Oxygen used in therapy should be prescribed with the same care as any drug; there should be a well
4 Bj'-level Positive Airways Pressure: air (if necessary enriched with oxygen 24% or 28%) is administered through a close fitting face-mask, at a positive pressure of 14-18 cm of water to support inspiration, then at a pressure of 4 cm of water during expiration to help maintain patency of small airways and increase gas exchange in alveoli.
5 Thomas Sydenham, 1624-89. He was referred to as the 'English Hippocrates' due to his classic description of diseases.
defined purpose and its effects should be monitored objectively.
The absolute indication to supplement inspired air is inadequate tissue oxygenation. As clinical signs may be imprecise, arterial blood gases should be measured whenever suspicion arises. Tissue hypoxia can be assumed when the Pa02 falls below 6.7 kPa (50 mmHg) in a previously normal acutely ill patient, e.g. with myocardial infarction, acute pulmonary disorder, drug overdose, musculoskeletal or head trauma. Chronically hypoxic patients may maintain adequate tissue oxygenation with a Pa02 below 6.7 kPa by compensatory adaptations including an increased red cell mass and altered haemoglobin-oxygen binding characteristics. Oxygen therapy is used as follows:
• High concentration oxygen therapy is reserved for a state of low PaOz in association with a normal or low PaC02 (type I respiratory failure), as in: pulmonary embolism, pneumonia, pulmonary oedema, myocardial infarction, and young patients with acute severe asthma. Concentrations of 02 up to 100% may be used for short periods, since there is little risk of inducing hypoventilation and C02 retention.
• Low concentration oxygen therapy is reserved for a state of low Pa02 in association with a raised PaC02 (type II failure), typically seen during exacerbations of chronic obstructive pulmonary disease. The stimulus to respiration is elevation of the PaC02 but this control is blunted in chronically hypercapnic patients whose respiratory drive comes from hypoxia. Elevating the PaOz in such patients by giving them high concentrations of oxygen removes their stimulus to ventilate, exaggerates C02 retention and may cause fatal respiratory acidosis. The objective of therapy in such patients is to provide just enough oxygen to alleviate hypoxia without exaggerating the hypercapnia and respiratory acidosis; normally the inspired oxygen concentration should not exceed 28% and in some 24% may be sufficient.
• Continuous long-term domiciliary oxygen therapy (LTOT) is given to patients with severe persistent hypoxaemia and cor pulmonale due to chronic obstructive pulmonary disease (see later). Patients are provided with an oxygen concentrator. Clinical trial evidence indicates that taking oxygen for more than 15 h per day improves survival.
Histamine, antihistamines and allergies
Histamine is a naturally-occuring amine that has long fascinated pharmacologists and physicians. It is found in most body tissue in an inactive bound form, predominantly within tissue mast cells, and pharmacologically active free histamine is released in response to stimuli such as physical trauma or IgE-mediated activation. Various chemicals can also cause release of histamine. The more powerful of these (proteolytic enzymes and snake venoms) have no place in therapeutics, but a number of useful drugs, such as d-tubocurarine and morphine, and even some antihistamines, cause histamine release. This anaphylactoid (i.e. IgE-independent) effect is usually clinically mild with a transient reduction in blood pressure or a local skin reaction; but significant bronchospasm may occur in asthmatics.
The physiological functions of histamine are suggested by its distribution in the body.
• In body epithelia (the gut, the respiratory tract and in the skin) it is released in response to invasion by foreign substances.
• In glands (gastric, intestinal, lachrymal, salivary) it mediates part of the normal secretory process.
• In most cells near blood vessels it plays a role in regulating the microcirculation.
Histamine acts as a local hormone (autacoid) similarly to serotonin or prostaglandins, i.e. it acts within the immediate vicinity of its site of release. In the context of gastric secretion, for example, stimulation of receptors on the histamine-containing cell causes release of histamine which in turn acts on receptors on parietal cells which then secrete hydrogen ions (see Gastric secretion, Ch. 31).
Actions. The actions of histamine which are clinically important are those on:
Smooth muscle. In general, histamine causes smooth muscle to contract (excepting arterioles, but including the larger arteries). Stimulation of the pregnant human uterus is insignificant. A brisk attack of bronchospasm may be induced in subjects who have any allergy, particularly asthma.
Blood vessels. Arterioles are dilated, with a consequent fall in blood pressure. This action, versus contraction of larger arteries, is partly due to nitric oxide release from the vascular endothelium of the arterioles in response to histamine receptor activation. Capillary permeability also increases especially at postcapillary venules, causing oedema. These effects on arterioles and capillaries represent the flush and the ivheal components of the triple response described by Thomas Lewis.6 The third part, the flare, is arteriolar dilatation due to an axon reflex releasing neuropeptides from C-fibre endings. Skin. Histamine release in the skin can cause itch. Gastric secretion. Histamine increases the acid and pepsin content of gastric juices. As may be anticipated from the above actions, anaphylactic shock, which is due in large part ot histamine release, is characterised by circulatory collapse and broncho-constriction. The most rapidly effective antidote is adrenaline (epinephrine) (see below), and an antihistamine (Hj-receptor) may be given as well.
Metabolism. Histamine is formed from the amino acid histidine and is inactivated largely by deamination and by methylation. In common with other local hormones, this process is extremely rapid.
HISTAMINE H,-AND H2-RECEPTOR ANTAGONISTS
The effects of histamine can be opposed in three ways:
• By using a drug with opposite effects, e.g. histamine constricts bronchi, causes vasodilatation and increases capillary permeability. Adrenaline (epinephrine), by activating a and (32 adrenoceptors, produces opposite effects — referred to as physiological antagonism.
• By blocking histamine binding to its site of action (receptors), e.g. using competitive Hj- and H2-receptor antagonists.
6 Lewis T et al 1924 Heart 11: 209.
• By preventing the release of histamine from storage cells; glucocorticoids and sodium cromoglicate can suppress IgE-induced release from mast cells. (32-agonists have a similar effect.
Drugs that competitively block Hj-histamine receptors were the first to be introduced and are conventionally called the 'antihistamines'. They effectively inhibit the components of the triple response and partially prevent the hypotensive effect of histamine, but they have no effect on histamine-induced gastric secretion. Indeed, the standard method of testing a patient's capacity to secrete gastric acid used to be to inject histamine after first giving a large dose of a conventional (H:-receptor) antihistamine to block the other (undesired) effects of the injection. The search for drugs that could selectively block histamine-induced gastric secretion (see Ch. 31) led to the discovery of the H2-receptor. A third receptor (H3-receptor) has now been cloned but its clinical importance is uncertain. In summary:
• Hj-receptor: mediates the oedema and vascular effects of histamine (see above)
• H2-receptor: mediates the effect on gastric secretion.
Thus, histamine antagonists are classified as:
• Histamine Hj-receptor antagonists (see account below)
• Histamine H2-receptor antagonists: cimetidine, famotidine, nizatidine, ranitidine (see Ch. 31).
HISTAMINE H,-RECEPTOR ANTAGONISTS
The term antihistamine is unsatisfactory because the older first-generation antagonists (see below) show considerable blocking activity against muscarinic receptors, and often serotonin and a-adrenergic receptors as well. These features are a disadvantage when H } -antihistamines are used specifically to antagonise the effects of histamine, e.g. for allergies. Hence the appearance of second-generation H,-antagonists that are more selective for Hj-receptors and largely free of antimuscarinic and sedative effects (see below) has been an important advance. They can be discussed together.
Actions. H1-receptor antihistamines oppose, to varying degrees, the effects of liberated histamine.
They strongly inhibit all components of the triple response (pure Hj-receptor effect), but only partially block the hypotensive effect of high-dose histamine (a mixed Hj- and H2-receptor effect). They are of negligible use in asthma, in which nonhistamine mediators, such as the cysteinyl-leukotrienes, are the predominant constrictors. The H, -antihistamines are generally competitive, surmountable inhibitors of the action of histamine. Hj-antihistamines are more effective if used before histamine has been liberated. Reversal of effects of histamine after it has been released is more readily achieved by physiological antagonism with adrenaline (epinephrine), which should be used first in life-threatening allergic reactions.
The older first-generation -antihistamines cause drowsiness and patients should be warned of this, e.g. about driving or operating machinery, and about additive effects with alcohol. Paradoxically, CNS stimulation may occur with absence epilepsy (petit mal) made worse on therapeutic dosing, and seizures following overdosing with these antihistamines. The newer second-generation H,-antihistamines penetrate the blood-brain barrier poorly and are largely devoid of these effects. Antimuscarinic effects of first-generation Hj-anti-histamines are sometimes put to therapeutic advantage in parkinsonism and motion sickness.
Pharmacokinetics. Hj-antihistamines taken orally are readily absorbed. They are mainly metabolised in the liver. Excretion in the breast milk may also be sufficient to cause sedation in infants. They are generally administered orally and can also be given i.m. or i.v.
INDIVIDUAL H,-RECEPTOR ANTIHISTAMINES
These newer drugs are relatively selective for Hj-receptors, enter the brain less readily than do the earlier antihistamines and lack antimuscarinic side effects. Differences lie principally in their duration of action.
Cetirizine (\l/2 7 h), loratadine (t^ 15 h) and terfenadine [tl/2 20 h) are effective taken once daily and are suitable for general use. Acrivastine (tV2 2 h) is so short acting that it is best reserved for intermittent therapy, e.g. when breakthrough symptoms occur in a patient using topical therapy for hay fever. Other nonsedating antihistamines are desloratadine, fexofenadine, levocetirazine and mizolastine.
Adverse effects. Terfenadine can prolong the QTc interval on the surface ECG. This is especially likely to occur when the recommended dose is exceeded or the drug is administered with substances that block hepatic metabolism. Since this is dependent solely on the 3A4 isoform of cytochrome P450, offending drugs include erythromycin, ketoconazole and even grapefruit juice. Fexofenadine is the active metabolite of terfenadine and appears safe in this respect.
Sedative first-generation agents
Chlorphenamine (tl/2 20 h) is effective when urticaria is prominent, and its sedative effect is then useful.
Diphenhydramine (t/2 32 h) is strongly sedative and has antimuscarinic effects; it is also used in parkinsonism and motion sickness.
Promethazine (tx/2 12 h) is so strongly sedative that it is used as an hypnotic in adults and children.
Alimemazine, azatadine, brompheniramine, clemastine, cyproheptadine, diphenylpyraline, doxylamine, hydroxyzine and triprolidine are similar.
Adverse effects. Apart from sedation, these include: dizziness, fatigue, insomnia, nervousness, tremors, and antimuscarinic effects, e.g. dry mouth, blurred vision and gastrointestinal disturbance. Dermatitis and agranulocytosis can occur. Severe poisoning due to overdose results in coma and sometimes in convulsions.
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If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.