Medical Pharmacology at a Glance. Michael J. Neal

and atracurium are commonly used agents. Vecuronium has no cardiovascular effects. It depends on hepatic inactivation and recovery can occur within 20–30 min, making it an attractive drug for short procedures. Atracurium has a duration of action of 15–30 min. It is only stable when kept cold and at low pH. At body pH and temperature, it decomposes spontaneously in plasma and therefore does not depend on renal or hepatic function for its elimination. It is the drug of choice in patients with severe renal or hepatic disease. Atracurium may cause histamine release with flushing and hypotension. Cisatracurium is an isomer of atracurium. Its main advantage is that it does not cause histamine release and its associated cardiovascular effects.

      Rocuronium has an intermediate duration of action of about 30 min, but with a rapid onset of action (1–2 min) comparable with that of suxamethonium (1–1.5 min). It has minimal cardiovascular effects.

      Reversal of neuromuscular blockade Neostigmine IV quickly reverses the action of competitive neuromuscular blockers. Atropine or glycopyrronium is given first to prevent parasympathetic effects. Sugammadex binds to the steroidal drugs vecuronium and rocuronium forming an inactive complex.

Depolarizing neuromuscular blocking drugs

      Suxamethonium (succinylcholine) is used because of its rapid onset and very short duration of action (2–6 min). The drug is normally hydrolysed rapidly by plasma pseudocholinesterase, but a few people (about 1 in 3000) inherit an atypical form of the enzyme and, in such individuals, the neuromuscular block may last for hours. Suxamethonium depolarizes the endplate and, because the drug does not dissociate rapidly from the receptors, a prolonged receptor activation is produced. The resulting endplate depolarization initially causes a brief train of muscle action potentials and muscle fibre twitches. Neuromuscular block then occurs as a result of several factors which include: (i) inactivation of the voltage‐sensitive Na⁺ channels in the surrounding muscle fibre membrane, so that action potentials are no longer generated; and (ii) transformation of the activated receptors to a ‘desensitized’ state, unresponsive to ACh. The main disadvantage of suxamethonium is that the initial asynchronous muscle fibre twitches cause damage, which often results in muscle pains the next day. The damage also causes potassium release. Repeated doses of suxamethonium may cause bradycardia in the absence of atropine (a muscarinic effect).

      Note

      1 * Pentameric nicotinic receptors also occur in autonomic ganglia and the brain. They have variants of the α‐ and β‐subunit and a different pharmacology.

7 Autonomic nervous system

      Many systems of the body (e.g. digestion, circulation) are controlled automatically by the autonomic nervous system (and the endocrine system). Control of the autonomic nervous system often involves negative feedback, and there are many afferent (sensory) fibres that carry information to centres in the hypothalamus and medulla. These centres control the outflow of the autonomic nervous system, which is divided on anatomical grounds into two major parts: the sympathetic system (left) and the parasympathetic system (right). Many organs are innervated by both systems, which in general have opposing actions. The actions of sympathetic (left) and parasympathetic (right) stimulation on different tissues are indicated in the inner columns, and the resulting effects on different organs are shown in the outer columns.

      The sympathetic nerves (left, ) leave the thoracolumbar region of the spinal cord (T1–L3) and synapse either in the paravertebral ganglia () or in the prevertebral ganglia () and plexuses in the abdominal cavity. Postganglionic non‐myelinated nerve fibres (left, ) arising from neurones in the ganglia innervate most organs of the body (left).

The transmitter substance released at sympathetic nerve endings is noradrenaline (norepinephrine; top left). Inactivation of this transmitter occurs largely by reuptake into the nerve terminals. Some preganglionic sympathetic fibres pass directly to the adrenal medulla (), which can release adrenaline (epinephrine) into the circulation. Norepinephrine and epinephrine produce their actions on effector organs by acting on α‐, β₁‐ or β₂‐adrenoceptors (extreme left).

      In the parasympathetic system, the preganglionic fibres (right, ) leave the central nervous system via the cranial nerves (especially III, VII, IX and X) and the third and fourth sacral spinal roots. They often travel much further than sympathetic fibres before synapsing in ganglia (), which are often in the tissue itself (right).

      The nerve endings of the postganglionic parasympathetic fibres (right, ) release acetylcholine (top right), which produces its actions on the effector organs (right) by activating muscarinic receptors. Acetylcholine released at synapses is inactivated by the enzyme acetylcholinesterase.

      All the preganglionic nerve fibres (sympathetic and parasympathetic, ) are myelinated and release acetylcholine from the nerve terminals; the acetylcholine depolarizes the ganglionic neurones by activating nicotinic receptors.

      A small proportion of autonomic nerves release neither acetylcholine nor norepinephrine. For example, the cavernous nerves release nitric oxide (NO) in the penis. This relaxes the smooth muscle of the corpora cavernosa (via cyclic guanosine monophosphate [cGMP], Chapter 16) allowing expansion of the lacunar spaces and erection. Sildenafil, used in male sexual dysfunction, inhibits phosphodiesterase type 5 and, by increasing the concentration of cGMP, facilitates erection.

      Adrenaline mimics most sympathetic effects, i.e. it is a sympatho‐mimetic agent (Chapter 9). Elliot suggested in 1904 that adrenaline was the sympathetic transmitter substance, but Dale pointed out in 1910 that noradrenaline mimicked sympathetic nerve stimulation more closely.

Effects of sympathetic stimulation

      These are most easily remembered by thinking of changes in the body that are appropriate in the ‘fight or flight reaction’. Note which of the following effects are excitatory and which are inhibitory.

      1 Pupillary dilatation (more light reaches the retina).

      2 Bronchiolar