Info

Year introduced

Tertatolol Carvedilol Esmolol Bopindolol Bisoprolol Celiprolol Betaxolol Befunolol Carteolol Mepindolol Penbutolol Carazolol Nadolol Acebutolol Bunitrolol Atenolol Metipranol Metoprolol Timolol Sotalol Talinolol Oxprenolol Pindolol Bupranolol Alprenolol

Propranolol_1975_1980_1985_1990_

B. Avalanche-like increase in commercially available ß-sympatholytics elimination

Antiadrenergics

Antiadrenergics are drugs capable of lowering transmitter output from sympathetic neurons, i.e., "sympathetic tone". Their action is hypotensive (indication: hypertension, p. 312); however, being poorly tolerated, they enjoy only limited therapeutic use.

Clonidine is an a2-agonist whose high lipophilicity (dichlorophenyl ring) permits rapid penetration through the blood-brain barrier. The activation of postsynaptic a2-receptors dampens the activity of vasomotor neurons in the medulla oblongata, resulting in a resetting of systemic arterial pressure at a lower level. In addition, activation of presynaptic a2-receptors in the periphery (pp. 82, 90) leads to a decreased release of both norepinephrine (NE) and acetylcholine.

Side effects. Lassitude, dry mouth; rebound hypertension after abrupt cessation of clonidine therapy.

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, is transported across the blood-brain barrier, decarboxylated in the brain to a-methyldopamine, and then hydroxylat-ed to a-methyl-NE. The decarboxylation of methyldopa competes for a portion of the available enzymatic activity, so that the rate of conversion of L-dopa to NE (via dopamine) is decreased. The false transmitter a-methyl-NE can be stored; however, unlike the endogenous mediator, it has a higher affinity for a2- than for a1-receptors and therefore produces effects similar to those of clonidine. The same events take place in peripheral ad-renergic neurons.

Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkinson-like symptoms (p. 88), cutaneous reactions, hepatic damage, immune-he-molytic anemia.

Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopa-mine = DA, serotonin = 5-HT) by inhibiting an ATPase required for the vesicular amine pump. The amount of NE re leased per nerve impulse is decreased. To a lesser degree, release of epineph-rine from the adrenal medulla is also impaired. At higher doses, there is irreversible damage to storage vesicles ("pharmacological sympathectomy"), days to weeks being required for their resynthesis. Reserpine readily enters the brain, where it also impairs vesicular storage of biogenic amines.

Adverse effects. Disorders of extrapyramidal motor function with development of pseudo-Parkinsonism (p. 88), sedation, depression, stuffy nose, impaired libido, and impotence; increased appetite. These adverse effects have rendered the drug practically obsolete.

Guanethidine possesses high affinity for the axolemmal and vesicular amine transporters. It is stored instead of NE, but is unable to mimic the functions of the latter. In addition, it stabilizes the axonal membrane, thereby impeding the propagation of impulses into the sympathetic nerve terminals. Storage and release of epinephrine from the adrenal medulla are not affected, owing to the absence of a re-uptake process. The drug does not cross the blood-brain barrier.

Adverse effects. Cardiovascular crises are a possible risk: emotional stress of the patient may cause sympatho-adrenal activation with epinephrine release. The resulting rise in blood pressure can be all the more marked because persistent depression of sympathetic nerve activity induces supersen-sitivity of effector organs to circulating catecholamines.

Bronchomotor Tone

Parasympathetic Nervous System

Responses to activation of the parasympathetic system. Parasympathetic nerves regulate processes connected with energy assimilation (food intake, digestion, absorption) and storage. These processes operate when the body is at rest, allowing a decreased tidal volume (increased bronchomotor tone) and decreased cardiac activity. Secretion of saliva and intestinal fluids promotes the digestion of foodstuffs; transport of intestinal contents is speeded up because of enhanced peristaltic activity and lowered tone of sphincteric muscles. To empty the urinary bladder (micturition), wall tension is increased by detrusor activation with a concurrent relaxation of sphincter tonus.

Activation of ocular parasympa-thetic fibers (see below) results in narrowing of the pupil and increased curvature of the lens, enabling near objects to be brought into focus (accommodation).

Anatomy of the parasympathetic system. The cell bodies of parasympa-thetic preganglionic neurons are located in the brainstem and the sacral spinal cord. Parasympathetic outflow is channelled from the brainstem (1) through the third cranial nerve (oculomotor n.) via the ciliary ganglion to the eye; (2) through the seventh cranial nerve (facial n.) via the pterygopalatine and sub-maxillary ganglia to lacrimal glands and salivary glands (sublingual, submandibular), respectively; (3) through the ninth cranial nerve (glossopharyngeal n.) via the otic ganglion to the parotid gland; and (4) via the tenth cranial nerve (vagus n.) to thoracic and abdominal viscera. Approximately 75% of all parasympathetic fibers are contained within the vagus nerve. The neurons of the sacral division innervate the distal colon, rectum, bladder, the distal ureters, and the external genitalia.

Acetylcholine (ACh) as a transmitter. ACh serves as mediator at terminals of all postganglionic parasympathetic fibers, in addition to fulfilling its transmitter role at ganglionic synapses within both the sympathetic and parasym-pathetic divisions and the motor endplates on striated muscle. However, different types of receptors are present at these synaptic junctions:

Localization

Agonist

Antagonist

Receptor Type

Target tissues of 2nd parasympathetic neurons

Muscarine

Atropine

Muscarinic (M) cholinoceptor; G-protein-coupled-receptor protein with 7 transmembrane domains

Sympathetic &

parasympathetic ganglia

Nicotine

Trimethaphan

Ganglionic type (a3 P4)

Nicotinic (N) cholinoceptor ligand-gated cation channel formed by five transmembrane subunits

Motor endplate

Nicotine

d-Tubocurarine

muscular type (a12P1yS)

The existence of distinct cholino- ses allows selective pharmacological ceptors at different cholinergic synap- interventions. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

Cholinergic Synapse

Cholinergic Synapse

Acetylcholine (ACh) is the transmitter at postganglionic synapses of parasympathetic nerve endings. It is highly concentrated in synaptic storage vesicles densely present in the axoplasm of the terminal. ACh is formed from choline and activated acetate (acetylcoenzyme A), a reaction catalyzed by the enzyme choline acetyltransferase. The highly polar choline is actively transported into the axoplasm. The specific choline transporter is localized exclusively to membranes of cholinergic axons and terminals. The mechanism of transmitter release is not known in full detail. The vesicles are anchored via the protein synap-sin to the cytoskeletal network. This arrangement permits clustering of vesicles near the presynaptic membrane, while preventing fusion with it. During activation of the nerve membrane, Ca2+ is thought to enter the axoplasm through voltage-gated channels and to activate protein kinases that phosphorylate syn-apsin. As a result, vesicles close to the membrane are detached from their anchoring and allowed to fuse with the presynaptic membrane. During fusion, vesicles discharge their contents into the synaptic gap. ACh quickly diffuses through the synaptic gap (the acetylcho-line molecule is a little longer than 0.5 nm; the synaptic gap is as narrow as 30-40 nm). At the postsynaptic effector cell membrane, ACh reacts with its receptors. Because these receptors can also be activated by the alkaloid musca-rine, they are referred to as muscarinic (M-)cholinoceptors. In contrast, at gan-glionic (p. 108) and motor endplate (p. 184) cholinoceptors, the action of ACh is mimicked by nicotine and they are, therefore, said to be nicotinic cholino-ceptors.

Released ACh is rapidly hydrolyzed and inactivated by a specific acetylchol-inesterase, present on pre- and post-junctional membranes, or by a less specific serum cholinesterase (butyryl chol-inesterase), a soluble enzyme present in serum and interstitial fluid.

M-cholinoceptors can be classified into subtypes according to their molecular structure, signal transduction, and ligand affinity. Here, the M1, M2, and M3 subtypes are considered. Mi receptors are present on nerve cells, e.g., in ganglia, where they mediate a facilitation of impulse transmission from pregan-glionic axon terminals to ganglion cells. M2 receptors mediate acetylcholine effects on the heart: opening of K+ channels leads to slowing of diastolic depolarization in sinoatrial pacemaker cells and a decrease in heart rate. M3 receptors play a role in the regulation of smooth muscle tone, e.g., in the gut and bronchi, where their activation causes stimulation of phospholipase C, membrane depolarization, and increase in muscle tone. M3 receptors are also found in glandular epithelia, which similarly respond with activation of phos-pholipase C and increased secretory activity. In the CNS, where all subtypes are present, cholinoceptors serve diverse functions, including regulation of cortical excitability, memory, learning, pain processing, and brain stem motor control. The assignment of specific receptor subtypes to these functions has yet to be achieved.

In blood vessels, the relaxant action of ACh on muscle tone is indirect, because it involves stimulation of M3-cho-linoceptors on endothelial cells that respond by liberating NO (= endothelium-derived relaxing factor). The latter diffuses into the subjacent smooth musculature, where it causes a relaxation of active tonus (p. 121).

^ Acetyl coenzyme A + choline ^ Choline acetyltransferase

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