NEUROTRANSMITTERS 1
NOTE ABOUT THIS LECTURE • This is a long, tough lecture at the end of the course, so you will be tested on it in segments: • Quiz 8 (slides 1 -54 = flashcards #1 -228) • Lecture exam 4 (all slides and flashcards) 2
Neuron Anatomy Soma (cell body) Axon (transmits signals) Axon hillock (trigger zone) Dendrites (receive signal) Synaptic knob (stimulates another cell) • Anatomy of a neuron –Dendrite - projections from the soma • the sensory portion of the neuron –Soma - main body of the neuron –Axon hillock- trigger zone –Axon - extends from soma to the knobs • the effector part of the neuron –Terminal bouton/synaptic knobs –Synaptic vesicles –Synaptic cleft 3
Function of Dendrites in Stimulating Neurons • Dendrites are spaced in all directions from the neuronal soma. – allows signal reception from a large spatial area providing the opportunity for summation of signals from many presynaptic neurons • Dendrites transmit signals after the opening of their LGC’s • LGC (Ligand-gated channels): these open when a ligand (neurotransmitter) binds to them. They do not need an action potential to open them. – LGC’s have receptors for neurotransmitters – LGC’s are located on dendrites Axon hillock LGC’s VGC’s 4
Types of Ligand Gated Channels (LGC’s) Many human diseases are associated with dysfunction of particular types of ion channels. Some Amino Acids have positive charges which repel ions with a positive charge. Some AA’s have negative charges and repel ions with a negative charge. Amino acids that make up the LGC’s therefore control ion selectivity (what ions may pass). Sodium (Na+) has its own LGC. So does potassium (K+) and Cloride (Cl-). -74 m. V Na+ LGC K+ LGC Cl- LGC 0 What would happen to the resting membrane potential if these channels opened? 5
• The Excitatory Postsynaptic Potential (EPSP) – Postsynaptic refers to the dendrite of the neuron receiving the signal. – The neurotransmitter binds to its LCG, which opens a Na+ ionophore. Na+ ions then rush to the inside of the cell membrane. They take their positive charge with them, so the inside of the cell membrane is now more positively charged than it was. – This increase in voltage above the normal resting potential (to a less negative value) is called the excitatory postsynaptic potential. – How many m. V do we need to reach threshold? Resting Membrane Potential is minus 74, and we need to get to +30 m. V to start an action potential. dendrite Na+: 20 m. Eq/L Membrane is somewhat depolarized, more likely to reach threshold soon. -74 plus +60 = -14 m. V +20 m. V axon -54 m. V 6
• The Inhibitory Postsynaptic Potential (IPSP) – A different NT lands on the dendrites and causes the K+ or Clchannels to open instead of Na+. – When a K+ channel opens, K+ rushes OUT of the cell, taking its positive charges with it. The inside of the cell membrane becomes MORE NEGATIVE. – When a Cl- channel opens, Cl- rushes INTO the cell, taking its negative charges with it. The inside of the cell membrane becomes MORE NEGATIVE. Both K+ and Cl- cause hyperpolarization of the neuron, making the neuron LESS likely to reach threshold. K+ : 4. 5 m. Eq/L Cl- : 107 m. Eq/L 20 m. V 8 m. V Losing +20 or gaining -8 m. V will both -74 plus the -94 m. V increase 20 =negativity of the charge inside the cell (hyperpolarization), making it 8 = -82 m. Vto reach threshold. -74 plus less likely axon 7
Whether a neuron “responds” or not, depends on temporal and spatial summation of EPSPs and IPSPs These channels open and close rapidly providing a means for rapid activation or rapid inhibition of postsynaptic neurons. There might be EPSP’s firing at the same time as IPSP’s. Add up all the charges from the excitatory and inhibitory potentials to see which one wins! Temporal summation: same presynaptic neuron fires repeatedly Spatial summation: additional presynaptic neurons fire 8
Spatial summation- stimuli from two different presynaptic neurons (different locations) 9
Stimulating an Excitable Cell (muscles, nerves, and glands) • Electrical stimulation (or even mechanical stimulation) can result in changes in voltage. • Depolarizing currents change the voltage on the membrane, bringing it toward threshold: –If stimuli are at threshold or above threshold stimuli, the result is an action potential. Excitatory and inhibitory neurons release their NT at the same time on the same neuron. The postsynaptic neuron has to summarize the input of positive and negative charges. If the overall effect is positive enough (+30 m. V), an action potential will begin. People with Parkinson’s disease have a problem coordinating the excitatory and inhibitory actions of their skeletal muscles. They have trouble starting and stopping any motion, and they shake at rest. 10
What happens at threshold? • • • At threshold, there is a temporary, short-lived membrane permeability change. The cell membrane becomes 40 x more permeable to Na+ and then quickly returns to previous state. How? By the opening and closing of Na+ voltage-gated channels (VGC), and they are located on the axon. Both VGCs and LGC’s allow Na+ into the cell. LGC’s do this when a ligand (neurotransmitter) binds to the cell membrane (like a key in the lock of the front door to your house). VGC’s do this when the voltage of the cell membrane goes from negative to +30 m. V (like when you push the button on your garage door opener). The VGC’s which are inhibitory of an action potential are those that open K+ and Cl- channels. These ions both increase the negative voltage of the cell membrane, making farther away from starting an action potential. The VGC’s that are excitatory are those that open Na+ or Ca++ channels. Both of these ions increase the positive voltage of the cell membrane. If the charge is enough to go from negative 74 m. V to +30 m. V, an action potential will be launched. 11
LGC and VGC Locations Axon hillock • LGC’s are on dendrites only. • VGC’s are on the axon, starting at the hillock and continuing to the synaptic knob. LGC’s VGC’s 12
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Ion channels Activation, Inactivation, deactivation closed Deactivation: Closed • Depolarization causes: but it also causes inactivation inactivated channels do not pass any ions (nonconducting state) By contrast, most K+ channels show activation and deactivation but not inactivation n n tiio za iz arr a oll po ep rre Na+ channels to activate (open) de po lar iz at ion inactivation open inactivated Activation: Open and working Inactivation: Open and not working 14 Copyright © 2006 by Elsevier, Inc.
Refractory Periods m. V 0 -40 Threshold -80 0 1 Absolute 2 3 4 5 msec Relative Because Na+ channels have an inactive phase, it causes a refractory period, which prevents a new action potential from starting right away. Refractory periods limit maximum frequency of action potentials (Aps) 15
Functions of action potentials • Information delivery to CNS Transfers all sensory input to CNS. Amplitude of the AP (how strong the AP is) does not change, but the frequency of APs varies. The frequency pattern is a code (like Morse Code) that transmits information about the stimulus (light, sound, taste, smell, touch) to the brain. • Rapid transmission over distance Neurons can rapidly fire thousands of times without depleting the sodium gradient. Note: speed of the Action Potential depends on the size of the neuron fiber and whether or not its axon is myelinated. The larger the neuron, the less resistance there is, so it is faster. The more lanes on the freeway, the faster you get home. Myelinated axons are also faster than unmyelinated. In non-nervous tissue, action potentials initiate a response. Muscle contraction Gland secretion 16
Figure 5 -17; Guyton & Hall Saltatory Conduction http: //www. brainviews. com/ab. Files/Ani Salt. htm The AP is a passive event: ions diffuse down their EC gradients when gated channels open. A “wave of depolarization” occurs along the neighboring areas. Occurs in one direction along the axon; actually, AP regenerates over and over, at each point by diffusion of incoming Na+ …. WHY? Refractory period (Na+ channels become inactivated). Saltatory Conduction This type of conduction is found with myelinated axons. AP’s only occur at the nodes (Na channels concentrated here!) increased velocity Na/K ATPase Pump energy conservation http: //www. youtube. com/watch? v= GTHWig 1 v. On. Y 17
Conduction velocity - non-myelinated vs myelinated - non-myelinated A neuron with myelin saves on ATP. A child under three should not be on a low fat diet because a lot of their myelin is being made during that time. 18
Multiple Sclerosis - MS is an autoimmune disorder where the body’s WBC’s destroy the myelin sheaths. - About 1 person per 1000 in US is thought to have the disease - The female-to-male ratio is 2: 1 - whites of northern European descent have the highest incidence http: //www. emedicine. com/pmr/topic 82. htm Copyright © 2006 by Elsevier, Inc. Patients have a difficult time describing their symptoms, which are bizarre and unrelated. Patients may present with paresthesias (tingling sensation) of a hand that resolves, followed in a couple of months by weakness in a leg or visual disturbances. Patients frequently do not bring these complaints to their doctors because they resolve. Eventually, the resolution of the neurologic deficits is incomplete or their occurrence is too frequent, and the 19 diagnosis of MS begins.
• Structures important to the function of the synapse: – presynaptic vesicles • contain neurotransmitter substances to excite or inhibit postsynaptic neuron The Synapse – mitochondria • provide energy to synthesize neurotransmitter • Membrane depolarization by an action potential causes emptying of a small number of vesicles into the synaptic cleft • Presynaptic membranes contain voltage - gated calcium channels. Voltage Gated Calcium Channel – depolarization of the presynaptic membrane by an action potential opens Ca 2+ channels Ca+2 – influx of Ca 2+ induces the release of the neurotransmitter substance (who let the dogs out? The milkman! The dogs are the NT, the milkman is the Ca 2+ channel) • Postsynaptic membrane contains receptor proteins for the transmitter released from the presynaptic terminal. 20
• Presynaptic neuron, axon: The VGCs allow Na+ to enter the inside of the cell membrane, then Na+ leaves again, and the AP is propagated (carried) down the length of the axon. • Presynaptic neuron, terminal knob: There are no more VGC’s for Na+. The VGC’s are now for Ca++. They let Ca++ into the interior of the cell. The Ca++ causes the vesicles in the knob to move towards the cleft and release their contents (the neurotransmitters) into the synaptic cleft. • Postsynaptic neuron, dendrite: The cell membrane on the dendrite contains proteins called LGC’s. The neurotransmitter attaches to them. This causes nearby VGC’s to open. If the VGC is excitatory (Golden retriever dogs with a key to unlock the door for you), a new AP begins in the postsynaptic cell. If the VGC is inhibitory, the AP will stop (Pit bull dogs that growl and keep you out of the house) In the meantime, an enzyme (dogcatcher) arrives at the synaptic cleft and deactivates the neurotransmitter. The mitochondria make more neurotransmitters (NT) and store them in new vesicles. Voltage Gated Sodium Channels (from hillock to end of axon) Voltage Gated Calcium Channels NT Ligand Gated Channels: Bind to NT and open nearby VGC’s Calcium 21
Synaptic Events -watch animation http: //highered. mcgraw-hill. com/sites/0072495855/student_view 0/chapter 14/animation__chemical_synapse__quiz_1_. html • Neurotransmitters (NT) are released and diffuse across synaptic cleft • NT bind to receptors (LGC’s) on the post-synaptic cell • The LGC opens, and ions diffuse in or out, depending on which LGC it is. The dogs either unlock the front door for you (Na+ gets in) or if inhibitory, it unlocks the door for K+ (gets out) or Cl(burglars get in) and the AP stops • The change in voltage causes depolarization or hyperpolarization • If depolarizing, called EPSP • If hyperpolarizing, called IPSP 22
NEUROTRANSMITTERS AND NEUROTRANSMITTER RECEPTORS We’re talking about signals and what they mean to a neuron! What happens if we block signals? 23
NEUROTRANSMITTERS 24
GENERAL SEQUENCE OF EVENTS AT CHEMICAL SYNAPSES • NT synthesis and storage in presynaptic cell • NT release by exocytosis (Ca++ triggered event) • Diffusion across cleft • NT reversibly binds to receptors (LGC) and opens gates, allowing ion diffusion • NT removal from synapse (destruction, diffusion away) or reuptake by presynaptic cell for recycling VOCC 25
NTS ACTION • NT diffuses across synaptic cleft to bind to receptor (LGC) on postsynaptic membrane • Can generate an electric signal there (EPSP’s or IPSP’s) • These are graded potentials (the more channels that are opened, the more the charge changes) • Effect depends which ions are allowed to diffuse across membrane, how many and for how long. Effect depends on the selectivity of the channel. • What if the LGC are…. . • Na+ selective • K+ selective • Cl- selective • What happens to the voltage on the postsynaptic cell? Is it an EPSP or an IPSP? 26
NEUROTRANSMITTERS (NTS) • NTs are present within the presynaptic neuron • They are released in response to presynaptic depolarization, which requires calcium • Specific receptors must be present on the postsynaptic cell • NT must be removed to allow another cycle of NT release, binding and signal transmission • Removal: reuptake by presynaptic nerve or degradation by specific enzymes or a combination of these 27
SYMPATHETIC AND PARASYMPATHETIC NERVOUS SYSTEM • • Sympathetic Neurons Increased heart rate and blood pressure Decreased food digestion “Fight or Flight” • • Parasympathetic Neurons Decreased heart rate and blood pressure Increased food digestion “Rest and Digest” Notice that the heart is innervated by both sympathetic and parasympathetic neurons…. 28
SYMPATHETIC AND PARASYMPATHETIC NEURONS • If an organ is dually innervated by sympathetic and parasympathetic nerves, how will the organ know if sympathetic or parasympathetic is barking louder? The receptors that have the most transmitter bound will cause the biggest result. • The heart has receptors that allow both para and sym to have effects. A lot of organs are dually innervated so they can adjust their physiology. • Furthermore, a sympathetic neuron cause excitation in one organ and inhibition in another organ. A parasympathetic neuron can also cause excitation in one organ and inhibition in another 29 organ.
SYMPATHETIC AND PARASYMPATHETIC NEURONS • There are two faucets in your bathroom (hot and cold), turn both on halfway, and water is lukewarm. To make it hot, either turn up hot water or turn down cold water, or both. If we suppress the parasympathetic system (cold water), the sympathetic system (hot water) will gain more control. If you stimulate the parasympathetic system, it will gain control. Parasympathetic and sympathetic neurons both fire onto the same organ at the same time. The question is when does the sympathetic system have more control? When does the parasympathetic system have more control? • If a particular drug mimics the parasympathetic system, then the parasympathetic system has more control. What effect does that have? The heart rate will be slower. If sympathetic is stronger, how will body act? Heart rate increases. • We can completely shut down parasympathetic and rev up sympathetic. In an ER show, when the patient’s heart stops, they get the epinephrine and get the atropine. The epinephrine is stimulating the sympathetic system and the atropine is blocking the parasympathetic system (shutting off the antagonist). 30
HEART TRANSPLANT PROBLEM • When you take out a heart, the nerves that innervate the heart are cut out too. There is no way to suture back the nerves when you put in a new heart. • The new heart will have a faster heart rate because cardiac cells like to beat fast. The parasympathetic neurons cause the heart rate to slow, but they are now cut. • The post-op patient cannot allow themselves to become overly anxious, angry, or sexually aroused after heart transplant. • When they have those emotions, the sympathetic system can still release epinephrine because it is a hormone, not a nerve. Epinephrine is made by adrenal glands and circulates in the blood. However, the patient no longer has parasympathetic neurons attached to the heart to counter the effects of epinephrine. • It will therefore take them a long time to calm down from the effects of epinephrine due to anger, anxiety, etc, because they have to wait for the epinephrine to be metabolized. There are no parasympathetic hormones to calm you down. • How can we use the parasympathetic system to make the heart cells less active? Use a medicine to open the potassium (K+) channels, making the inside of the cell more negative (hyperpolarized). The number one way heart 31 rate (HR) is regulated is by potassium.
CLASSIFICATION OF NTS • Chemical Classification • Large Molecule • Peptides • Small Molecule • Cholinergic (Ach) • Catecholamines • Adrenergic • Dopaminergic • Serotonergic • Amino Acid NT’s • Functional Classification • Metabotropic • Ionotropic 32
CHEMICAL CLASSIFICATION 1) Large Molecule (Peptide) NTs • ADH (anti-diuretic hormone, aka vasopression); increases blood volume/blood pressure • Angiotensin; vasoconstriction (raises BP) • Bradykinin; vasodilation (lowers BP) We will talk about large molecule NTs in later lectures. This lecture will focus on small molecule NTs. 2) Small Molecule NTs • Cholinergic (Acetylcholine; ACh) • Catecholamines • Amino Acid Neurotransmitters 33
SMALL MOLECULE NEUROTRANSMITTERS Irish setter dog named Coleen • Cholinergic • Acetylcholine (ACh) • m. ACh • n. ACh Dog goes to muscle man or smoker house Go to the catacombs: three tunnels to choose CATECHOLAMINES Adrenergic catecholamines: • Norepinephrine Add a nerd: Twin • Epinephrine hyperactive boys Dopaminergic catecholamine: • Dopamine (inhibitory) • Amino Acid NTs Sneak some dope • Glutamate Glues sparkles Serotonergic catecholamine: • GABA (inhibitory) Don’t want to • Serotonin do anything Take a nap with Sara • Glycine (inhibitory) 3 mean old sisters Neurons that make acetylcholine are called Cholinergic neurons. Neurons that make epinephrine or norepinephrine are called Adrenergic neurons Neurons that make dopamine are called Dopaminergic neurons 34 Neurons that make serotonin are called Serotonergic neurons
ACETYLCHOLINE (ACH) • Neurons that use this NT are called cholinergic neurons. • All skeletal muscle is innervated by cholinergic neurons. • Also used by sympathetic and parasympathetic neurons • Ach is removed from the synaptic cleft by the enzyme Acetylcholine esterase (ACh. E) 35
GLUTAMATE • Very important in CNS • Nearly all excitatory neurons use it • Too much glutamate (stroke) causes excitotoxicity due to unregulated calcium influx • Antagonists to Glutamate receptor help stop neuronal death after stroke • Too little glutamate leads to psychosis (delusional, paranoid, lack of contact with reality) 36
GLUTAMATE • Dangerous: someone with stroke or trauma releases a lot of NTs, causes damage to undamaged neurons, The healthy neurons are being over stimulated, too much calcium, causes cytotoxicity. Too much NT can kill the cell. • Only 10% of people with Parkinson’s and Alzheimer’s are caused by bad genes; the rest are caused by calcium dyshomeostasis (The calcium is not being monitored properly in the body). • Those who have stroke are given a glutamate antagonist to protect them. • If you don’t have enough glutamate, inhibitory NTs will gain momentum. • Too little glutamate leads to psychosis, perceives reality differently than normal. 37
GABA AND • Major inhibitory neurotransmitter in CNS Decreased GABA causes seizures Anticonvulsants target GABA receptors or act as GABA agonists Benzodiazepines (valium) and ethanol (drinking alcohol) both trigger GABA receptors……use benzodiazepines during alcohol detox. GLYCINE • Glycine- also inhibitory • Mostly in spinal cord and brainstem motor neurons http: //pharma 1. med. osaka-u. ac. jp/textbook/Anticonvulsants/GABA-syp. jpg 38
GABA • Alcohol stimulates GABA receptors, so you are causing IPSPs, reflexes slow down, reach threshold less quickly. They have to work at overcome their lazy tongue to get words out. • When they try to stop drinking all at once, the excitatory NTs gain control, and they get tremors, seizures, and visual overstimulation. Need benzodiazepam (valium) while weaning off the alcohol. • GABA agonists (drugs that act like GABA, such as anti-convulsants) can also be given. 39
GABA • Benzodiazepines (such as valium) enhance the effect of gamma-aminobutyric acid (GABA), which results in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic action. • These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. • However, valium is highly addictive. 40
SMALL MOLECULE NEUROTRANSMITTERS • Cholinergic • Acetylcholine (ACh) • m. ACh • n. ACh • Amino Acid NTs • Glutamate • GABA (inhibitory) • Glycine (inhibitory) CATECHOLAMINES Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine (inhibitory) Serotonergic catecholamine: • Serotonin Neurons that make acetylcholine are called Cholinergic neurons. Neurons that make epinephrine or norepinephrine are called Adrenergic neurons Neurons that make dopamine are called Dopaminergic neurons Neurons that make serotonin are called Serotonergic neurons 41
CATECHOLAMINES • These are released by adrenal glands (on top of the kidney) in response to stress; they are part of the sympathetic nervous system (fight or flight). They circulate in the bloodstream. • Removed by reuptake into terminals via sodium dependent transporter • Mono-amine oxidase (MAO) is an enzyme that degrades catecholamines. Therefore, an MAO inhibitor will allow catecholamines to excite the nervous system. • Anti-anxiety and anti-depression medicines are MAO-inhibitors • DO NOT MIX SYMPATHOMIMETIC (those that imitate catecholamines) WITH MAO INHIBITORS. It doubles the excitatory effect in the nervous system and can be deadly. • Examples of Sympathomimetic are medicines for cardiac arrest, low blood pressure, and some meds that delay premature labor. • MAO inhibitors plus sympathomimetics allow the excitatory effect of fight-or-flight to continue to excess, and the person’s blood pressure goes up to a crisis level. • In other words, don’t mix anti-depressant meds with meds for cardiac arrest, low blood pressure, and some meds that delay premature labor. 42
CATECHOLAMINES • Epinephrine (“above the kidney”) • Epinephrine is secreted by the adrenal gland, which sits above the kidney. • It’s action is excitatory (fight or flight) • Norepinephrine is secreted by neurons from CNS and by neurons in sympathetic ganglia • Its action is mainly excitatory, can be inhibitory. • Dopamine • Secreted by neurons in CNS • Its action is inhibitory • Epi and norepi are made from dopamine • Serotonin • Secreted by neurons in the CNS • Its action is mainly excitatory. It can excite one cell but inhibit another. 43
DOPAMINE • Parkinson’s Disease (Parkinsonism) • Loss of dopamine (inhibitory) from neurons in substantia nigra of midbrain • Resting tremor, “pill rolling”, bradykinesia (slow walking) gait • Treat with L-dopa. (Crosses BBB) or MAO inhibitors • Side effects (hallucinations, motor problems) The Case of the Frozen Addicts, by Langston, J. W 44
BRAIN REGIONS • The motor cortex is the region of the brain that contains the upper motor neurons that move the muscles of the skeleton. • The basal nuclei region of the brain (between the corpus callosum and thalamus) inhibits some motor neurons so that unwanted body movements do not occur. The basal nuclei regulate stopping, starting, and coordination of movements. The basal nuclei are inhibitors of movement. They are like strict parents that tie their kids up to keep them from doing wild things. • The substantia nigra region of the brain secretes dopamine, which inhibits the basal nuclei (it inhibits the inhibitor). Thus, the excitatory neurons can make the body move. The substantia nigra and Dopamine are like social workers who tell the parents (basal nuclei) not to be so restrictive with the kids. With the inhibitor out of control, the kids throw a house party. 45
BRAIN REGIONS • If the substantia nigra (the social worker) is damaged (no more dopamine), the basal nuclei (the parents) are no longer inhibited. So the parents stay home and tie the kids up to keep them from moving throwing a party. This is the problem in Parkinson’s disease. • If the basal nuclei (the parents) are damaged (social worker is controlling them too much) the patient will have excessive movement. This is Huntington’s disease. • Thus, there are two ways the basal nuclei (the parents) can be a problem: either the basal nuclei themselves are dysfunctional (not enough inhibition of movement; the parents leave town and the kids throw a party; Huntington’s disease), or the dopamine levels (the social worker) are too low the parents are too strict and tie the kids up; Parkinson’s disease). 46
PARKINSON’S DISEASE • Parkinson’s Disease is a problem in the substantia nigra region of the midbrain; that area secretes dopamine. • People with Parkinson’s disease lack dopamine (the social worker), so the basal nuclei (the parents) inhibit body movements. • Therefore, the patient has trouble initiating body movements. They also develop a “pill rolling” tremor at rest. • Parkinson’s Disease symptoms are the opposite of Huntington’s disease. • Parkinson’s Disease patients cannot initiate movements. • Huntington Disease patients have sudden, jerky movements. 47
HUNTINGTON’S DISEASE • Huntington’s disease: rapid, jerky motions. • Since the basal nuclei are damaged, the inhibition of the motor cortex is removed, so excitatory neurons go unchecked, and the person has sudden jerky movements. Their body writhes around like they are dancing (chorea). • Other symptoms include cognitive decline and psychiatric problems. • Huntington’s disease is hereditary (50% chance of each child getting it if one parent has it). • Age of onset is usually 35 -45 years of age, so symptoms do not manifest until after they have 48 children and pass on the bad gene.
DOPAMINE • Using too much of the drug “Meth” will kill Dopaminergic neurons, causing Parkinson’s symptoms. • Dopamine is used in the substantia nigra portion of the midbrain where excitatory and inhibitory neurons need to integrate. • If you lose excitatory neurons, you will gain inhibitory stimulus. • Parkinson’s patients have problems starting movements, and coordinating the excitatory/inhibitory stimulus to muscles while walking. Stopping motions is also hard. They need a trained dog to pull them up from a seated position and help them to take the first step, and to stop them when they want to stop. • Treatment is an MAO inhibitor or L-dopa, which can cross BBB, unlike dopamine. Cells can convert L-dopa to the required dopamine earlier on in the disease, but as cells die later, they cannot perform this conversion. • Stem cells can be injected to cause the remaining neurons to replicate and help them get more control. 49
SEROTONIN • Synthesized from the amino acid tryptophan (found in turkey) • Mood elevator, “feelgood” neurotransmitter • Serotonin reuptake inhibitors (get rid of the dog catcher so the dog can stay longer) are anti-depressant drugs • Ecstasy causes more release! 50
SEROTONIN • At certain times of the day you get your serotonin surge. Some are morning people, some are night people. • If you take an SSR inhibitor, it helps serotonin to stay in cleft longer, feel good longer. • These types of drug are prescribed for depression. • The street drug, Ecstasy, mimics serotonin. If you meet someone while taking Ecstasy, you will fall in love. Better wait six months for it to clear out your system before you marry them! 51
DISORDER OF PHENYLALANINE METABOLISM PHENYLKETONURIA (PKU) • Catecholamines (such as epinephrine) are derived from the amino acid tyrosine. • PKU is a genetic, autosomal recessive disorder (1: 20, 000 births) • Lack of enzyme phenylalanine hydroxylase • Inability to convert phenylalanine (aa) from the diet to tyrosine (aa) • Without this enzyme, waste products (ketones) build up in the blood and are toxic to neurons. The ketones are spilled in the urine as well. Symptoms are seizures, poor motor development and mental retardation in a developing child. phenylalanine Phenylalanine hydroxylase Tyrosine Phenylalanine TYROSINE L-DOPA dopamine norepinephrine 52
DISORDER OF PHENYLALANINE METABOLISM PHENYLKETONURIA (PKU) • Routine testing at birth by heel stick blood sample • Prevented by dietary restriction of phenylalanine (PHE), which is often found in diet sodas and other things with artificial sweeteners. • No whole protein during childhood, while nervous system is developing (until age 20), otherwise, they will become retarded. • After that, the person can go off the diet, but the ketones will begin to accumulate. When they start to feel sluggish, and can’t finish a task on time, they need to go back on the diet for a while. • A woman must stay on the diet during pregnancy or the ketones will cross the placental and kill the neurons of her baby. • Artificial sweeteners such as Sweet N Low, and diet sodas are high in phenylalanine, and must be avoided in PKU patients. • This genetic condition is more likely to occur if you have a child 53 with your first cousin (or closer relative)
EFFECTS OF CNS NEUROTRANSMITTERS 54
End of material for Quiz 8 RECEPTORS FOR NEUROTRANSMITTERS 55
SMALL MOLECULE NEUROTRANSMITTERS • Cholinergic • Acetylcholine (ACh) • m. ACh • n. ACh • Amino Acid NTs • Glutamate • GABA (inhibitory) • Glycine (inhibitory) CATECHOLAMINES Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine (inhibitory) Serotonergic catecholamine: • Serotonin 56
WAYS TO CLASSIFY NT RECEPTORS • Functional Classification • Ionotropic • Metabotropic • Structural Classification • ACh Receptors • Muscarinic ACh receptors • Nicotinic ACh receptors • Adrenergic Receptors • Alpha 1 and Alpha 2 receptors • Beta 1 and Beta 2 receptors • Dopaminergic Receptors • Serotonergic Receptors • Glutamate, GABA, and Glycine Receptors 57
FUNCTIONAL CLASSIFICATION OF NT RECEPTORS • Ionotropic receptors bind to a NT and have a channel that extends into cell. They are the receptor and the transporter • Metabotropic receptors need a series of enzymatic actions to change a gated channel somewhere else. The binding of the NT outside of the cell activates a G-protein on the inside of the cell which breaks apart into two pieces. One of those pieces goes somewhere else in the membrane to open up another channel. • G protein receptors are involved in many diseases, and are also the target of approximately 30% of all 58 modern medicinal drugs.
Ionotropic Metabotropic 59
G-PROTEINS • When the G-Protein is activated, it breaks into two pieces. One of the pieces is called the second messenger, which is the part that opens the nearby ion channel. • It also activates other enzymes inside the cell which may cause various changes. • These changes include activation of gene transcription (to form new proteins, changing the metabolism; used especially in making new memories) 60
Receptor Types • Some of the cell membranes in the body have receptors which are activated by voltage, like when the owner of a house comes home and enters by clicking the garage door opener. • Some receptors are activated by a ligand, which is like a key that fits exactly into a specific lock. It is like the owner of a house coming home and enters by using a key on the front door. • Thyroid Stimulating Hormone (TSH) from the pituitary gland acts as a ligand on the thyroid gland cell. It causes activity in the thyroid gland, and the gland produces thyroid hormone. 61
LIGAND RECEPTORS USE G-PROTEINS • When TSH acts as a ligand to bind to the cell membrane, it activates the “Butler” protein, called a G-protein on the inside of the cell. • The G-protein breaks apart into two pieces. One of those pieces goes somewhere else in the membrane to change the activity in the cell. • It is like the owner of a mansion who comes home, puts his key in the lock of the front door, and twin butlers greet him at the door. One of the butlers holds the door open for the owner while the other (called the second messenger) runs off and tells the other servants in the house that the master has arrived, so get busy! 62
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G PROTEINS • Step 1: Ligand binds to receptor • Step 2: The G proteins activate • Step 3: Second messenger activates another protein called the late effector protein • Step 4: A protein kinase in the thyroid gland cell becomes activated. • We ultimately want kinase activity, which phosphorylates (puts a phosphate molecule on) other proteins in a cell. • This increases the activity level of the cell. • The servants of the mansion get busy! 64
SEQUENCE OF EVENTS OF A METABOTROPIC RECEPTOR • Step 1: NT binds to receptor • Ach binds to muscarinic receptors • Norepi and epi bind to adrenergic receptors • Step 2: The G proteins activate • The G-protein (used by both muscarinic and adrenergic receptors) is found inside every cell of the body. There are different types of G proteins; either GS (stimulating G protein) or GI (inhibiting G protein). GS means the G protein will lead to events that lead to an increase in activity in the cell. We will only focus on these. You will hear about the GI proteins in pharmacology. • Step 3: Second messenger activates another protein called the late effector protein • G-Proteins of sympathetic s neurons activate protein kinase A • G-Proteins of parasympathetic s neurons activate protein kinase B 65
SMALL MOLECULE NEUROTRANSMITTERS • Acetylcholine (ACh) • m. ACh (“cholinergic”) • n. ACh (“cholinergic”) • Amino Acid NTs • Glutamate • GABA (inhibitory) • Glycine (inhibitory) Catecholamines Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine Serotonergic catecholamine: • Serotonin IONOTROPIC RECEPTORS ARE IN RED METABOTROPIC RECEPTORS ARE IN BLACK 66
STRUCTURAL CLASSIFICATION OF NT RECEPTORS • • • Two Types of ACh Receptors (Acetylcholine) Muscarinic ACh receptors Nicotinic ACh receptors Two Types of Adrenergic Receptors (epi and norepi) Alpha adrenergic receptors • Alpha 1 receptors • Alpha 2 receptors • Beta adrenergic receptors • Beta 1 receptors • Beta 2 receptors • There also receptors for Dopamine, Serotonin, Glutamate, GABA, and Glycine, but we will not cover them. 67
ACH RECEPTORS • Muscarinic ACh receptors (m. ACh. R) • more sensitive to muscarine than to nicotine • Muscarinic substances activate the parasympathetic nervous system (rest and digest). Increased saliva, tears, diarrhea. • Antidote for overdose is atropine. • They use G-proteins to activate a nearby ion channel • Nicotinic ACh receptors (n. ACh. R) • more sensitive to nicotine than to muscarine • They do not use G-proteins; they open ion channels directly • Both Muscarinic and nicotinic receptors are found on skeletal muscle, which contract when ACh binds there. These receptors are also found in the CNS. 68
MUSCARINIC ACETYLCHOLINE RECEPTORS • All m. ACH receptors use the G-proteins, so their functional classification is “metabotropic”. Drugs that block the m. ACh receptor include: Medicines that treat Parkinson's disease Atropine (to dilate the pupil for eye exam) Scopolamine (to prevent motion sickness) Ipratropium (treatment of COPD) Amanita muscaria, the mushroom from which muscarine was first isolated. 69
The G-protein can be excitatory or inhibitory, depending on which ion channel it opens. 70
NICOTINIC ACETYLCHOLINE RECEPTORS • All n. ACH receptors use a ligand-gated ion channel mechanism. • The opening of an ion channel, permits either K+, Na+, Cl- or Ca++ to diffuse into or out of the cell. • If a K+ channel opens, K+ will leak out of the cell. If the Clchannel opens, Cl-, it will leak into the cell. Both of these outcomes will make the inside of the cell more negative, so it will inhibit an action potential (inhibitory). GABA, Glycine and Dopamine are the NT’s that will do this. • If a Na+ or Ca++channel opens, those will leak into the cell, bringing their positive charges with them, causing an action potential (excitatory). Glutamate, serotonin, and ACH using a n. ACH receptor will do this. • The functional classification of all n. ACH receptors is “ionotropic”. 71
IONOTROPIC RECEPTORS Nicotinic ACH Serotonin Glutamate GABA These use an ionizer to freshen the air! Glycine 72
SMALL MOLECULE NEUROTRANSMITTERS • Acetylcholine (ACh) • m. ACh (“cholinergic”) • n. ACh (“cholinergic”) • Amino Acid NTs • Glutamate • GABA (inhibitory) • Glycine (inhibitory) Catecholamines Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine Serotonergic catecholamine: • Serotonin IONOTROPIC RECEPTORS ARE IN RED METABOTROPIC RECEPTORS ARE IN BLACK 73
WHAT NEURONS SECRETE ACH? • Somatic motor neurons to skeletal muscle use ACH • What about the ANS motor neurons? They have TWO lower motor neurons: pre and post ganglionic. • All ANS preganglionic neurons (sympathetic and parasympathetic) and postganglionic parasympathetic neurons secrete Ach, using nicotinic receptors there. • About 98% of postganglionic sympathetic neurons secrete norepi and use an adrenergic receptor, but 2% of postganglionic sympathetic neurons secrete Ach (those that supply the sweat glands), and use muscarinic receptors. 74
Somatic Nervous System Nicotinic (Ionotropic) Muscarinic (Metabotropic) Nicotinic (Ionotropic) ACh Adrenergic (Metabotropic) Muscarinic (Metabotropic) 2% Sweat Glands 98% Cardiac muscle Smooth muscle Glands Cardiac muscle Smooth muscle Skeletal muscle 75
EFFECTS OF NICOTINE • Acts as a stimulant: increases dopamine (in the reward center of the brain), which causes euphoria and relaxation, and it is addictive. • Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle. • Tobacco smoke contains MAO inhibitors (antidepressant medicine). MAO enzymes break down dopamine, norepinephrine, and serotonin. Smoking prevents the breakdown of these neurotransmitters so they stay longer, stimulating the reward centers in the brain. • This contributes to the addictive properties of 76 tobacco.
NICOTINIC RECEPTORS • Nicotinic acetylcholine receptors can be blocked by curare, hexamethonium and toxins present in the venoms of snakes and shellfishes, such as αbungarotoxin. Drugs such as the neuromuscular blocking agents bind reversibly to the nicotinic receptors in the neuromuscular junction and are used routinely in anesthesia. • Nicotinic receptors are the primary mediator of the effects of nicotine. In myasthenia gravis, the receptor at NMJ is targeted by antibodies, leading to muscle weakness. Muscarinic acetylcholine receptors can be blocked by the drugs atropine and scopolamine. 77
SMALL MOLECULE NEUROTRANSMITTERS • Acetylcholine (ACh) • m. ACh (“cholinergic”) • n. ACh (“cholinergic”) • Amino Acid NTs • Glutamate • GABA (inhibitory) • Glycine (inhibitory) Catecholamines Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine Serotonergic catecholamine: • Serotonin IONOTROPIC RECEPTORS ARE IN RED METABOTROPIC RECEPTORS ARE IN BLACK 78
ADRENERGIC RECEPTORS • Alpha adrenergic receptors • Alpha 1 receptors • Causes vasoconstriction • increases blood pressure • Decreases GI motility • Alpha 2 receptors • Causes vasodilatation • decreases blood pressure • Decreases GI motility • Beta adrenergic receptors • Beta 1 receptors • Increases heart rate • Increases cardiac output • Beta 2 receptors • Causes vasodilatation • Decreases blood pressure • Opens bronchioles • Decreases GI motility All of these receptors use G-Protein (the functional classification is metabotropic) 79
Alpha 1 What effect? 1) blood vessels 2) Blood pressure 3) GI motility 80
ALPHA 2 What effect? 1) blood vessels 2) Blood pressure 3) GI motility Ran out of food! No GI motility 81
BETA 1 What effect on the paramedic? 1) Heart rate 2) Cardiac output 82
BETA 2 BETTER APPLEBEE’S: NON-SMOKING PLACE, CAN BREATHE BETTER What effect? 1) blood vessels 2) Blood pressure 3) GI motility 4) Bronchioles Ran out of food! No GI motility 83
SMALL MOLECULE NEUROTRANSMITTERS • Acetylcholine (ACh) • m. ACh (“cholinergic”) • n. ACh (“cholinergic”) • Amino Acid NTs • Glutamate • GABA (inhibitory) • Glycine (inhibitory) Catecholamines Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine Serotonergic catecholamine: • Serotonin IONOTROPIC RECEPTORS ARE IN RED METABOTROPIC RECEPTORS ARE IN BLACK 84
Ionotropic Metabotropic 85
METABOTROPIC RECEPTORS WHICH ARE METABOTROPIC Muscarinic Acetylcholine receptors Mostly used by post-ganglionic parasympathetic neurons Alpha and Beta-Adrenergic receptors Mostly used by sympathetic neurons Dopaminergic receptors Mostly used by sympathetic neurons Who lives in the mansion with the butler (metabotropic) and who uses the ionizer to freshen the air (ionotropic)? 86
Small Molecule Neurotransmitters • Acetylcholine (ACh) – m. ACh (“cholinergic”) – n. ACh (“cholinergic”) • Amino Acid NTs – Glutamate – GABA (inhibitory) – Glycine (inhibitory) Catecholamines Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine Serotonergic catecholamine: • Serotonin IONOTROPIC RECEPTORS ARE IN RED METABOTROPIC RECEPTORS ARE IN BLACK 87
Somatic Nervous System Nicotinic (Ionotropic) Muscarinic (Metabotropic) Nicotinic (Ionotropic) ACh Adrenergic (Metabotropic) Muscarinic (Metabotropic) 2% Sweat Glands 98% Cardiac muscle Smooth muscle Glands Cardiac muscle Smooth muscle Skeletal muscle 88
ADRENERGIC RECEPTORS • Alpha adrenergic receptors • Alpha 1 receptors • Causes vasoconstriction • increases blood pressure • Decreases GI motility • Alpha 2 receptors • Causes vasodilatation • decreases blood pressure • Decreases GI motility • Beta adrenergic receptors • Beta 1 receptors • Increases heart rate • Increases cardiac output • Beta 2 receptors • Causes vasodilatation • Decreases blood pressure • Opens bronchioles • Decreases GI motility All of these receptors use G-Protein (the functional classification is metabotropic) 89
DRUGS AND TOXINS Spastic paralysis vs. flaccid paralysis 90
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. 91
VESICLE BLOCKERS • Clostridium botulinum: • Bacterium that has a protease (enzyme that breaks down proteins) called botulism. Botulinum breaks down the docking proteins that anchor NT 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. It is also used for migraines. 92
SODIUM VGC BLOCKERS • Lidocaine- used as local anesthesia • Tetrodotoxin(TTX)puffer fish and newts • Saxitoxin(SXT) - caused by red tide; a type of red algae called dinoflagellates accumulates in shellfish • Curare: poison arrows All these cause flaccid paralysis 93
SODIUM VGC BLOCKERS • Na+ VGC blockers will block the sodium channel, 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! 94
SODIUM VGC BLOCKER • Curare • n. ACH-R blocker/ competitor • From tree sap • Causes flaccid paralysis • Large dose: asphyxiation 95
CURARE • 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 (n. ACH-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. This is considered a Na+ VGC blocker. 96
MACH-R BLOCKER/ COMPETITOR • Atropine • Flaccid paralysis • Smooth muscle, heart, and glands m. ACH receptors are metabotropic (use the G protein), so atropine blocks the Na+ VGC indirectly. 97
MACH-R BLOCKER/ COMPETITOR • Atropine and other m. ACH-R blockers are not classified as a Na+ VGC blocker because they use m. ACH receptors, which are metabotropic (use the G protein), so atropine blocks the Na+ VGC indirectly. • Only substances that use ionotropic receptors (such as n. ACH) can block the Na+ VGC directly. Examples are lidocaine, tetrodotoxin, saxitoxin, and curare. Atropine is not in this category, even though all of them result in flaccid paralysis because of the sodium channel being blocked. 98
MACH-R BLOCKER/ COMPETITOR • m. ACH receptor blockers will block the parasympathetic system, so the sympathetic gets more control. • Blocking the parasympathetic neurons (e. g. atropine for pre-op med) will cause flaccid paralysis in the intestines. That’s why a patient who had a general anesthetic cannot go home until after sounds of peristalsis are auscultated. • If heart has stopped, inject atropine to block m. ACH receptors on cardiac muscles, and heart rate will increase. 99
MACH-R BLOCKER/ COMPETITOR • Your iris has smooth muscle. If we block Ach, the muscles will pull, opening pupil. • Opium derivatives (morphine) block muscarinic Ach receptors, causes dilated pupils. • m. ACH-R stimulator: 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. 100
ATROPINE • Atropine is a competitive muscarinic acetylcholine receptor antagonist. It is a naturally occurring alkaloid extracted from the deadly nightshade plant (Atropa belladonna). • • The species name "belladonna" ("beautiful woman" in Italian) comes from the original use of deadly nightshade to dilate the pupils of the eyes for cosmetic effect. Both atropine and the genus name for deadly nightshade derive from Atropos, one of the three Fates who, according to Greek mythology, chose how a person was to die. 101
ATROPINE • In general, atropine counters the "rest and digest" activity of glands regulated by the parasympathetic nervous system. This occurs because atropine is a competitive antagonist of the muscarinic acetylcholine receptors. Atropine dilates the pupils, increases heart rate, and reduces salivation and other secretions. • It is often given as a pre-op med to dry out secretions before a general anesthetic. 102
ATROPINE • Secretions and bronchodilatation • Atropine's actions on the parasympathetic nervous system inhibit salivary and mucus glands. The drug may also inhibit sweating via the sympathetic nervous system. This can be useful in treating hyperhidrosis, and can prevent the death rattle of dying patients. Even though atropine has not been officially indicated for either of these purposes by the FDA, it has been used by physicians for these purposes. 103
ATROPINE • Atropine is not an actual antidote for organophosphate poisoning such as insecticides and sarin gas. However, by blocking the action of acetylcholine at muscarinic receptors, it serves as a treatment for poisoning by these toxins. • Troops who are likely to be attacked with chemical weapons often carry autoinjectors with atropine for rapid injection into the thigh muscles. • However, if they are exposed to sarin gas for too long before being given atropine, they must be put on an artificial ventilator and pressure chamber. • Insecticide poisoning is just treated with atropine. 104
ATROPINE • Atropine is given as a treatment for SLUDGE syndrome (salivation, lacrimation, urination, diaphoresis, gastrointestinalmotility, emesis) symptoms caused by organophosphate poisoning. Another mnemonic is DUMBBELSS, which stands for diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (as of muscle in the form of fasciculations and CNS), lacrimation, salivation, and sweating (only sympathetic innervation using Musc receptors). 105
ATROPINE • A common mnemonic used to describe the physiologic manifestations of atropine overdose is: "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter". These associations reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased sweating/lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrome, and may also be caused by other drugs with anticholinergic effects, such as scopolamine, diphenhydramine, phenothiazine antipsychotics, and benztropine. 106
ACHE (ACETYLCHOLINE ESTERASE) BLOCKERS • Neostigmine • Physostigmine • Spastic paralysis • These drugs are used to treat Myasthenia Gravis, an autoimmune disease that causes ptosis (droopy eyelid) 107
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 108 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. 109
ACH-ASE INHIBITOR: NEOSTIGMINE • Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor. • Neostigmine stimulates both nicotinic and muscarinic receptors. Unlike physostigmine, neostigmine does not enter the CNS. • Its effect on skeletal muscle is greater than that of physostigmine. • Neostigmine’s duration of action is 2 -4 hours. 110
ACH-ASE INHIBITOR: NEOSTIGMINE • It is used to improve muscle tone in people with myasthenia gravis and routinely in anesthesia to reverse the effects of muscle relaxants at the end of an operation. • It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity. • Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in critically ill patients. • Sometimes, hospitals use an intravenous version of neostigmine to delay the effects of snakebite 111 venom.
ACH-ASE INHIBITOR: NEOSTIGMINE • Though it is one of only two treatments available for myasthenia gravis, this drug is no longer available in the United States to anyone using the Medicare Part D program. The other drug is Pyridostigmine, which has to be used with caution in people with asthma. • So if you are on Medicare part D, and have asthma……don’t get bitten by a snake or get MG. • Neostigmine will cause slowing of the heart rate (bradycardia); for this reason it is usually given along with a parasympatholytic drug such as atropine for people who have tachycardia (fast heart beat). 112
NURSING CONSIDERATIONS FOR MYASTHENIA GRAVIS Monitor respiratory status Check gag reflex before feeding Use energy conservation measures Provide small, high calorie meal give meals when meds are peaking • Sit upright when eating and use thickener as necessary • Lubricating eye drops and eye patch at night if patients are unable to completely close their eyes • • 113
COMPLICATIONS MYASTHENIC CRISIS (undermedication) CHOLINERGIC CRISIS (overmedication) Respiratory muscle weakness (mechanical ventilation) Muscle twitching to the point of respiratory muscle weakness (mechanical ventilation) Hypertension Hypotension Weakness, incontinence, fatigue Hypersecretions (nausea, diarrhea) hypermotility Tensilon test =temporary improvement Tensilon test= no effect or worsens the if symptoms Symptoms improve after atropine (anticholinergic) is given
ACHE (ACETYLCHOLINE ESTERASE) BLOCKERS • Neostigmine • Physostigmine • Spastic paralysis • These drugs are used to treat Myasthenia Gravis, an autoimmune disease that causes ptosis (droopy eyelid) 115
ACH-ASE INHIBITOR: PHYSOSTIGMINE • Physostigmine is also a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor. • However, it is not used to treat myasthenia gravis. • It is used to treat glaucoma, Alzheimer's disease, and orthostatic hypotension (fainting when standing up too fast). • It can cross the blood–brain barrier, so it is also used to treat the central nervous system effects of atropine, scopolamine and other anticholinergic drug overdoses. Physostigmine is the antidote of choice for Belladona poisoning. 116
ACHE INHIBITOR VS. ACH ANTAGONISTS • ACH-E inhibitor • 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: spastic paralysis • ACH Antagonists • 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. 117
IRREVERSIBLE ACH-E INHIBITOR • Sarin gas • Spastic paralysis • Ventilator until Ach. E turnover • This is a permanent Ach. E 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). 118
SARIN GAS ATTACK BY SYRIA, 2013 • https: //www. youtube. c om/watch? v=doyt. ZVNl tc 4 • Video 119
INHIBITORY NEURON BLOCKERS • Tetanus toxin • Blocks release of inhibitory neurotransmitters • Muscles can’t relax • Spastic paralysis • Opposing flexor and extensor muscles contract 120
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 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. 121
SPIDER VENOM • Black widow: causes ACh release • Lack of inhibitory neurotransmitters • Spastic paralysis • Brazilian Wandering Spider (banana spider) • Most venomous of all spiders/ more human deaths • Spider venom increases nitric oxide release • Video: start at 1: 45 • http: //www. youtube. com/watch? v=z. OMgx 7 GQre. Y • • Brazilian Wandering Spider Warning Dance http: //www. youtube. com/watch? v=N 5 y. JS 9 mc. Ec 8 122
SPIDER VENOM • Spider venom works like tetanus toxin. • The Banana spider makes a lot of nitric oxide, which stimulates receptors of the 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. 123
SUMMARY • Know the following slides well for the final exam 124
Small Molecule Neurotransmitters • Acetylcholine (ACh) – m. ACh (“cholinergic”) – n. ACh (“cholinergic”) • Amino Acid NTs – Glutamate – GABA (inhibitory) – Glycine (inhibitory) Catecholamines Adrenergic catecholamines: • Norepinephrine • Epinephrine Dopaminergic catecholamine: • Dopamine Serotonergic catecholamine: • Serotonin IONOTROPIC RECEPTORS ARE IN RED METABOTROPIC RECEPTORS ARE IN BLACK 125
Somatic Nervous System Nicotinic (Ionotropic) Muscarinic (Metabotropic) Nicotinic (Ionotropic) ACh Adrenergic (Metabotropic) Muscarinic (Metabotropic) 2% Sweat Glands 98% Cardiac muscle Smooth muscle Glands Cardiac muscle Smooth muscle Skeletal muscle 126
Adrenergic Receptors • Alpha adrenergic receptors – Alpha 1 receptors • Causes vasoconstriction – increases blood pressure • Decreases GI motility – Alpha 2 receptors • Causes vasodilatation – decreases blood pressure • Decreases GI motility • Beta adrenergic receptors • Beta 1 receptors • Increases heart rate • Increases cardiac output • Beta 2 receptors • Causes vasodilatation • Decreases blood pressure • Opens bronchioles • Decreases GI motility All of these receptors use G-Protein (the functional classification is metabotropic) 127
Flaccid Paralysis Na+ VGC Blockers • • Lidocaine Tetrodotoxin Saxitoxin Curare Ach Blockers • Atropine (m. ACH) Vesicle Blocker • Botulism toxin
Spastic Paralysis • Ach-ase inhibitors • • Neostigmine Physostigmine Sarin gas Insecticides • Ach competitors • Chemical warfare drugs (other than sarin gas) • Increases nitric oxide release • Banana Spider venom • Blockers of NT which inhibit Ach • Tetanus toxin • Black widow spider toxin
WHAT TO FOCUS ON • Know the classifications, including metabotropic vs ionotropic. • Which NT is for skeletal muscle? Smooth? Cardiac? Glands? • Which NT is used for the illnesses mentioned (stroke, myasthenia gravis)? • How does alcohol affect a NT or its receptors? • Know the effects of Alpha, Beta (1 and 2), muscarinic, and nicotinic receptors. • Know the drugs and toxin section VERY WELL. • Where are the n. ACH and m. ACH receptors found in the body? What part of the ANS do they effect: Sympathetic or Parasympathetic? • Know the diseases, and which receptors are affected. • Know which diseases cause flaccid vs. spastic paralysis. • Know which branch of the ANS (sym vs parasymp) uses metabotropic and which uses ionotropic receptors. 130
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