Batrachotoxin:

Na⁺ channel Activator

Mechanism: increases Na⁺ permeability, depolarizing, and inactivating the Na⁺ channels (can't fire signal)

Result: paralysis, respiratory failure, arrhythmias, cardiac arrest, and excessive ACh release

TTX (Tetrodotoxin)

Na⁺ channel blocker

Mechanism: blocks Na⁺ channel extracellularly

(can't fire signal)

Result: respiratory paralysis

Note: found in pufferfish, also can be used as treatment for Batrachotoxin

STX (Saxitoxin)

Na⁺channel blocker

Blocks it extracellularly (can't fire signal)

Result: Respiratory paralysis

Note: red tide, dinoflagellates

μ-conotoxin

Na⁺ channel blocker

Extracellular, (signal can't fire)

Results: respiratory paralysis

Cardiac glycosides

NKA (Na⁺-K⁺ pump) blocker

Cardiac glycoside -> inhib. NKA -> ↓[Na⁺]_e -> inhib. NCX (Na⁺-Ca⁺ exchanger) -> ↑[Ca²⁺]_i -> stronger contraction

Local anesthetics: e.g. cocaine, procaine, lidocaine, tetracaine

Intracellular Na⁺ channel blocker

signal can't fire, can't feel pain

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Na⁺ channel genetic defect (SCN4A): skeletal muscle

-> ↑[K⁺]_e -> channel can't inactivate/repolarize -> muscle reamins contracted -> muscle weakness

Aggravating factors: foods rich in K⁺ and vigorous exercise

Paramyotonia congenita (PMC)

Na⁺ channel genetic defect (SCN4A): skeletal muscle

-> ↑[K⁺]_e -> channel can't inactivate/repolarize -> muscle reamins contracted (prolonged contraction)-> excessive muscle excitability

Aggravating factors: cold temperature -> muscle stiffness ->repetitive firing of muscle action potentials

Potassium-aggravated myotonias (PAM)

Na⁺ channel genetic defect (SCN4A): skeletal muscle

-> ↑[K⁺]_e -> channel can't inactivate/repolarize -> muscle reamins contracted (prolonged contraction)->

muscle stiffness

Aggrevating factors: eating potassium-rich foods

long QT syndrome

Na⁺ channel genetic defect: cardiac muscle

or Kv channel genetic defect: cardiac muscle

Mutations in cardiac α subunit SCN5A (Na+ channel) or KCNQ1 (K+ channel), prolonged ventricular repolarization - arrhythmias

Mechanism (Na): incomplete inactivation – sustained Na+ influx, leads to longer QT-intervals in EKG

Mechanism (K): defective repolarization -> sustained heartbeats, asynchronous ventricular contraction

Generalized epilepsy w/ febrile seizures (GEFS)

Na⁺ channel genetic defect: neurons

Mutations in the gene encoding the β-subunit of the human neuronal Na+ channel (SCN1B)  ->

slows the rate of inactivation of the Na+ channel.

sulfonylureas (e.g. tolbutamide and glibenclamide)

K⁺-ATP channel blocker

-> more [K] intercellularly -> depolarization -> [Ca] channel stimulation -> more [Ca] intercellularly -> insulin release

CC: For patients with diabetes

Episodic ataxia type-1

Reducing K+ current (Kv channel)

-> prolonging action potential and inducing repetitive firing -> excessive and unregulated NT release.

Gene: KCNA1

Tissue: PNS and CNS

Minoxidil

Potassium-channel opener

in vascular smooth muscle -> hyperpolarizes -> closes Ca2+ channels -> dec. intracellular Ca2+. -> relaxes smooth muscle -> less contractile force, vasodilation

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treatment of cardiovascular disorders:

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Lambert-Eaten syndrome

Ca²⁺channel genetic defect

presynaptic blocker at NMJ

Immune system produces antibodies against these channels that somehow reduce the number of these channels to function in the depolarization-induced influx of Ca²⁺ for NT release

as opp. to Myastenia gravis, repetitive stimulation of motor nerve results in inc. in the strength of muscle contraction, sincle accumulation of Ca2+ ions

Hypokalemic periodic paralysis

Episodic ataxia type II

Sedative and hypnotic agents (e.g. benzodiazepines (diazepam = valium) and barbiturates (pentobarbital) )

Strychnine

[Cl-] channel blocker

seizures, muscular contractions, spasms, paralysis of respiratory muscles -> death

Myotonia Congenita

 [Cl-] channel genetic defect: Skeletal

-> unable to repolarize membrane -> repeated action potentials -> stiffness

Generalized myotonia

 [Cl-] channel genetic defect: Skeletal

-> unable to repolarize membrane -> repeated action potentials -> stiffness

Cystic Fibrosis

Cl^- channel genetic defect: Epithelial

CFTR is a camp-regulated Cl- channel; mutations in the channel don't allow Cl to leave the cell, resulting in thick mucous -> infection

KCl

Nernst Equation

E_A-E_B = 60 mV/z * log [X]_B/log[X]_A

Gibbs-Donnon Equilibrium

[K+]_A[Cl-]_A = [K+]_B[Cl-]_B

Takes into account large negative ions that are nonpermeable to membrane

Hereditary stomatocytosis

membrane (RBC) is 3 times more permeable to Na than normal

Na+ and water to accumulate in RBC and burst, burst spleen

Hypokalemia

 excessive hyperpolarization

↓[K+]_e -> excessive hyperpolarization -> a greater than normal stimulus is required for depolarization of the membrane in order to initiate an action potential

 caused by: long-term use of diuretics

-> fatigue, muscle weakness, weak, irregular pulse or arrhythmias

Hyperkalemia

Guillain-Barré syndrome, or

acute inflammatory demyelinating polyneuropathy (AIDP)

Multiple Sclerosis

amyotrophic lateral sclerosis  (ALS)

Tetanus exotoxin

Charcot-Marie-Tooth

Progressive degeneration of PNS (Cx32 -> gap junctions in Schwann cells)

hyperekplexia

Glycine receptor mutation

extremely startled by an unexpected noise or sight.

myasthenia gravis

Neuromuscular disorder that has CC for anesthetics

-blocks ACh binding and degrades ACh receptors

muscle relaxant -> blocks leftover ACh receptors -> paralysis -> stop breathing

exception: succinylcholine

-repetivtive stimulation of motor nerve results in decrease of strenth of muscle contraction (as opp. to Lambert-Eaten syndrome)

spinal muscular atrophy (SMA) and ALS

Neuromuscular disorder (loss of motor neurons->inc. of Ach receptors) that has CC for anesthetics

when succinylcholine is applied -> (since more Ach receptors) -> opens K+ channels and causes massive K+ release in serum -> stops heart

malignant hyperthermia

Neuromuscular genetic disorder that has CC for anesthetics, esp. succinylcholine

anesthetics -> Ca2+ influx -> persistent contraction and elevated temperature -> (since defect in ryanodine receptors leads to excessive Ca2+, overworking the reuptake of Ca²⁺ by SR-> ATP consumption -> heat)

Mutation in RYR1 gene

dantrolene treatment

GABA deficiency

-> lack of GABA-dependent inhibition of neural pathways

Black Widow Spider Toxin

presynaptic releaser of ACh NT

Causes an excessive release (and depetion) of vessicles (as opp. to botox)

Botulinus toxin (Botox)

presynaptic blocker of ACh release

blocks the release of vesicles => total blockade, paralysis of respiratory muscles, and death (as opp. to Black Widow Toxin)

Curare

post-synaptic blocker of ACh receptor

competitive inhibitor => decreases size of EPP => (high doses) respiratory paralysis => death

Succinylcholine

depolarizing blocker: binds to ACh receptor and causes persistant depolarization

=> densensitization/inactivation of ACh receptor => muscle paralysis

Cobra Toxin (α-bungarotoxin)

post-synaptic blocker: binds irreversibly and competitively to the acetylcholine receptor

found at the neuromuscular junction, causing paralysis, respiratory failure and death in the victim.

Neostigmine

Anticholinesterase (AChE inhibitor)

reversibly inhibits AChE

used to treat Myasthenia gravis -> enhances cholinergic (increases ACh) transmission in the CNS, ANS, and NMJ

Diisopropyl phosphorofluoridate (DFP)

Irreversible anticholinesterase (irreversibly binds AChE)

=>ACh persistance in synaptic cleft => prolonged/uncontrolled muscle contractions => paralysis (ACh receptors desensitized) => death

fibrodysplasia ossificans progressiva (FOP)

ossification of muslce, tendons, and CT

mutation in ACVR1 gene

Cerebral vasospasm

pathological smooth muscle contraction

=> narrowing of major cerebral arteries and ischemia

etiology: following a subarachnoid hemorrhage

treatment: mechanical dilation of the spastic cerebral arteries (no pharmacological solution available)

Asthma

inflammation/tightening muscles surrounding airways, fluid/mucus

treatment: smooth muscle relaxant

Lymphedema Distichiasis (LD)

Myofibroblasts in fibrosis

Myofibroblasts proliferation in...

1. cirrhosis of the liver (drinking/drugs)

2. fibrosis of the lung (smoking)

Atherosclerosis

Buildup of smooth muscle in the wall of the arteries

Hypertension

increased pressure in blood vessels (smooth muscle contraction)