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DRUGS AND TOXINS Spastic paralysis vs. flaccid paralysis 1 SPASTIC VS. FLACCID PARALYSIS • Flaccid paralysis is when the muscle cannot contract at all. The muscle stays weak and floppy. • Spastic paralysis is when the muscle stays in contraction. You still cannot move the muscle properly, but in this case, the muscle is too rigid. SODIUM VGC BLOCKERS • Lidocaine- used as topical anesthesia • Tetrodotoxin-puffer fish and newts (TTX) • Saxitoxin- caused by red tide; a type of red algae called dinoflagellates accumulates in shellfish (SXT) • Causes flaccid paralysis 3 SODIUM VGC BLOCKERS • Na VGC blockers will block the opening of the sodium, so you can’t have AP at all. Get flaccid paralysis. • When preparing a puffer fish for food, if the chef makes one nick in its liver, it will contaminate the whole meat with TTX toxin, which paralyzes the diaphragm. • Salamanders and newts have this toxin as well. Sometimes the toxins can get through the skin just by handling them; get tingling. Don’t lick a salamander! VESICLE BLOCKERS • Clostridium botulinum: • Bacterium that has a protease (enzyme that breaks down proteins). Botulinum breaks down the docking proteins that anchor vesicles to the cell membrane) • Inhibits ACh neurotransmitter release; muscles can’t contract. • Botulism is found in undercooked turkey and dented cans of food. If ingested orally, will paralyze the diaphragm; die of suffocation. • It causes flaccid paralysis • It is the muscle killer in “BOTOX” injections. The muscles die so the wrinkle lines relax. These small facial muscles can grow back in three months; need another shot. 5 MACH-R BLOCKER/ COMPETITOR • Atropine • Flaccid paralysis • Smooth muscle, heart, and glands 6 MACH-R BLOCKER/ COMPETITOR • These block the parasympathetic system, so the sympathetic gets more control. • Blocking the parasympathetic neurons will cause flaccid paralysis in the intestines. • If heart has stopped, inject atropine to block mACH receptors on cardiac muscles, and heart rate will increase. MACH-R BLOCKER/ COMPETITOR • Your iris has smooth muscle. If we block Ach, the muscles will pull, opening pupil. • Opium derivatives block muscarinic Ach receptors, causes dilated pupils. • Chemical warfare drugs that stimulate the muscarinic Ach receptors causes the parasympathetic system to gain more control; increase gut motility, sweat, diarrhea, salivation. A type of mushroom does this, too, and it can kill you. NACH-R BLOCKER/ COMPETITOR • Curare • From tree sap • Causes flaccid paralysis • Large dose: asphyxiation 9 NACH-R BLOCKER/ COMPETITOR • South American Indians use curare as a poison on the tips of arrows. Injecting it into the bloodstream causes death of the animal. However, the digestive system can deactivate it, so it is safe to eat an animal that was killed with curare. How does it kill? • Nicotinic Ach receptors (nACH-R) are mainly found in skeletal muscle. If you block them with curare, you block the ability for ionotropic receptors to open, so Na+ cannot move in. That blocks excitation, so muscle will not contract, and you get flaccid paralysis. ACHE (ACETYLCHOLINE ESTERASE) BLOCKERS • Neostigmine • Physostigmine • Spastic paralysis • These drugs are used to treat Myasthenia Gravis, an autoimmune disease that causes ptosis (droopy eyelid) 11 MYASTHENIA GRAVIS • Myasthenia Gravis (autoimmune disorder). The body’s antibodies attacks the nicotinic Ach receptors, so there are fewer of them, less Na+ coming in, fewer action potentials. • Symptoms usually begin in the eyelid and facial muscles, and manifests as drooping muscles on half or both sides of the face, drooping eyelids, and slurred speech. • Their eyelid muscles are often the first muscles to become fatigued. • To test for this, force open the eyelids, have them look up, and will quickly cause fatigue, and their lids will droop (ptosis). MYASTHENIA GRAVIS • Treatment is to give a medicine to inhibit ACh-ase. • That way, the ACh will not be deactivated and it can stay around longer to keep muscles contracting. Too much will cause spastic paralysis. • Neostigmine is an anti-cholinesterase drug which reduces the symptoms by inhibiting Ach-ase activity, preventing the breakdown of Ach. Consequently, Ach levels in the synapse remain elevated, so Ach is available to bind to those few functional Ach receptors that are left. • Neostigmine is reversible, so you need to keep taking it daily. It is therefore useful as a medicine. ACETYLCHOLINE ANTAGONISTS • Some INSECTICIDES inhibit acetylcholinesterase, so Ach accumulates in the synaptic cleft and acts as a constant stimulus to the muscle fiber. The insects die because their respiratory muscles contract and cannot relax. • Other poisons, such as CURARE, the poison used by South American Indians in poison arrows, bind to the Ach receptors on the muscle cell membrane and prevent Ach from working. That prevents muscle contraction, resulting in flaccid paralysis. IRREVERSIBLE ACHE INHIBITOR • Sarin gas • Spastic paralysis • Ventilator until AchE turnover • This is a permanent Ach inhibitor. The people who survive Sarin gas attack are hospitalized. They have to work to breathe (diaphragm stops working, so they use their abdominal muscles), so they need a ventilator and pressure chambers until there is a turnover in Ach after enough gene expression (takes a few weeks). 15 INHIBITORY NEURON BLOCKERS • Tetanus toxin • Blocks release of inhibitory neurotransmitters • Muscles can’t relax • Spastic paralysis • Opposing flexor and extensor muscles contract 16 INHIBITORY NEURON BLOCKERS • When you walk, it takes coordination with activating and inhibiting muscles. Extension of leg activates quadriceps and inhibits hamstrings. Where does this coordination originate? • The somatic motor neurons innervate these muscles. When it reaches threshold, will release ACh onto inhibitory neurons and excitatory neurons. This causes flexor muscles to contract and extensor muscles to relax, then viceversa, so you can walk. • If you have a toxin that prohibits release of inhibitory NT, then excitatory will override, and cause more muscle contraction. • That is what happens with tetanus toxin. When all of the NT is excitatory and none are inhibitory, all muscle groups contract, causing back arching, and diaphragm contracts too, and stays that way. Person dies from suffocation. • Treatment is Ach-ase blockers like Curare. But you have to be careful with that medicine…. Not just nicotinic, but muscarinic receptors also bind to ACh in skeletal muscle. Atropine will also help. SPIDER VENOM • Black widow: causes ACh release • Lack of inhibitory neurotransmitters • Spastic paralysis • Brazilian Wandering Spider (banana spider) • Spider venom increases nitrous oxide release • Most venomous of all spiders/ more human deaths 18 SPIDER VENOM • Spider venom works like tetanus toxin. • The Banana spider makes a lot of nitric oxide, which stimulates receptors of in penis, causing it to flood with blood, causing erection. • Pharmaceutical companies decided to modify this toxin and add it to Viagra, making the Viagra longer lasting. Spider venom and Viagra both work by blocking the enzyme that degrades nitric oxide.