книги студ / Color Atlas of Pharmacology

Migraine

Migraine is a syndrome characterized by recurrent attacks of intense headache and nausea that occur at irregular intervals and last for several hours. In classic migraine, the attack is typically heralded by an “aura” accompanied by spreading homonymous visual field defects with colored sharp edges (“fortification” spectra). In addition, the patient cannot focus on certain objects, has a ravenous appetite for particular foods, and is hypersensitive to odors (hyperosmia) or light (photophobia). The exact cause of these complaints is unknown; however, a disturbance in cranial blood flow is the likely underlying pathogenetic mechanism. In addition to an often inherited predisposition, precipitating factors are required to provoke an attack, e.g., psychic stress, lack of sleep, certain foods. Pharmacotherapy of migraine has two aims: stopping the acute attack and preventing subsequent ones.

Treatment of the attack. For symptomatic relief, headaches are treated with analgesics (acetaminophen, acetylsalicylic acid), and nausea is treated with metoclopramide (p. 330) or domperidone. Since there is delayed gastric emptying during the attack, drug absorption can be markedly retarded, hence effective plasma levels are not obtained. Because metoclopramide stimulates gastric emptying, it promotes absorption of ingested analgesic drugs and thus facilitates pain relief.

If acetylsalicylic acid is administered i.v. as the lysine salt, its bioavailability is complete. Therefore, i.v. injection may be advisable in acute attacks.

Should analgesics prove insufficiently effective, ergotamine or one of the 5-HT1, agonists may help control the acute attack in most cases or prevent an imminent attack. The probable common mechanism of action is a stimulation of serotonin receptors of the 5-HT1D (or perhaps also the 1B and 1F) subtype. Moreover, ergotamine has affinity for dopamine receptors (! nausea, eme-

sis), as well as α-adrenoceptors and 5- HT2 receptors (" vascular tone, " platelet aggregation). With frequent use, the vascular side effects may give rise to severe peripheral ischemia (ergotism). Overuse (>once per week) of ergotamine may provoke “rebound” headaches, thought to result from persistent vasodilation. Though different in character (tension-type headache), these prompt further consumption of ergotamine. Thus, a vicious circle develops with chronic abuse of ergotamine or other analgesics that may end with irreversible disturbances of peripheral blood flow and impairment of renal function.

Administered orally, ergotamine and sumatriptan, eletriptan, naratriptan, rizatriptan, and zolmitriptan have only limited bioavailability. Dihydroergotamine may be given by i.m. or slow i.v. injection, sumatriptan subcutaneously or by nasal spray.

Prophylaxis. Taken regularly over a longer period, a heterogeneous group of drugs comprising propranolol, nadolol, atenolol, and metoprolol (β-blockers), flunarizine (H1-histamine, dopamine, and calcium antagonist), pizotifen (pizotyline, 5-HT-antagonist), methysergide (partial 5-HTID-agonist and nonselective 5-HT-antagonist, p. 126), NSAIDs (p. 200), and calcitonin (p. 264) may decrease the frequency, intensity, and duration of migraine attacks. Among the β- blockers (p. 90), only those lacking intrinsic sympathomimetic activity are effective.

Common Cold

The common cold—colloquially the flu, catarrh, or grippe (strictly speaking, the rarer infection with influenza viruses)— is an acute infectious inflammation of the upper respiratory tract. Its symptoms, sneezing, running nose (due to rhinitis), hoarseness (laryngitis), difficulty in swallowing and sore throat (pharyngitis and tonsillitis), cough associated with first serous then mucous sputum (tracheitis, bronchitis), sore muscles, and general malaise can be present individually or concurrently in varying combination or sequence. The term stems from an old popular belief that these complaints are caused by exposure to chilling or dampness. The causative pathogens are different viruses (rhino-, adeno-, parainfluenza v.) that may be transmitted by aerosol droplets produced by coughing and sneezing.

Therapeutic measures. First attempts of a causal treatment consist of zanamavir, an inhibitor of viral neuraminidase, an enzyme necessary for virus adsorption and infection of cells. However, since symptoms of common cold abate spontaneously, there is no compelling need to use drugs. Conventional remedies are intended for symptomatic relief.

Rhinitis. Nasal discharge could be prevented by parasympatholytics; how- ever, other atropine–like effects (pp. 104ff) would have to be accepted. Therefore, parasympatholytics are hardly ever used, although a corresponding action is probably exploited in the case of H1 antihistamines, an ingredient of many cold remedies. Locally applied (nasal drops) vasoconstricting α- sympathomimetics (p. 90) decongest the nasal mucosa and dry up secretions, clearing the nasal passage. Long-term use may cause damage to nasal mucous membranes (p. 90).

Sore throat, swallowing problems. Demulcent lozenges containing surface anesthetics such as ethylaminobenzoate (benzocaine) or tetracaine (p. 208) may provide relief; however,

the risk of allergic reactions should be borne in mind.

Cough. Since coughing serves to expel excess tracheobronchial secretions, suppression of this physiological reflex is justified only when coughing is dangerous (after surgery) or unproductive because of absent secretions. Co- deine and noscapine (p. 212) suppress cough by a central action.

Mucous airway obstruction. Mu- colytics, such as acetylcysteine, split disulfide bonds in mucus, hence reduce its viscosity and promote clearing of bronchial mucus. Other expectorants (e.g., hot beverages, potassium iodide, and ipecac) stimulate production of watery mucus. Acetylcysteine is indicated in cystic fibrosis patients and inhaled as an aerosol. Whether mucolytics are indicated in the common cold and whether expectorants like bromohexine or ambroxole effectively lower viscosity of bronchial secretions may be questioned.

Fever. Antipyretic analgesics (acetylsalicylic acid, acetaminophen, p. 198) are indicated only when there is high fever. Fever is a natural response and useful in monitoring the clinical course of an infection.

Muscle aches and pains, headache. Antipyretic analgesics are effective in relieving these symptoms.

Decongestion of mucous membranes

H1-Antihistamines

Caution: sedation

Viral infection

Causal therapy impossible

Surface anesthetics

Caution:

risk of sensitization

Antitussive:

Dextrometorphan

Codeine

Mucolytics

Acetylcysteine

Expectorants:

Stimulation of bronchial secretion

Give

warm fluids

Potassium iodide solution

Sniffles, runny nose

Common cold

Flu

Sore throat

Cough

Airway congestion

Accumulation in airways of mucus, inadequate expulsion by cough

Allergic Disorders

IgE-mediated allergic reactions (p. 72) involve mast cell release of histamine (p. 114) and production of other mediators (such as leukotrienes, p. 196). Resultant responses include: relaxation of vascular smooth muscle, as evidenced locally by vasodilation (e.g., conjunctival congestion) or systemically by hypotension (as in anaphylactic shock); en- hanced capillary permeability with transudation of fluid into tissues— swelling of conjunctiva and mucous membranes of the upper airways (“hay fever”), cutaneous wheal formation; contraction of bronchial smooth muscle— bronchial asthma; stimulation of intestinal smooth muscle—diarrhea.

1.Stabilization of mast cells.

Cromolyn prevents IgE-mediated release of mediators, although only after chronic treatment. Moreover, by interfering with the actions of mediator substances on inflammatory cells, it causes a more general inhibition of allergic inflammation. It is applied locally to: conjunctiva, nasal mucosa, bronchial tree (inhalation), intestinal mucosa (absorption almost nil with oral intake). Indications: prophylaxis of hay fever, allergic asthma, and food allergies.

2.Blockade of histamine recep-

tors. Allergic reactions are predominantly mediated by H1 receptors. H1 antihistamines (p. 114) are mostly used orally. Their therapeutic effect is often disappointing. Indications: allergic rhinitis (hay fever).

3. Functional antagonists of mediators of allergy. a) α-Sympathomi- metics, such as naphazoline, oxymetazoline, and tetrahydrozoline, are applied topically to the conjunctival and nasal mucosa to produce local vasoconstriction, and decongestion and to dry up secretions (p. 90), e.g., in hay fever. Since they may cause mucosal damage, their use should be short-term.

b) Epinephrine, given i.v., is the most important drug in the management of anaphylactic shock: it constricts blood

vessels, reduces capillary permeability, and dilates bronchi.

c)β2-Sympathomimetics, such as terbutaline, fenoterol, and albuterol, are employed in bronchial asthma, mostly by inhalation, and parenterally in emergencies. Even after inhalation, effective amounts can reach the systemic circulation and cause side effects (e.g., palpitations, tremulousness, restlessness, hypokalemia). During chronic administration, the sensitivity of bronchial musculature is likely to decline.

d)Theophylline belongs to the

methylxanthines. Whereas caffeine (1,3,7-trimethylxanthine) predominantly stimulates the CNS and constricts cerebral blood vessels, theophylline (1,3-dimethylxanthine) possesses additional marked bronchodilator, cardiostimulant, vasorelaxant, and diuretic actions. These effects are attributed to both inhibition of phosphodiesterase (→ c AMP elevation, p. 66) and antagonism at adenosine receptors. In bronchi- al asthma, theophylline can be given orally for prophylaxis or parenterally to control the attack. Manifestations of overdosage include tonic-clonic seizures and cardiac arrhythmias as early signs.

e)Ipratropium (p. 104) can be inhaled to induce bronchodilation; however, it often lacks sufficient effectiveness in allergic bronchospasm.

f)Glucocorticoids (p. 248) have

significant anti-allergic activity and probably interfere with different stages of the allergic response. Indications: hay fever, bronchial asthma (preferably local application of analogues with high presystemic elimination, e.g., beclomethasone, budesonide); anaphylactic shock (i.v. in high dosage)—a probably nongenomic action of immediate onset.

Glucocorticoids

Bronchial Asthma

Definition: a recurrent, episodic shortness of breath caused by bronchoconstriction arising from airway inflammation and hyperreactivity.

Asthma patients tend to underestimate the true severity of their disease. Therefore, self-monitoring by the use of home peak expiratory flow meters is an essential part of the therapeutic program. With proper education, the patient can detect early signs of deterioration and can adjust medication within the framework of a physician-directed therapeutic regimen.

Pathophysiology. One of the main pathogenetic factors is an allergic inflammation of the bronchial mucosa. For instance, leukotrienes that are formed during an IgE-mediated immune response (p. 326) exert a chemotactic effect on inflammatory cells. As the inflammation develops, bronchi become hypersensitive to spasmogenic stimuli. Thus, stimuli other than the original antigen(s) can act as triggers (A); e.g., breathing of cold air is an important trigger in exercise-induced asthma. Cyclooxygenase inhibitors (p. 196) exemplify drugs acting as asthma triggers.

Management. Avoidance of asthma triggers is an important prophylactic measure, though not always feasible. Drugs that inhibit allergic inflammmatory mechanisms or reduce bronchial hyperreactivity, viz., glucocorticoids, “mast-cell stabilizers,” and leukotriene antagonists, attack crucial pathogenetic links. Bronchodilators, such as β2-sym- pathomimetics, theophylline, and ipratropium, provide symptomatic relief.

The step scheme (B) illustrates successive levels of pharmacotherapeutic management at increasing degrees of disease severity.

First treatment of choice for the acute attack are short-acting, aerosolized β2-sympathomimetics, e.g., salbutamol, albuterol, terbutaline, fenoterol, and others. Their action occurs within minutes and lasts for 4 to 6 h.

If β2-mimetics have to be used more frequently than three times a week, more severe disease is present. At this stage, management includes antiinflammatory drugs, such as “mast-cell stabilizers” (in children or juvenile patients) or else glucocorticoids. Inhala- tional treatment must be administered regularly, improvement being evident only after several weeks. With proper use of glucocorticoids undergoing high presystemic elimination, concern about systemic adverse effects is unwarranted. Possible local adverse effects are: oropharyngeal candidiasis and dysphonia. To minimize the risk of candidiasis, drug administration should occur before morning or evening meals, or be followed by rinsing of the oropharynx. Anti-inflammatory therapy is the more successful the less use is made of asneeded β2-mimetic medication.

Severe cases may, however, require an intensified bronchodilator treatment with systemic β2-mimetics or theophyl- line (systemic use only; low therapeutic index; monitoring of plasma levels needed). Salmeterol is a long-acting inhalative β2-mimetic (duration: 12 h; onset ~20 min) that offers the advantage of a lower systemic exposure. It is used prophylactically at bedtime for nocturnal asthma.

Zafirlukast is a long-acting, selective, and potent leukotriene receptor (LTD4, LTE4) antagonist with anti-in- flammatory/antiallergic activity and efficacy in the maintenance therapy of chronic asthma. It is given both orally and by inhalation. The onset of action is slow (3 to 14 d). Protective effects against inhaled LTD4 last up to 12 to 24 h.

Ipratropium may be effective in some patients as an adjunct anti-asth- matic, but has greater utility in preventing bronchospastic episodes in chronic bronchitis.

Emesis

In emesis the stomach empties in a retrograde manner. The pyloric sphincter is closed while the cardia and esophagus relax to allow the gastric contents to be propelled orad by a forceful, synchronous contraction of abdominal wall muscles and diaphragm. Closure of the glottis and elevation of the soft palate prevent entry of vomitus into the trachea and nasopharynx. As a rule, there is prodromal salivation or yawning. Coordination between these different stages depends on the medullary center for emesis, which can be activated by diverse stimuli. These are conveyed via the vestibular apparatus, visual, olfactory, and gustatory inputs, as well as viscerosensory afferents from the upper alimentary tract. Furthermore, psychic experiences may also activate the emetic center. The mechanisms underlying motion sickness (kinetosis, sea sickness) and vomiting during pregnancy are still unclear.

Polar substances cannot reach the emetic center itself because it is protected by the blood-brain barrier. However, they can indirectly excite the center by activating chemoreceptors in the area postrema or receptors on peripheral vagal nerve endings.

Antiemetic therapy. Vomiting can be a useful reaction enabling the body to eliminate an orally ingested poison. Antiemetic drugs are used to prevent kinetosis, pregnancy vomiting, cytotoxic drug-induced or postoperative vomiting, as well as vomiting due to radiation therapy.

Motion sickness. Effective prophylaxis can be achieved with the parasympatholytic scopolamine (p. 106) and H1 antihistamines (p. 114) of the diphenylmethane type (e.g., diphenhydramine, meclizine). Antiemetic activity is not a property shared by all parasympatholytics or antihistamines. The efficacy of the drugs mentioned depends on the actual situation of the individual (gastric filling, ethanol consumption), environmental conditions (e.g., the behavior of

fellow travellers), and the type of motion experienced. The drugs should be taken 30 min before the start of travel and repeated every 4 to 6 h. Scopolamine applied transdermally through an adhesive patch can provide effective protection for up to 3 d.

Pregnancy vomiting is prone to occur in the first trimester; thus pharmacotherapy would coincide with the period of maximal fetal vulnerability to chemical injury. Accordingly, antiemetics (antihistamines, or neuroleptics if required) should be used only when continuous vomiting threatens to disturb electrolyte and water balance to a degree that places the fetus at risk.

Drug-induced vomiting. To prevent vomiting during anticancer chemotherapy (especially with cisplatin), effective use can be made of 5-HT3- receptor antagonists (e.g., ondansetron, granisetron, and tropisetron), alone or in combination with glucocorticoids

(methylprednisolone, dexamethasone).

Anticipatory nausea and vomiting, resulting from inadequately controlled nausea and emesis in patients undergoing cytotoxic chemotherapy, can be attenuated by a benzodiazepine such as lorazepam. Dopamine agonist-induced nausea in parkinsonian patients (p. 188) can be counteracted with D2-receptor antagonists that penetrate poorly into the CNS (e.g., domperidone, sulpiride).

Metoclopramide is effective in nausea and vomiting of gastrointestinal origin (5-HT4-receptor agonism) and at high dosage also in chemotherapyand radi- ation-induced sickness (low potency antagonism at 5-HT3- and D2-recep- tors). Phenothiazines (e.g., levomeprom- azine, trimeprazine, perphenazine) may suppress nausea/emesis that follows certain types of surgery or is due to opioid analgesics, gastrointestinal irritation, uremia, and diseases accompanied by elevated intracranial pressure.

The synthetic cannabinoids dronab- inol and nabilone have antinauseant/antiemetic effects that may benefit AIDS and cancer patients.