As previously discussed (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological effect’, p. 139), proteins span the cell membrane and can affect the rate of flow or direction of ions. These proteins are of two main types:

Both play in important role in conduction of a nerve impulse and muscle contraction.

Production of an Action Potential

Normally:

• The potassium concentration inside a cell is higher than the potassium concentration outside the cell.

• The sodium concentration outside the cell is higher than the sodium concentration inside the cell.

The sodium–potassium pump (Figure 31.1) is a form of active transport as both the sodium and potassium are moving against a gradient. It is responsible for maintaining an electrical balance across a cell membrane. The sodium–potassium pump actively pushes sodium molecules out of the cell and pumps potassium molecules in against a gradient. With each cycle, three Na⁺ ions are pumped out and two K⁺ ions are pumped in. The net result, as there are also negative ions such as Cl⁻ (chlorine) present both inside and outside the cell, is a net negative charge inside the cell and a positive charge outside the cell. This means that there is a potential difference across the cell membrane, known as the resting potential. To produce an action potential (Figure 31.2):

(i) The normal resting potential of a cell membrane is −60 to −70 mV, which means the inside of the cell is 60 to 70 mV less than the outside. If the membrane of the cell suddenly becomes more permeable to the ions then this situation will change. Permeability to ions is selective and occurs through ion channels, which will only permit certain ions to pass through them. Once the channel is open, the ion will pass either in or out of the cell down the concentration gradient. This dramatically changes the potential across the cell membrane.

(ii) In a nerve or muscle cell, if the ion channel for sodium is opened the sodium floods into the cell down the concentration gradient, taking its positive charge with it. The potential difference across the membrane now becomes positive. In other words, the inside of the cell becomes more positive than the outside. This is the depolarization phase. When the membrane reaches a certain threshold level, the nerve cell fires or the muscle cell contracts; if this threshold level is not reached, the nerve cell will not fire and the muscle cell will not contract. The size of the action potential (the spike in Figure 31.2) that is produced when the threshold level is reached is fixed; the action potential always fires at this size. This is the all-or-none principle.

(iii) When the action potential has been produced, the sodium gates start to close and the potential difference across the membrane opens the potassium gates, which allow potassium to flood out of the cell. This is the repolarization phase.

(iv) There is an overshoot, until the voltage across the membrane closes the potassium gate allowing the sodium–potassium pump to restore the balance once again (i). Blockage of these channels can be achieved by local anaesthetics (see Chapter 32 ‘Analgesia and relief of pain’, p. 254) and some anticonvulsant medication (Chapter 33 ‘Neurological disease’, p. 255).

Figure 31.1 The sodium–potassium pump mechanism. (i) Sodium pump before phosphorylation. (ii) Sodium pump after phosphorylation (which provides the energy for the pump); sodium moves into the gate. (iii) The gate opens and sodium moves out. (iv) Potassium moves in. (v) The gate closes. (vi) The concentrations of potassium and sodium are reversed temporarily until (i) is restored by normal movement down the concentration gradient.

Figure 31.2 The function of ion channels due to membrane potential (see text for explanation).

The action potential activates the voltage-gated calcium ion channels (channels opened by change in voltage across them) on the end of the axon at the synapse. The principle is very much the same as that for the sodium–potassium channel. Calcium enters the axon membranes, stimulating the release of the neurotransmitter acetylcholine into the neuromuscular synapse. This is taken up by the nicotinic receptors (see below) on the motor endplate. The sodium and potassium ion channels then open, allowing the sodium into the endplate and the potassium out. As the membrane is more permeable to sodium, the amount of sodium entering the cell is greater than the potassium leaving it, making the overall charge on the inside of the cell more positive. This action potential then spreads through the T-tubule network of the muscle fibres, ultimately releasing calcium ions from the endoplasmic reticulum in the muscle cells.

The actin filaments in the muscle cells are composed of three protein components:

Figure 31.3 illustrates the process of muscle contraction. In (i) and (ii), the released calcium ions interact with the troponin units, making them change shape and allowing the tropomyosin to slide out of its groove to expose the actin myosin-binding sites and allow the cross-bridge components of the myosin to interact with the actin (Figure 31.4). Figure 31.3(iii) shows how this interaction results in the head of the myosin tilting towards the arm and dragging the actin filament with it (the power stroke). At the end of this power stroke (iv) the myosin head is cocked back. Adenosine triphosphate (ATP) is released and binds to the myosin head, releasing it from the actin filament. The myosin head swings back ready to attach again and take another power stroke. In this way, the filaments are walked past one another, or ‘ratcheted’. The cross-bridges are reputed to work independently, each one attaching, pulling along and detaching in a continuous cycle.

Figure 31.3 The process of muscle contraction.

Figure 31.4 The action of the topomyosin–troponin complex: the myosin head to attaches to myosin binding sites on the actin filament.

As the action potential passes, the calcium ions are pumped back into the sarcoplasmic reticulum and, as the calcium is removed from the muscle fibres, the muscle relaxes. The theory is that, the greater number of cross-bridges that are attached at one time, the greater the force of contraction. All this is very energy dependent; the power source is ATP (see Figure 12.3, p. 91).

The sympathetic and parasympathetic nervous systems comprise the autonomic nervous system. The physical and chemical arrangement of each differs (Figure 31.5). Both systems use neurotransmitters.

Figure 31.5 The components of the autonomic nervous system.

Neurotransmitters are chemicals that enable neurons to pass signals to each other. There are three main groups:

Figure 31.6 Production of various neurotransmitters and isovaleric acid found in valerian, which is structurally similar to gamma-amino butyric acid (GABA).

Figure 31.7 Neurotransmitters, including ephedrine (from Ephedra spp.) and amphetamine, which interact with the noradrenaline (norepinephrine) receptors and two phytochemicals (atropine and scopolamine) that interact with the acetylcholine receptors.

Phytochemistry note: alkaloids, such as atropine and scopolamine (hyoscine) and ephedrine, bind to the muscarinic receptors in the nervous system, where they compete with acetylcholine.

The function of the peripheral nervous system (PNS) is a great deal less compli-cated than that of the brain. The PNS utilizes acetylcholine and noradrenaline (norepinephrine) as its neurotransmitters; the brain has many more neurotransmitters because it is required to manage some very complicated functions, such as emotion. Not only are the transmitters in the central nervous system more diverse, but so are their actions:

Monoamines

• Dopamine

The basal ganglia (Figure 31.8) are a collection of nuclei embedded deep in the white matter of the cerebral cortex. The substantia nigra is a part of the basal ganglia. The ganglia are responsible, with the cerebellum, for organizing movement on a moment-to-moment basis (hence the problems associated with Parkinson’s disease).

Figure 31.8 Location of the basal ganglia.

Dopamine (DA) is concentrated in the basal ganglia. If levels of dopamine are not optimal, movements are jerky, clumsy and uncoordinated. Dopaminergic neurons are widespread in the brain and distribute in three dopamine pathways. The main dopamine-containing area of the brain is the substantia nigra, which is important in body movements.

Dopamine is synthesized in neurons in the substantia nigra from l-dopa (levodopa), which is used for treating Parkinson’s disease. Dopa decarboxylase inhibitor has to be given to prevent metabolism of l-dopa before it can have a therapeutic effect.

Drugs Enhancing Dopamine Activity

Used for:

• Parkinson’s disease: decreased levels of dopamine are present in Parkinson’s disease.

• Chorea.

• Dystonia.

• Hallucinations and delusions.

• Antiemetic activity.

Drugs Reducing Dopamine Activity

Used in:

• Schizophrenia; overactivity at dopamine synapses is associated with schizophrenia.

• Delusion.

• Chorea.

• Parkinsonism.

• Tics.

• Nausea.

• Vertigo.

Cocaine and amphetamines increase activity at dopamine synapses.

Dopamine is a contributor to voluntary movement and pleasurable emotions, depending on which receptor it acts on.

• Serotonin (5-hydroxytryptamine (5-HT))

Serotonin is synthesized from the amino acid tryptophan. There are several types of serotonin receptor, and drugs act on these receptors in several different ways:

• Agonists: lithium, sumatriptan.

• Partial agonists: buspirone, LSD (lysergic acid).

• Antagonists: e.g. clozapine, the antagonists have different degrees of ability to occupy sites.

• Re-uptake inhibitors: fluoxetine, sertraline, venlafaxine, MDMA (methylenedioxy methamphetamine; ecstasy).

Actions of Serotonin

The CNS contains less than 2% of the total serotonin in the body. It is mainly localized in the neurons emerging from a group of nuclei at the centre in the midbrain, pons and medulla. The pathways then branch out over much of the CNS. Serotonin is thought to be involved in many brain disorders. Serotonin is also involved in the regulation of sleep and wakefulness, eating and aggression, pain perception, body temperature, blood pressure and hormonal activity.

Low serotonin levels are thought to create insomnia and depression. Abnormal levels are thought to contribute to depression and obsessive–compulsive disorder.

• Histamine

This potent agent is believed to be involved in the regulation of sleeping and waking states.

• Noradrenaline (Norepinephrine) and Adrenaline (Epinephrine)

There are four types of adrenoreceptor, alpha-1, alpha-2, beta-1 and beta-2:

• Alpha receptor stimulation: leads to vasoconstriction of the arterioles and pupillary dilation.

• Beta-1 receptor stimulation: leads to an increase in pulse and contractility of the heart.

• Beta-2 receptor stimulation: leads to bronchodilatation, uterine relaxation and arteriolar vasodilatation.

Drugs enhancing adrenergic activity are used in asthma (adrenaline administrated in emergency) and heart failure. Interestingly monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs; see Chapter 33 ‘Neurological disease’, p. 262) are thought to act by increasing synaptic noradrenaline (norepinephrine) in the CNS.

Drugs that reduce adrenergic activity are used in angina, hypertension, arrhythmias, thyrotoxicosis anxiety. Cocaine and amphetamines increase the activity at nerve-ending synapses.

Action of Noradrenaline (Norepinephrine)

Noradrenaline (norepinephrine) is found in cell bodies in the pons and medulla. These bodies project neurons to the hypothalamus, thalamus, limbic system and cerebral cortex. It comes as no great surprise, therefore, to discover that noradrenaline contributes to control of mood and arousal and can affect sleep patterns.

Depletion of noradrenaline (norepinephrine) in the brain has been shown to cause a decrease in drive and motivation and might be linked to depression. It is part of the ‘fight or flight’ response, which increases heart rate, etc.

Ephedra spp. (Ma Huang)

Ephedrine:

• Displaces noradrenaline (norepinephrine) from storage vesicles in presynaptic neurons.

• The displaced noradrenaline (norepinephrine) is released in large quantities into the synapse, where it activates the adrenergic receptors.

Amphetamine (Figure 31.7) works in a similar way, to cause:

• Increased heart rate.

• Bronchodilation by acting as a bronchial muscle relaxant, hence its use in asthma.

• Vasoconstriction of the blood vessels leading to raised blood pressure.

Ephedrine has moderately potent bronchial muscle relaxant properties and is therefore used for symptomatic relief in milder cases of asthmatic attacks. It is also used to reduce the risk of acute attacks in the treatment of chronic asthma.

High doses of Ephedra (Ma Huang) can cause:

• restlessness and anxiety

• dizziness

• insomnia

• tremor

• rapid pulse

• sweating

• respiratory difficulties

• confusion

• hallucinations

• delirium

• convulsions.

Points to note:

• High blood pressure and rapid irregular heart rate are very dangerous symptoms.

• This can be brought about by only two or three times the therapeutic dose.

• The elderly are particularly sensitive to overdose.

• There have been instances of psychosis similar to amphetamine psychosis.

Drug interactions include:

• digoxin

• antihypertensives such as beta-blockers.

• monoamine oxidase inhibitors (MAOI)

• other neurotransmitter-related drugs.

• Acetylcholine (Muscarinic and Nicotinic Receptors)

There are two types of acetylcholine receptor, which are named for the substances that block them:

• muscarinic

• nicotinic.

Although acetylcholine sets off each response, the different types of receptor are responsible for a different physiological effect:

Nicotinic

• Fast onset (voltage-gated receptor, therefore fast acting).

• Short duration.

• Excitatory.

• Blocked by the alkaloid nicotine.

Muscarinic

• G protein, therefore slower (see Chapter 19 ‘Pharmacodynamics: how drugs elicit a physiological response’, p. 141).

• Excitation or inhibition.

• Blocked by the alkaloid muscarine.

The cholinergic pathways in the specific regions of the brainstem are thought to be involved in cognitive function, particularly memory. Alzheimer’s disease is thought to be due to advanced damaged of these pathways.

Peripherally, acetylcholine is the main neurotransmitter of the parasympathetic nervous system. This is why some of the antidepressants that block cholinergic receptors have the side effect of a dry mouth: the salivary glands are not stimulated to produce saliva.

• Centrally acting anticholinergic drugs used in: parkinsonism, dystonias, motion sickness.

• Peripheral antimuscarinic drugs used in: asthma, incontinence, pupil dilation (so that the interior of the eye can be more easily examined).

• Peripheral cholinergic agonist used in: glaucoma (pilocarpine from the Pilocarpus spp.; see also carbonic anhydrase inhibitors, Figure 26.5, p. 198 for different approach), myasthenias.

• Atropine, a tropane alkaloid (see Figure 23.4, p. 178) extracted from Atropa belladonna (deadly nightshade) is used to open the iris for examination or surgical procedures.