Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia

ANTICHOLINERGIC DRUGS (Muscarinic receptor antagonists, Atropinic, Parasympatholytic)

Conventionally, the term ‘anticholinergic drugs’ is restricted to those which block actions of ACh on autonomic effec tors and in the CNS exerted through muscarinic receptors. Though nicotinic receptor antagonists also block certain actions of ACh, they are generally referred to as ‘ganglion blockers’ and ‘neuromuscular blockers’. Atropine, the prototype drug of this class, is highly selective for muscarinic receptors, but some of its synthetic substitutes do possess signi ficant nicotinic blocking property in addition. The selective action of atropine can easily be demon strated on a piece of guinea pig ileum where ACh induced contractions are blocked without affecting those evoked by histamine, 5HT or other spasmogens. The selectivity is, how ever, lost at very high doses. All anticholinergics are competitive antagonists.

In addition, many other classes of drugs, i.e. TCAs, phenothiazines, anti histamines and disopyramide possess significant antimuscarinic actions. The atropinic natural alkaloids are found in plants of the solanaceae family. The levoisomers are much more active than the dextroisomers. At ropine is racemic while scopolamine is lhyoscine.

PHARMACOLOGICAL ACTIONS

The actions of atropine can be largely predicted from knowledge of parasympathetic responses. Prominent effects are seen in organs which normally receive strong parasympathetic tone. Atropine blocks all subtypes of muscarinic receptors.

1. CNS Atropine has an overall CNS stimu lant action. However, these effects are not appre ciable at low doses which produce only peripheral effects because of restricted entry into the brain. Hyoscine produces central effects (depressant) even at low doses. • Atropine stimulates many medullary centres —vagal, respiratory, vasomotor. • It depresses vestibular excitation and has antimotion sickness property. The site of this action is not clear—probably there is a cholinergic link in the vestibular pathway, or it may be exerted at the cortical level. • By blocking the relative cholinergic over activity in basal ganglia, it suppresses tremor and rigidity of parkinsonism. • High doses cause cortical excitation, restless ness, disorientation, hallucinations and delirium followed by respiratory depression and coma.

2. CVS Heart The most prominent effect of atro pine is tachycardia. It is due to blockade of M2 receptors on the SA node through which vagal tone decreases HR. Higher the existing vagal tone— more marked is the tachycardia (maximum in young adults, less in children and elderly). On i.m./s.c. injection transient initial bradycardia often occurs. Earlier believed to be due to stimulation of vagal centre, it is now thought to be caused by blockade of muscarinic auto receptors (M1 ) on vagal nerve endings, thereby augmenting ACh release. This is suggested by the finding that selec tive M1 antagonist pirenzepine is equipotent to atropine in causing bradycardia. Moreover, atropine substitutes which do not cross blood brain barrier also produce initial bradycardia. Atropine abbreviates refractory period of AV node and facilitates AV conduc tion, especially if it has been depressed by high vagal tone. PR interval is shortened. BP Since cholinergic impulses are not in volved in the maintenance of vascular tone, atropine does not have any consistent or marked effect on BP. Tachycardia and vasomotor centre stimulation tend to raise

BP, while histamine release and direct vasodilator action (at high doses) tend to lower BP. Atropine blocks vasodepressor action of cholinergic agonists.

3. Eye The autonomic control of iris muscles and the action of mydriatics as well as miotics is illustrated in Fig. 8.1. Topical instillation of atropine causes mydriasis, abolition of light reflex and cycloplegia lasting 7–10 days. This results in photophobia and blurring of near vision. The ciliary muscles recover somewhat earlier than sphincter pupillae. The intraocular tension tends to rise, especially in narrow angle glaucoma. However, conventional systemic doses of atropine produce minor ocular effects.

4. Smooth muscles All visceral smooth musc les that receive parasympathetic motor innerva tion are relaxed by atropine (M3 block ade). Tone and amplitude of contractions of stomach and intestine are reduced; the passage of chyme is slowed—constipation may occur, spasm may be relieved. However, peristalsis is only incomp letely sup pressed because it is

primarily regula ted by local reflexes in the enteric plexus, and other neurotransmitters (5 HT, enkephalin, etc.) are involved. Enhanced motility due to injected choli nergic drugs is more completely antago nised than that due to vagal stimulation, because intramural neurones which are activated by vagus utilize a number of noncholinergic transmitters as well.

Atropine causes bronchodilatation and redu ces airway resistance, especially in COPD and asthma patients. Inflammatory mediators like SECTION 2 histamine, PGs, leucotrienes and kinins which participate in asthma increase vagal activity in addition to their direct stimulant action on bron chial muscle and glands. Atropine attenuates their action by antagonizing the reflex vagal component. Atropine has relaxant action on ureter and urinary bladder; urinary retention can occur in older males with prostatic hypertrophy. However, this relaxant action can be beneficial for increas ing bladder capacity and controlling detrusor hyperreflexia in neurogenic bladder/enuresis. Relaxation of biliary tract is less marked and effect on uterus is minimal. Atropine causes bronchodilatation and redu ces airway resistance, especially in COPD

5. Glands Atropine markedly decreases sweat, salivary, tracheobronchial and lacrimal secretion (M3 blockade). Skin and eyes become dry, talking and swallowing may be difficult. Atropine decreases secretion of acid, pepsin and mucus in the stomach, but the primary action is on volume of secretion so that pH of gastric contents may not be elevated unless diluted by food. Since bicarbonate secretion is also reduced, rise in pH of fasting gastric juice is only modest. Relatively higher doses are needed and atropine is less efficacious than H2 blockers in reducing acid secretion. Intestinal and pancreatic secre tions are not significantly reduced. Bile produc tion is not under cholinergic control, so not affected.

6. Body temperature Rise in body tempera ture occurs at higher doses. It is due to both inhibition of sweating as well as stimula tion of temperature regulating centre in the hypothala mus. Children are highly susceptible to atropine fever.

7. Local anaesthetic Atropine has a mild anaes thetic action on the cornea Atropine more effectively blocks responses to exogenously administered cholinergic drugs than those to parasympathetic nerve activity. This may be due to release of ACh very close to the receptors by nerves and involvement of cotransmitters (see p. 108). Hyoscine This natural anticholinergic alkaloid differs from atropine in many respects; these differences are presented in Table 8.1

PHARMACOKINETICS

Atropine and hyoscine are rapidly absorbed from g.i.t. Applied to eyes they freely pen etrate cornea. Passage across bloodbrain barrier is somewhat restricted. About 50% of atropine is metabolized in liver and rest is excreted unchanged in urine. It has a t½ of 3–4 hours. Hyoscine is more completely metabolized and has better bloodbrain barrier penetration

ATROPINE SUBSTITUTES

Many semisynthetic derivatives of belladonna alkaloids and a large number of synthetic com pounds have been introduced with the aim of producing more selective action on certain functions. Most of these differ only marginally from the natural alkaloids, but some appear promising. Quaternary compounds These drugs have certain common features—

• Incomplete oral absorption (10–30%).

• Poor penetration in brain and eye; central and ocular effects are not seen after parenteral/ oral administration.

• Elimination is generally slower; majority are longer acting than atropine.

• Have higher nicotinic blocking property. Some degree of ganglionic blockade may occur at clinical doses producing postural hypotension and impotence as additional side effects.

• At high doses some degree of neuromus cular blockade may also occur.

Drugs in this category are—

1. Hyoscine butyl bromide 20–40 mg oral, i.m., s.c., i.v.; less potent and longer acting than atro pine; used for esophageal and gastrointestinal spastic conditions. BUSCOPAN 10 mg tab., 20 mg/ml amp.

2. Atropine methonitrate 2.5–10 mg oral, i.m.; for abdominal colics and hyperacidity. MYDRINDON 1 mg (adult), 0.1 mg (child) tab; in SPASMOLYSIN 0.32 mg tab; SECTION 2

3. Ipratropium bromide 40–80 µg by inha lation; it acts selectively on bronchial muscle without altering volume or consistency of respiratory secretions. Another desirable feature is that in contrast to atropine, it does not depress muco ciliary clearance by bronchial epithelium. It has a gradual onset and late peak (at 40–60 min) of bronchodilator effect in comparison to inhaled sympathomimetics. Thus, it is more suitable for regular pro phylactic use rather than for rapid sympto matic relief during an attack. Action lasts 4–6 hours. It acts on receptors located mainly in the larger central airways (contrast sympathomi metics whose primary site of action is peripheral bronchioles, see Fig. 16.2). The parasympathetic tone is the major reversible factor in chronic obstructive pulmo nary disease (COPD). There fore, ipratropium is more effective in COPD than in bronchial asthma. Transient local side effects like dry ness of mouth, scratching sensation in trachea, cough, bad taste and nervousness are reported in 20–30% patients, but systemic effects are rare because of poor absorption from the lungs and g.i.t. (major fraction of any inhaled drug is swallowed)

4. Tiotropium bromide A newer congener of ipratropium bromide which binds very tightly to bronchial M1 /M3 muscarinic receptors producing long lasting broncho dilatation. Binding to M2receptors is less tight, confering relative M1 /M3 selectivity (less likely to enhance ACh release from vagal nerve endings in lungs due to M2 receptor blockade). Like ipratropium, it is not absorbed from respiratory and g.i. mucosa and has exhibited high bronchial selectivity of action. TIOVA 18 µg rotacaps; 1 rotacap by inhalation OD.

5. Propantheline 15–30 mg oral; it was a popular anticholinergic drug used for peptic ulcer and gastritis. It has some ganglion block ing activity as well and is claimed to reduce gastric secretion at doses which produce only mild side effects. Gastric emptying is delayed and action lasts for 6–8 hours. Use has declined due to availability of H2 blockers and proton pump inhibitors. PROBANTHINE 15 mg tab.

6. Oxyphenonium 5–10 mg (children 3–5 mg) oral; similar to propantheline, recommended for peptic ulcer and gastrointestinal hypermotility. ANTRENYL 5, 10 mg tab.

7. Clidinium 2.5–5 mg oral; This antisecretory antispasmodic has been used in combina tion with benzodiazepines for nervous dyspep sia, gastritis, irritable bowel syndrome (IBS), colic, peptic ulcer, etc. In SPASRIL, ARWIN 2.5 mg tab with chlordiazepoxide 5 mg. NORMAXIN, CIBIS 2.5 mg with dicyclomine 10 mg and chlordiazepoxide 5 mg.

8. Cimetropium bromide A quaternary ammonium anticholinergicantispasmodic drug, especially promoted for IBS. About 50% patients of IBS get 30–70% relief in abdominal pain and loose motion. Dryness of mouth is the commonest side effect. Dose: 50 mg 2–3 times a day. IBSCIM 50 mg tab.

9. Isopropamide 5 mg oral; indicated in hyper acidity, nervous dyspepsia, IBS and other gastrointestinal problems, specially when associ ated with emotional/mental disorders. In STELABID, GASTABID 5 mg tab. with trifluopera zine 1 mg.

10. Glycopyrrolate 0.2–0.4 mg i.m. (4–5 µg/ kg), potent and rapidly acting antimuscarinic lacking central effects. It is almost exclusively used for pre anaesthetic medication and during anaesthesia .

Tertiary amines

1. Dicyclomine 20 mg oral/i.m., children 5–10 mg; has direct smooth muscle relaxant action in addition to weak and somewhat M1 selective anti cholinergic action. It exerts anti spasmodic action at doses which produce few atropinic side effects. However, infants have exhibited atropinic toxicity symptoms and it is not recommended below 6 months of age. It also has antiemetic property: has been used in morn ing sickness and motion sickness. Dysmenor rhoea and irritable bowel are other indications. CYCLOSPAS-D, 20 mg with dimethicone 40 mg tab; CYCLOPAM INJ. 10 mg/ml in 2 ml, 10 ml, 30 ml amp/vial, also 20 mg tab with paracetamol 500 mg; in COLIMEX, COLIRID 20 mg with paracetamol 500 mg tab, 10 mg/ml drops with dimethicone.

2. Valethamate: The primary indication of this anticholinergicsmooth muscle relaxant is to hasten dilatation of cervix when the same is delayed during labour, and as visceral anti spasmodic, for urinary, biliary, intestinal colic. Dose: 8 mg i.m., 10 mg oral repeated as required. VALAMATE 8 mg in 1 ml inj, EPIDOSIN 8 mg inj., 10 mg tab.

3. Pirenzepine It selecti vely blocks M1 muscarinic recep tors (see p. 112) and inhibits gastric secretion without producing typical atropinic side effects (these are due to blockade of M2 and M3 receptors). The more likely site of action of pirenzepine in stomach is intramu ral plexuses and ganglionic cells rather than the parietal cells themselves. It was indicated in peptic ulcer, but has been overshadowed by H2 blockers and proton pump inhibitors.

Vasicoselective anticholinergics

1. Oxybutynin This anti muscarinic has high affinity for receptors in urinary bladder and salivary glands alongwith additional smooth muscle relaxant and local anaesthetic properties. It is relatively selective for M3 and M1 subtypes

with less action on the M2 subtype. Because of vasico selective action, it is used for detru sor instability resulting in urinary frequency and urge inconti nence. Beneficial effects have been demonstrated in postprostatectomy vasi cal spasm, neurogenic bladder, spina bifida and nocturnal enuresis. Anticholinergic side effects are common after oral dosing, but intravesical instillation increases bladder capacity with few side effects. Oxybutynin is metabolized by CYP3A4; its dose should be reduced in patients being treated with inhibitors of this isoenzyme. Dose: 5 mg BD/TDS oral; children above 5 yr 2.5 mg BD

2. Tolterodine: This relatively M3 selective muscarinic antagonist has preferential action on urinary bladder; less likely to cause dryness of mouth and other anticholinergic side effects. It is indicated in overactive bladder with urinary frequency and urgency. Since it is metabolized by CYP3A4, dose should be halved in patients receiving CYP3A4 inhibitors (erythromycin, ketoconazole, etc.)

3. Flavoxate It has properties similar to oxybuty nin and is indicated in urinary fre quency, urgency and dysuria associated with lower urinary tract infection.

4. Darifenacin Another relatively M3 selective antimuscarinic with preferential action on blad der muscles; indicated in urinary incontinence, urgency and frequency. The biological t½ is 13–19 hours and the extended release tablet works for 24 hours.

5. Solifenacin It is similar to darifenacin; no clinically significant difference between the two has been observed in clinical trials on patients with overactive bladder