Drugs Acting on ANS

Drugs acting on ANS Part I

What are the three main divisions under ANS?

enteric, parasympathetic, sympathetic

How does a preganglionic neuron differ from a postganglionic neuron?

Preganglionic neuron: The cell body is located within the CNS. These neurons emerge from the brainstem or spinal cord and synapse in autonomic ganglia. The ganglia function as relay stations between the preganglionic neuron and the postganglionic neuron.

Postganglionic neuron: The cell body originates in the ganglion, is generally nonmyelinated, and terminates on effector organs such as visceral smooth muscle, cardiac muscle, and exocrine glands

The ANS carries nerve impulses from the CNS to the effector organs via two types of efferent neurons?

preganglionic and postganglionic neurons

what is the ANS known for and its fans?

• know as involuntary nervous system

• regulates everyday requirements of vital body functions

what are autonomic drugs?

Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the ANS

how do autonomic agents act?

By stimulating portions of the ANS or by blocking the action of the autonomic nerves.

Differentiate between sympathetic and parasympathetic system

What are the key features of enteric nervous system?

• third division of the ANS

• Nerve fibers innervate the GI tract, pancreas, and gallbladder

• Functions independently of the CNS

• Controls motility, exocrine and endocrine secretions, and microcirculation of the GI tract

• Modulated by input from both sympathetic and parasympathetic systems

• Sends afferent impulses to sympathetic ganglia and the CNS

What are the sympathetic and parasympathetic actions on the eye,lacrimal glands, heart, bronchioles, bladder and GIT?

Eye

• Sympathetic: contraction of the iris radial muscle (pupil dilates)

• Parasympathetic: contraction of the iris sphincter muscle (pupil contracts), Contraction of the ciliary muscle (lens accommodation for near vision)

Lacrimal Glands

• parasympathetic: stimulation of tears

Heart

• Sympathetic: ↑ heart rate and ↑ contractility

• Parasympathetic: ↓ heart rate and ↓ atrial contractility (M2)

Bronchioles

• Sympathetic: Dilation

• Parasympathetic: Constriction, increased secretions

Bladder

• Sympathetic: Detrusor relaxation, contraction of the sphincter and the trigone

• Parasympathetic: Detrusor contraction, relaxation of the sphincter and the trigone

GIT

• Sympathetic: ↓ muscle motility and tone, contraction of sphincters, secretion

• Parasympathetic: ↑ muscle motility and tone

What are the consequences of stimulation/blockade of ANS receptors in the eye?

α1 stimulation in iris dilator → induces contraction→ mydriasis

M3 stimulation in iris sphincter → induces contraction→ miosis

M3 stimulation in ciliary muscle → induces contraction→ accommodation

β-adrenoceptor stimulation → ciliary muscle relaxation → restoration of normal lens shape

β-adrenoceptor blockade (associated w ciliary epi) → ↓ aqueous humor secretion → ↓ IOP

What is the main role of the sympathetic and parasympathetic system on the body?

Sympathetic system: Adjusts body responses to stress (trauma, fear, hypoglycemia, cold, exercise), ↑ heart rate, ↑ BP, dilates pupils and bronchioles, ↓ GI motility, and mediates the fight-or-flight response

Parasympathetic system: Maintains body homeostasis, essential bodily functions like digestion and elimination and opposes sympathetic actions

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Know this well

Differentiate between a cholinergic and adrenergic neuron

Cholinergic neuron: Uses acetylcholine as its neurotransmitter

Adrenergic neuron: Uses norepinephrine as its neurotransmitter

Fxn of acetylcholine

• Mediates the transmission of nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems

• The autonomic nerve fibers can be divided into two groups based on the type of neurotransmitter release

• If transmission is mediated by acetylcholine, the neuron is termed cholinergic

Fxn of norepinephrine (noradrenaline)

•  When norepinephrine is the neurotransmitter, the fiber is termed adrenergic

•  In the sympathetic system, norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to effector organs.

What is the main rate-limiting step in the synthesis of catecholamines? Name the enzyme involved (COULDN’T FIND ANS ON SLIDE)

The rate-limiting step in catecholamine synthesis is the conversion of tyrosine to DOPA, catalyzed by tyrosine hydroxylase

Differentiate between ionotropic and metabotropic receptor. What are the two main second messenger systems?

Ionotropic receptors: Post-synaptic cholinergic nicotinic receptors in skeletal muscle cells are directly linked to membrane ion channels

Metabotropic receptors: they mediate the effects of ligands by activating a second messenger system inside the cell (G-protein coupled receptors that activate intracellular second messengers)

Second messenger systems:

• Adenylyl cyclase system

• Calcium/phosphatidylinositol system

what are cholinergic receptors further classfied as

nicotinic or muscarinic

what does the binding of neurotransmitters do to ionotropic receptors

directly affexts ion permeability

The binding of chemical signals to receptors activates enzymatic processes within the cell membrane, resulting in cellular responses such as:

• Phosphorylation of intracellular proteins or

• Changes in the conductivity of ion channels

The receptors in the ANS effector cells are classified as what? Also, what binds to these receptors?

The receptors in the ANS effector cells are classified as adrenergic or cholinergic based on the neurotransmitters or hormones that bind to them.

• Epinephrine and norepinephrine bind to adrenergic receptors

• Acetylcholine binds to cholinergic receptors

Briefly outline the steps involved in neurotransmission at cholinergic neurons

1. Synthesis of ACh

2. Storage of ACh

3. Release of ACh

4. Binding of ACh to receptor

5. Degradation of ACh in synaptic cleft

6. Recycling of choline

What are the two main cholinergic receptors and how do they differ from each other?

Nicotinic receptors: Ionotropic, ligand-gated ion channels

Muscarinic receptors: Metabotropic, G-protein coupled receptors

Note: Cholinoceptor stimulants are classified pharmacologically by their spectrum of action, depending on the type of receptor— muscarinic or nicotinic—that is activated.

Cholinomimetics are also classified by their mechanism of action:

• Some bind directly to (and activate) cholinoceptors

• Others act indirectly by inhibiting the hydrolysis of endogenous acetylcholine

what group of drugs mimic acetylchline (cholinometics)?

Acetylcholine-receptor stimulants and cholinesterase inhibitors make up a large group of drugs that mimic acetylcholine (cholinomimetics)

Acetylcholine is used as a neurotrasnmitter by:

• Preganglionic fibers terminating in the adrenal medulla

• Autonomic ganglia (both parasympathetic and sympathetic)

• Postganglionic fibers of the parasympathetic division

• Postganglionic sympathetic division of sweat glands.

• Cholinergic neurons innervating the muscles of the somatic system

• Neurons in the central nervous system (CNS)

Give the location of M2 and M3 receptors and their associated G protein

• M2 receptors: Heart, nerves, smooth muscle — Gi/o protein

• M3 receptors: Glands, smooth muscle, endothelium — Gq/11 protein

What are cholinergic agonists? How are they classified?

Cholinergic agonists are drugs that mimic acetylcholine by binding directly to cholinoceptors (muscarinic or nicotinic).

They are classified as:

Choline esters- includes endogenous Ach and synthetic esters of choline, such as carbachol and bethanechol,

Naturally occurring alkaloids, such as nicotine and pilocarpine

what is a key characteristic of direct acting cholingeric drugs

have longer duration of action than Ach

what drugs are considered “more therapeutically useful” and what do they typically bind too?

More therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors

What is the influence of acetylcholine on the heart, blood pressure, bladder, eye and secretions?

Heart: Decreases heart rate and cardiac output (Acetylcholine mimics vagal stimulation, so when given IV, it slows SA node firing, causing bradycardia and decreased cardiac output)

Blood pressure: Causes vasodilation and decreases BP (cuz Injection of acetylcholine lowers blood pressure indirectly by activating M3 receptors on endothelial cells, which release nitric oxide, causing smooth muscle relaxation and vasodilation)

Bladder: Contracts detrusor muscle → urination

Eye: Causes miosis and accommodation (involved in stimulation of ciliary muscle contraction, topical for near vision and constriction of the sphincter muscle causing miosis)

Secretions: Increases salivary, gastric, intestinal and bronchial secretions and also increases intestinal motility

What is the adverse effect of direct acting cholinergic agonists on blood pressure, lungs, salivary and sweat glands and GIT? (DK ANS TO THIS)

Blood pressure: Decreased BP (FC THIS)

• Dilation (via EDRF). Constriction (high-dose direct effect)

Lungs: Bronchoconstriction in bronchial muscle, secretion in bronchial glands (maybe even bronchospasm FC this)

Salivary & sweat glands: Excessive secretion

GIT: Abdominal pain, diarrhea, increased motility

What is the adverse influence of pilocarpine on the eye?

Pilocarpine causes blurred vision, night blindness, brow ache, and spasm of accommodation

•  Potent stimulator of secretions such as sweat, tears, and saliva,

Give the therapeutic applications of pilocarpine

• Treatment of open-angle and angle-closure glaucoma to lower IOP in emergency

• Reversal of atropine-induced mydriasis

• Treatment of xerostomia (promotes salivation to dry mouth) resulting from irratiation of head and neck

• Oral tablets useful in treatment of Sjögren syndrome (characteritized by dry mouth and lack of tears)

know this chart

what is instilled into eye during opthalmic surgery

Ach (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery

Give the characterisitcs of Bethanechol

• Carbamoyl ester, structurally related to ACh

• Not hydrolyzed by acetylcholinesterase (AChE), but inactivated through by other esterases

• No nicotinic action but strong muscarinic activity

• Acts mainly on smooth musclature (bladder + GI tract)

• Duration of action ≈ 1 hour

Actions of bethanechol

• Directly stimulates muscarinic receptors, causing increased intestinal motility and tone

•  It also stimulates the detrusor muscle of the bladder stimulating urination.

therapeutic uses of Bethanechol

• To stimulate the atonic (acontractile) bladder in postpartum or

  postoperative, nonobstructive urinary retention.

• Neurogenic atony (bladder function related to neurological

  damage)

• Megacolon (abnormal dilation of the colon accompanied by paralysis

  of peristalsis).

Adverse effects of bethanechol

  Sweating

  Salivation

  Flushing

  Decreased blood pressure (with reflex tachycardia)

  Nausea

  Abdominal pain

  Diarrhea and bronchospasm

Key characterisitcs of Carbachol (Miostat)

•  Has both muscarinic and nicotinic actions.

• An ester of carbamic acid and a poor substrate for AChE.

• Biotransformed by other esterases, but at a much slower rate.

Actions of Carbachol (Miostat)

• Strong effects on cardiovascular + GI system (cuz of ganglionic activity → First stimulates, then depresses these systems)

• Nicotinic action causes epinephrine release from the adrenal medulla

• mimics effect of ACh in the eye causes miosis (pupil constriction) + spasm of accommodation

• Due to accomodation spasm, vision becomes fixed at one distance making it impossible to focus

Therapeutic uses of Carbochol and Adverse effects

Therapeutic uses of Carbachol

• Intraocular use provides miosis for eye surgery

• Lowers intraocular pressure in the treatment of glaucoma.

Adverse effects

• Few adverse effects with ophthalmologic use due to lack of systemic penetration

Characterisitics of Pilocarpine (Pilocar)

• Stable to hydrolysis by AChE

• Uncharged and can penetrate the CNS at therapeutic doses

• Exhibits muscarinic activity and is used primarily in ophthalmology