Comprehensive Study Notes on Cholinergic and Adrenergic Systems, and Autacoids

Organization of the Autonomic Nervous System and Cholinergic Physiology

The nervous system is bifurcated into two primary divisions: the Central Nervous System (CNS), comprising the brain, brain stem, and spinal cord; and the Peripheral Nervous System (PNS), which includes all nerves situated outside the CNS. The PNS is further divided into the Somatic Nervous System, which governs voluntary actions, and the Autonomic Nervous System (ANS), which regulates autonomous actions. The ANS is divided into the Sympathetic nervous system, mediated primarily by norepinephrine (noradrenaline), and the Parasympathetic nervous system, mediated entirely by acetylcholine (ACh).

Nerves that release ACh, whether they are central, somatic, or autonomic, are designated as cholinergic nerves. The chemical structure of acetylcholine can be conceptualized as having two heads connected by a methylene bridge: a cationic head consisting of the quaternary nitrogen of choline ($N^+$) and an esteratic head consisting of an acetyl group ($Ac$).

The Acetylcholine Life Cycle and Metabolic Regulation

The life cycle of acetylcholine involves five critical stages: synthesis in cholinergic nerve cells, storage in vesicles within nerve endings, release upon need, interaction with cholinergic receptors on target organs, and metabolism by cholinesterase enzymes. A sixth stage involves the recycling of choline back into the neuron. Synthesis involves the transport of choline into the neuron, a process inhibited by hemicholinium. Release is blocked by botulinum toxin and stimulated by black widow spider venom.

Metabolism occurs via hydrolysis by the enzyme Choline Esterase (ChE), which exists in two isozymes. True Choline Esterase is found in cholinergic nerves and RBCs; it is essential for life, specific to ACh, and takes 120 days to regenerate. Pseudocholine Esterase is found in the plasma; it is not essential for life, is specific for succinylcholine, and is rapidly regenerated by the liver in approximately 1 day. The degradation process of ACh involves three steps: the binding of the cationic head to the anionic site of the enzyme and the acetyl group to the esteratic site, cleavage of choline leaving an acetylated enzyme, and finally hydrolysis to recover the free enzyme.

Classification and Function of Cholinergic Receptors

Cholinergic receptors are categorized into Nicotinic (N) and Muscarinic (M) receptors. Nicotinic receptors are named after the alkaloid nicotine and are invariably excitatory. They include $N_m$ receptors, present only in skeletal muscle where they facilitate contraction, and $N_n$ receptors, found in autonomic ganglia, presynaptic motor nerves (increasing ACh release), and the adrenal medulla (stimulating norepinephrine and epinephrine release).

Muscarinic receptors are named after the alkaloid muscarine and are subdivided into three main types. $M_1$ receptors are excitatory and primarily neuronal, located in extrapyramidal centers (corpus striatum), vestibular pathways (where they are excitatory to the vomiting center), and the cerebral cortex. $M_3$ receptors are excitatory and located in smooth muscles and exocrine glands. They induce secretions in the lacrimal, salivary, respiratory, GIT, and sweat glands, but notably do not affect mammary glands. They contract smooth muscles (pupillary miosis, ciliary accommodation, bronchospasm, defecation, and urination) but uniquely relax blood vessels. $M_2$ receptors are inhibitory and found mainly in the heart, where they induce S.A. node depression (negative chronotropic effect), A.V. node depression (negative dromotropic effect), and atrial depression (negative inotropic effect), though the ventricles are not innervated by these receptors.

Parasympathomimetic Drugs: Direct and Indirect Acting

Parasympathomimetics (Cholinomimetics) are divided into directly acting and indirectly acting groups. Directly acting drugs include choline esters like Acetylcholine (rarely used due to rapid metabolism), Methacholine (used for Paroxysmal Atrial Tachycardia and peripheral vascular disease), Carbachol (used for glaucoma), and Bethanechol (commonly used for megacolon, GERD, and post-operative paralytic ileus or urine retention). Bethanechol is poorly absorbed orally and cannot cross the Blood-Brain Barrier (BBB). Natural alkaloids include Pilocarpine, which is a tertiary amine that passes the BBB and is selective for $M_3$ receptors; it is used for glaucoma, to counteract mydriatics, as a hair growth tonic, and for Sjögren's syndrome.

Indirectly acting drugs act as anticholinesterases and are categorized into reversible and irreversible types. Reversible carbamates include Physostigmine (used for glaucoma and atropine toxicity), Neostigmine (used for myasthenia crisis and post-operative ileus), and Pyridostigmine (longer duration, used for myasthenia gravis). Donepezil is the drug of choice for Alzheimer's Dementia as it crosses the BBB. Irreversible organophosphorus compounds like echothiophate, malathion (insecticide for scabies), and war gases (Tabun, Sarin, Soman, VX) inhibit both true and pseudo-cholinesterase, leading to enzyme "aging" within minutes to hours.

Toxicity and Treatment of Organophosphorus Compounds

Acute Organophosphorus (OP) toxicity can occur through accidental, suicidal, or homicidal exposure. Clinical manifestations include muscarinic effects (excessive secretions like rhinorrhea, acute pulmonary edema, and pinpoint pupils), nicotinic effects (fasciculations and muscle flaccidity), and CNS effects (convulsions and apnea). VX is a highly adhesive liquid, while GA (Tabun), GB (Sarin), and GD (Soman) series are gaseous agents.

Treatment involves removing the compound by washing the skin with water or bleach. Vital functions are maintained via artificial respiration and Diazepam ($10\,mg$ IV) for convulsions. Specific treatments include Atropine ($2\text{--}5\,mg$ every 5 minutes until full atropinization occurs, marked by the cessation of bronchial secretions) and oximes like Pralidoxime (PAM) or obidoxime ($1\,g$ by IV infusion) before enzyme aging occurs. Aging for GD (Soman) happens within 2 minutes, while for GB (Sarin) it takes 3 to 4 hours. Prophylaxis for war gases includes Pyridostigmine tablets taken three times daily.

Cholinergic Blockers: Anticholinergics and Neuromuscular Blockers

Blockers of cholinergic actions include anticholinergics (muscarinic blockers), neuromuscular blockers (nicotinic blockers on skeletal muscle), ganglion blockers, and botulinum toxin. Atropine is a prototype tertiary amine that crosses the BBB and acts as a competitive antagonist at M receptors. It has diverse effects: anti-emetic, anti-Parkinsonian, increased heart rate (+VE chronotropic and dromotropic), and mydriasis/cycloplegia in the eye (lasting up to 7 days). It also displaces histamine, causing vasodilation. Specific substitutes include Scopolamine (for motion sickness and amnesia), Ipratropium (short-acting, used for asthma), and Tolterodine (for overactive bladder). Atropine-like side effects include dry mouth, blurred vision, tachycardia, and urinary retention.

Neuromuscular blockers are categorized into non-depolarizing (competitive) agents like Tubocurarine, Cisatracurium, and Rocuronium (reversible by Sugammadex), and depolarizing agents like Succinylcholine. Succinylcholine has a very short duration (less than 10 minutes) but can cause "succinylcholine apnea" in patients with genetic pseudocholine esterase deficiency. It also triggers malignant hyperthermia when combined with halothane, characterized by intense muscle spasms and hyperthermia, which is managed with Dantrolene.

Botulinum Toxins (BTX types A and B) interfere with the presynaptic release of ACh by cleaving docking proteins: BTX-A cleaves SNAP-25, and BTX-B cleaves VAMP. Indications include hyperhidrosis, blepharospasm, cervical dystonia, cerebral palsy, and cosmetic glabellar lines.

Adrenergic Physiology: Synthesis, Release, and Receptors

Adrenergic physiology revolves around norepinephrine (NE) and epinephrine (Ep). Synthesis begins with phenylalanine being converted to tyrosine, then to DOPA, dopamine, and finally NE. Epinephrine is synthesized in the adrenal medulla through N-methylation stimulated by corticosteroids. Metyrosine inhibits the rate-limiting step (tyrosine hydroxylase), making it useful in phaeochromocytoma. Termination of NE action occurs primarily through re-uptake (Uptake I into nerves, Uptake II into target organs). Metabolism involves Monoamine Oxidase (MAO) and Catechol-O-methyl transferase (COMT), resulting in metabolites such as Vanillylmandelic acid (VMA), which is measured in urine for diagnosing phaeochromocytoma.

Adrenoceptors are G-protein coupled receptors divided into: $\alpha_1$ (excitatory on smooth muscles), $\alpha_2$ (inhibitory neuronal sites), $\beta_1$ (excitatory on heart muscle and renin secretion), $\beta_2$ (inhibitory on smooth muscle like bronchi and pregnant uterus, also mediates glycogenolysis), and $\beta_3$ (fat cell lipolysis and inhibitory on bladder neck).

Sympathomimetic and Sympatholytic Agents

Sympathomimetic drugs are categorized as direct, indirect, or mixed-acting. Adrenaline (Epinephrine) acts on $\alpha_1$, $\beta_1$, and $\beta_2$ receptors, showing a dual effect on blood pressure: hypertensive via $\alpha_1$ and hypotensive via $\beta_2$. It is life-saving in anaphylactic shock. Dopamine is used for shock with renal impairment because, at low doses, it causes renal vasodilation (D1 agonist). Selective agents include Phenylephrine ($\alpha_1$ agonist for nasal decongestion), Clonidine ($\alpha_2$ agonist for hypertension), and Salbutamol ($\beta_2$ agonist for asthma).

Sympatholytics (Adrenergic Blockers) include alpha blockers like Prazosin (selective $\alpha_1$ for hypertension and BPH) and Phenoxybenzamine (irreversible for phaeochromocytoma). Beta blockers are split into lipophilic (e.g., Propranolol, which crosses the BBB) and hydrophilic (e.g., Atenolol). They are used for hypertension, angina (except vasospastic), heart failure, and glaucoma (Timolol). Side effects include bradycardia, bronchospasm, and nightmares. Ergot alkaloids like Ergotamine are used for migraines due to direct spasmogenic actions, while Bromocriptine is a dopamine agonist for hyperprolactinaemia.

Autacoids: Histamine, Serotonin, and Eicosanoids

Autacoids are chemically diverse substances produced locally. Histamine is synthesized from L-histidine and stored in mast cells. It mediates allergies and anaphylactic shock via $H_1$ receptors and gastric acid secretion via $H_2$ receptors. First-generation antihistamines (e.g., Chlorpheniramine) penetrate the BBB and cause sedation, whereas second-generation drugs (e.g., Loratadine) do not.

Serotonin ($5\text{-}HT$) is synthesized from tryptophan and plays roles in anxiety, migraine, and GIT motility. Sumatriptan (selective $5\text{-}HT_{1B/1D}$ agonist) is used for acute migraine. Serotonin Syndrome is a life-threatening toxicity caused by excess serotonin activity, presenting with mental status changes, autonomic instability, and neuromuscular hyperactivity (tremors, rigidity). It is managed by discontinuing the causative agents and using the antidote Cyproheptadine.

Eicosanoids include Prostaglandins (PG), Leukotrienes (LT), and Thromboxanes (TX), synthesized from arachidonic acid. PGs are used for labor induction (Dinoprostone), maintaining PDA (Alprostadil), and glaucoma (Latanoprost). NSAIDs inhibit cyclooxygenase, the enzyme responsible for PG synthesis.

Questions & Discussion

Q: Where does the synthesis of acetylcholine occur? A: In the nerve cells.

Q: Which choline esterase isozyme is essential for life? A: True choline esterase.

Q: Are nicotinic cholinergic receptors always excitatory or inhibitory? A: They are always excitatory.

Q: Which part of the heart is insensitive to muscarinic receptor blockade? A: The ventricles, because they are not innervated by muscarinic receptors.

Q: Which enzyme metabolizes succinylcholine? A: Pseudocholine esterase.

Q: What is the drug of choice for hypertension during pregnancy? A: Alpha-methyl dopa (Aldomet).