongata , which is the lowermost part of the brain. These neurons reach some nerve centers in the periphery, which are named gan-glia (singular: ganglion), where they trigger activity in sec-ondary neurons...