Exam 2: Pharm: Ganglionic & neuromuscular blockers (Dr Dick)

Prolonged block risk?

- Prolonged neuromuscular blockade or paralysis may occur with the long-acting agent, Pancuronium, compared to the shorter-acting agents. - Prolonged blockade can result in muscle paralysis, apnea, dyspnea, or respiratory depression. At risk: conditions or receiving medications that impair neuromuscular function (e.g., myasthenia gravis) or potentiate the pharmacological actions of neuromuscular blockers (e.g., electrolyte imbalance).

Malignant Hyperthermia triggered by? Initiated by?

-Combination of certain anesthetics and neuromuscular blocking drugs (or alone) -uncontrolled release of Ca++ from the sarcoplasmic reticulum in skeletal muscle -more commonly seen with depolarizing blockers given with an anesthetic, even though it has also been reported with succinylcholine alone or a volatile anesthetic alone

Mivacurium duration/onset? Effects?

-Mivacurium has been re-offered after being off the market for several years. -short-acting with a longer onset time but shorter duration than Rocuronium.

Decamethonium comprised of a ____ carbon chain separating two ________ (Quats)

10, tri-methyl amines

FDA approval granted for Sugammadex on _________ after multiple rejections for:

12/15/2015, allergic reactions

How was curare introduced to anesthesia?

1940's discovered that curare gave adequate skeletal muscle relaxation during operative anesthesia without using excessive amounts of general anesthetics

Nicotinic 2 receptor: What is it? How is it opened?

5 subunit ligand-gated ion channel located at neuromuscular junction, 2 x AcH binds to open Na+ channel = depolarization = action potential @ NMJ

Neuromuscular blockers Curare is a plant _____ and has been used for centuries by South American Indians to: It was first used in humans in _____ for:

Alkaloid, kill wild animals to eat, 1932, the treatment of tetanus and spasticity

Heart, Iris, Ciliary muscle: Predominant tone? Effects of ganglionic block?

All Para (cholinergic) H: tachy I: mydriasis C: cycloplegia (focus far)

Arterioles & veins: Predominant tone? Effects of ganglionic block?

All Sympathetic (adrenergic) A: vasodilation, inc periph BF, hypotension V: Dilation, dec venous return, dec CO

GI tract: Predominant tone? Effects of ganglionic block?

All para (cholinergic) Dec tone & motility, constipation, dec gastric secretions, dec pancreatic secretions

5 Subunits of nicotinic 2 receptor?

Alpha (2), beta, delta and gamma or epsilon Ionophores- pentameric structures -2 Ach to open channel Picture: Normal ACh binding to neuromuscular nicotinic receptor N+ (quaternary amine) + drawn to anionic binding site Ester (ester) provides H+ binding -cause electron withdrawing functions inside protein that changes structure slightly=> open channel

Secondary receptors on the ganglia (muscarinic, adrenergic, and others) believed to:

Amplify or suppress this signal; (cannot initiate AP)

In addition to its use to promote skeletal muscle relaxation during surgery, tubocurarine has been used as:

An aid to mechanical respiration, to prevent trauma during electroconvulsive therapy and as an aid to the diagnosis of myasthenia gravis

Neuromuscular blockers Curare is also a generic historic term used extensively to describe?

An arrowhead poison capable of killing by causing skeletal muscle paralysis.

What may you pretreat Succs with to reduce bradyarrythmias?

Anticholinergic agents, e.g., atropine

pH and temperature and rate of elimination with Hofmann elimination?

As temp and pH decrease, the rate of Hofmann elimination decreases, they increase, so does reaction rate

Agents with histamine-releasing properties precautions for:

Asthma or cardiac disease, flushing, hypotension, sinus tachycardia, and bronchospasm

Intermediate-acting nondepolarizing NMB agents:

Atracurium, Cisatracurium (Nimbex), and Vecuronium, have neuromuscular blocking effects for 30 to 60 minutes

Newer, and currently available synthetic competitive nondepolarizing neuromuscular blocking agents with differing onsets or durations of action, metabolism, elimination, and side effects include:

Atracurium, cisatracurium, rocuronium, and vecuronium

Sugammadex structure is a complex cyclodextrin 'cage' with high lipophilicity that works by:

Binding the neuromuscular blocker and allowing removal

Curare alkaloids, snake alpha toxins act at the motor endplate by:

Blockade of depolarization (EPP) - increase permeability to Na+ and K+

Symptoms of ganglionic blockade are due to:

Blockade of the predominant tone on each tissue, allowing the non-predominant autonomic effects to override and be expressed

Hexamethonium works by:

Blocking the ion channel after it opens - like a plug

Bladder & Salivary glands: Predominant tone? Effects of ganglionic block?

Both Para (cholinergic) B: Urinary retention S: xerostomia (dry mouth)

How are the chemical makeups of atracurium and mivacurium similar?

Both have a long spacer Carbon chains

How do you recognize steroids?

Characterized by a molecular structure of 17 carbon atoms arranged in four rings Picture: Vecuronium (amino-steroid) binding to neuromuscular Nicotinic receptor Steroid nucleus structure with several amine Compound in to structure, +/- ester binds -binding keeps receptors from binding to ach and keep ion channel from being open

Neuromuscular blockers: d-tubocurarine chloride was derived from a plant extract of_____ _____

Chondodendron Tomentosum

Non-Depolarizing blockers MOA?

Competitive antagonists of ACh at the neuromuscular junction (blocks the ability of ACh to stimulate the muscle at the motor end plate, resulting in muscle weakness (at lower doses) or paralysis (at higher doses) )

Although little use today (primarily experimental) ganglionic blockers were used to:

Control blood pressure, but very dangerous (wide range SE)

CNS and Mecamylamine?

Crosses BBB easily, blocks nicotinic receptors in the brain, as well as at the ganglia. In brain = decrease dopamine and norepinephrine release from specific neurons as well as modulating neuroendocrine responses

Succinylcholine is considered to have ____ - like properties b/c of it being a:

Curare like properties a unique neuromuscular blocker with depolarizing properties

Hofmann Elimination is the spontaneous chemical ______ elimination that occurs in aqueous environments at specific temperatures and pH

Deamination

What blocks the N2 & N1 receptor?

Decamethonium blocks the N2 while hexamethonium blocks N1 receptors Picture: Decamethonium binding to neuromuscular Nicotinic receptor Amine (positive quarternary) interact anionic site No ester site like Ach Instead has two quaternary amines separated by 10 Carbon. (Deca) -provides ability to fit inside neuromuscular nicotinic receptor Neuronal nicotinic receptors- find hexamethonium -acts like Deca (in neuromuscular sites) -Hexa only has 6 C, fits 2 quarternary amines into anionic sites of ganglionic site nicotinic

Succinylcholine and decamethonium act at the motor endplate by:

Depolarization and phase II block

Mecamylamine concerns:

Due to potential peripheral activity, should not be used in patients with a history of myocardial infarction, glaucoma, or any cerebrovascular disease (i.e. stroke). Avoid sudden discontinuation of use (rebound hypersensitivity effects possible). Use should also be avoided in pregnancy since the drug crosses the placenta well

NMB Duration: Atracurium, Cisatracurium, Doxacurium, Mivacurium, Pancuronium, Rocuronium, Succinylcholine, Tubocurarine, Vecuronium

Duration: Succs (5), Miva (15), Roc (20-60), Vec (25-30), Tubo (25-90), Cis (60), Atra (60), Panc (65), Doxa (100)

Excess of Ca++ act at the motor endplate by:

Enhances AcH release

How are the actions of ganglionic blockers complex and unpredictable?

Esp true of depolarizing meds like nicotine which can increase heart rate by initial stim of the sympathetic ganglia or depressing the parasympathetic cardiac ganglia, and vice versa. -Also nicotine acts on chemoreceptors and the medullary centers = send increased or decreased signals to the heart via compensatory responses -Nicotine can triggers release of epinephrine from the adrenal medulla which increases cardiac rate and blood pressure

metabolism of esterase and hoffman

Esterase Cleave on of amine => quaternary acid and quaternary alcohol Cleaved more into 2 quaternary acid and OH-dub-OH Hoffman Cleave C attached to N each side Leaves laudanosine and spacer molecule

At low doses of Mecamylamine the CNS effects are seen with:

Few peripheral side effects

Hexamethonium, a _____ blocker with a ___ carbon chain between the two _______ (Quats)

Ganglionic, 6, tri-methyl amines

Other type of ganglionic blockade (i.e., _____) doesn't stimulate the receptor, instead acts by:

Hexamethonium, Competing for ACh binding site only (non-depolarizing)

Cisatracurium metabolization?

Hofmann degradation but due to greater potency and lower doses, laudanosine risks are limited

What makes Succs unique?

Its depolarizing mechanism and is also the shortest-acting (both onset and duration) NMB with effective intubation condition within 60 sec, persist 2-3 min

Atracurium and metabolization?

Metabolized by nonspecific serum esterases and spontaneous Hofmann elimination to produce laudanosine, a metabolite which may have CNS excitatory activity = seizures -also metabolized somewhat in tissues and a small amount eliminated unchanged.

In asthmatic patients treated with steroids and steroidal neuromuscular blockers while on mechanical ventilation have experienced an acute _____ lasting days to weeks

Myopathy

Adverse reactions of Mecamylamine?

N/V, anorexia, constipation, mydriasis, syncope, weakness and fatigue, among others

Only _____ ganglionic blockers can completely block the transmission through ganglia

Nicotinic

NMB Onset: Atracurium, Cisatracurium, Doxacurium, Mivacurium, Pancuronium, Rocuronium, Succinylcholine, Tubocurarine, Vecuronium

Onset: 1 min: Succs (.5-1), Roc (1) Cis (1.5) 2 min: Panc (2-4), Tubo (2-5), Vec (2.5) 3 min: Atra (3-5), Miva 5 min: Doxa

Mecamylamine granted ____ ____ status by the FDA for treating specific nicotine-responding neurological disorders such as _____ ______ (only reason it's still on the market)

Orphan drug, Tourette's syndrome

Renally eliminated agents include _______, which may require dosage reduction and careful monitoring in patients with renal impairment

Pancuronium

The long-acting neuromuscular blocking agent, __________, has effects lasting from about 60 to 120 minutes

Pancuronium

_____ & ____ has been reported with peripheral intravenous administration of non-depolarizing neuromuscular blockers

Phlebitis and pain

Agents that lack significant histamine-releasing effects and do not block cardiac muscarinic receptors:

Rocuronium and Vecuronium

What nondepolarizing agent has been shown to be an effective alternative to Succs?

Rocuronium is classified as a short-acting(?), -effective alternative to succinylcholine for rapid sequence endotracheal intubation, due to it's short onset and fairly short duration of action

Agents which are primarily excreted by hepatic metabolism or biliary excretion include _____ and _____; (precautions for use in patients with hepatic disease)

Rocuronium, Vecuronium

Sugammadex (Bridion) is a: Designed as a reversal agent for _____ but works fairly well with ____ & ______

Selective relaxant binding agent (SRBA) Rocuronium, vecuronium and pancuronium

Mecamylamine: Originally used to treat ___________, but not anymore because:

Severe and malignant hypertension, much safer and better antihypertensives available today

Depolarizing type blockers initially _____ the ganglia like ACh then _____ due to:

Stimulate, block, a persistent depolarization (i.e. nicotine)

Depolarizing agents cause an initial _____ (_____) of the receptor, followed by ________ (due to keeping receptor depolarized, and not able to repolarize for re-stimulation)

Stimulation (depolarization), Long-term blockade

Example of depolarizing blocker (one used still and one not):

Succinylcholine (anectine) still used (due to short duration; 1-2 min) and Decamethonium (not clinically used - experimental neuromuscular nicotinic blocker)

Histamine release: Moderate? Min - mod?

Succs: Mod, Cis (very minimal) and atracurium mild - mod (more dose dependant)

Genital tract: Predominant tone? Effects of ganglionic block?

Sympathetic & parasympathetic dec stimulation

Sweat glands: Predominant tone? Effects of ganglionic block?

Sympathetic (cholinergic) = Anhidrosis

Pancuronium: Most common effect?

Tachycardia due to blockade of muscarinic receptors. May be enhanced by other conditions such as age, electrolyte imbalance, and renal or hepatic failure

Why would Mecamylamine be a problem in patient's with previous MI? Glaucoma?

The heart's predominant tone is controlled via parasympathetic control = slower HR; if that is blocked the sympathetic takes over = tachy Glaucoma: dilation push against canal of Schlemm (drainage canal of aqueous humor)=> cannot drain, ^ IOP

What demonstrates the difference in physical layout of the two ACh sites on ganglionic and neuromuscular nicotinic receptors?

The number of Carbon spacing between the sites (decamethonium having a 10 carbon chain and hexamethonium having a 6 carbon chain

Mivacurium metabolized

plasma esterases

Mecamylamine shown to be useful in treating ______ & ______ addictions

some cocaine and nicotine

Succs can cause:

transient Brady w/ hypotension, cardiac arrhythmias, tachycardia, and possible cardiac arrest by increased vagal stimulation, -hyperkalemia -significant histamine release = BP drop esp in those more prone to it

The rapid depolarization and passage of an excitatory postsynaptic potential (EPSP) is due to: in which _____ rapidly enters the cell through the ligand gated channel

•Ganglia function is much more complex than the simple idea of a cholinergic nerve entering and acting on a ganglionic nicotinic receptor (neuronal). • Actually several receptors in ganglia. The nicotinic receptor (N2, ganglionic nAChR) (blocked by hexamethonium), Na+

Mecamylamine:

•Mecamylamine is a non-depolarizing blocker that acts at a secondary site (non-competitive) to decrease ACh binding (negative allosterism). •Only GB drug in market

Symptoms of ganglionic blockade, such as seen with hexamethonium include:

•increased bloodflow to the skin (warm and pink) -decreased sweating -inhibited lacrimation and salivation -mydriasis and cycloplegia -decreased GI tone and motility -hypotension -urinary retention, constipation, and hypoglycemia.