Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
95 Cards in this Set
- Front
- Back
|
Sympathetic outflow? Parasympathetic? |
Sympathetic - thoracolumbar
Parasympathetic - crainiosacral |
|
|
Where do sympathetic preganglionic cells terminate/ synapse?
Neurotransmitter ? |
All use ACh
Paravertebral chains - sympathetic trunk
Prevertebral ganglia (overlying the aorta)
Directly with the adrenal medulla |
|
|
Sympathetic postsynaptic neurons
Neurotransmitter? |
Noradrenline mainly.
ACh to sweat glands |
|
|
CN with parasympathetic outflow? |
3 7 9 10 Mainly
Then 3rd/4th sacral nerves |
|
|
Where do parasympathetic preganglionic neurons synapse?
Name the PSNS ganglia. |
Mainly in ganglia at the target organ but a few external ganglia exist
Ciliary, pterygopalatine, submandibular, Otic and pelvic |
|
|
What is the enteric NS?
Name its components. |
Large, highly organised collection of neurons in the GIT - controls both motor and secretory functions
Myenteric plexus (Auerbach) Submucous plexus (Miessner)
Receives input from PSNS (preganglionic) + SNS (postganglionic) |
|
|
What are other substances released by postsynaptic nerves? |
PSNS - ACh -- Nitric oxide and peptides
SNS - NA, ACh -- dopamine
Adrenal medulla (embryologically equivalent to postsynaptic cell) - NA + adrenaline |
|
|
What are some potential targets for drug therapy regarding neurotransmitter function? |
5 targets
1. Synthesis 2. Storage 3. Release 4. Termination of action 5. Receptor effects |
|
|
What are VAMPs and SNAPs? |
VAMPs - vehicle associated membrane proteins - on the vesicle SNAPs - synaptosomal nerve associated proteins - at the nerve terminal
Interacting fusion proteins that allow fusion of the vesicle to the synaptic cleft membrane for release of NT |
|
|
What does choline acetyltransferase do? |
Creates ACh from acetyl-coA and choline in the cytoplasm |
|
|
Describe how ACh is formed and stored in vesicles. |
Choline is brought into the cell by a choline transporter. Then ACh is created from choline and acetyl-coA by choline acetyltransferase ACh is moved into vesicles by VAT ( vesicle associated transporter using H+ gradient) Inside the vesicles it is bound to VPG (vesicular proteogylcan) |
|
|
What protein allows for vesicles to cluster at the terminal? |
VAMPs - subtype -- SNAREs -- Esp. SYNAPTOBREVIN |
|
|
What protein allows for vesicles to cluster at the terminal? |
VAMPs - subtype -- SNAREs -- Esp. SYNAPTOBREVIN |
|
|
What triggers vesicle release? |
Action potential --> Ca influx --> interacts with SYNAPTOTAGAMIN --> triggers fusion |
|
|
What protein allows for vesicles to cluster at the terminal? |
VAMPs - subtype -- SNAREs -- Esp. SYNAPTOBREVIN
SNAPs - esp syntaxin and snap25 |
|
|
How does botulinum toxin work? |
Prevents fusion of ACh vesicles with the terminal via enzymatic modification of the fusion proteins |
|
|
How is ACh removed from the synaptic cleft? |
Acetylcholinesterase - AChE |
|
|
How is ACh removed from the synaptic cleft? |
Acetylcholinesterase - AChE
This is a very rapid process |
|
|
Process of adrenergic nerve terminals from precursor molecules to completion |
Tyrosine uptake by Na/tyrosine co transporter --> tyrosine to Dopa via tyrosine hydroxylase (rate limiting step) --> dopa to dopamine --> noradrenaline --> VMAT (vesicular monoamine transporter) --> into vesicle
Vesicle fuses (via VAMPs and SNAPs) with terminal via Ca influx
Noradrenline re-uptake 1 via NET (norepinephrine transporter) and metabolism via COMT and MAO + diffusion away from the synapse |
|
|
How does cocaine work? |
Blocks NET (Norepinephrine transporter)
Thus increases the effect of NA in the synapse
Also blocked by some tricyclic antidepressants |
|
|
High Catecholamine turnover is reflected in? |
High urinary VMA and metanephrines in a 24h sample
(Catecholamine metabolites) |
|
|
What does trophotropic and ergotrophic mean? |
Trophotropic - PSNS - leading to growth - rest and digest
Ergotrophic - SNS - energy expenditure - fight or flight |
|
|
What does activation of ACh M1/3/5 receptors do on a cellular level ? |
Formation of IP3 and DAG
Increase cellular Ca2+ |
|
|
What happens on activation of ACh M2/4 receptors - on a cellular level? |
Opening of K+ channels Inhibition of adenylyl Cyclase |
|
|
What happens on a cellular level with activation of nicotinic ACh receptors ? |
Opening of Na+, K+ channels
Depolarization |
|
|
What happens on a cellular level with activation of nicotinic ACh receptors ? |
Opening of Na+, K+ channels
Depolarization |
|
|
What happens on a cellular level with activation of beta receptors vs alpha receptors ? |
Alpha1 - formation of IP3 and DAG, increased Ca2+
Alpha 2 - Inhibition of adenylyl Cyclase --> decreased cAMP
Beta 1/2 - Stimulation of adenylyl Cyclase --> increased cAMP |
|
|
Cellular effects of different dopamine receptors? |
D1 - stimulate adenylyl Cyclase - increased cAMP
D2/3/4 - inhibition of adenylyl Cyclase - decreased cAMP |
|
|
Sympathetic / parasympathetic effects on the eyes? |
SNS - relaxes ciliary muscle, contracts radial iris muscle --> DILATION
PSNS - CONSTRICTION - constracts iris circular muscle and ciliary muscle |
|
|
Sympathetic / parasympathetic effects on the eyes? |
SNS - relaxes ciliary muscle, contracts radial iris muscle --> DILATION
PSNS - CONSTRICTION - constracts iris circular muscle and ciliary muscle |
|
|
Sympathetic / parasympathetic effects on the heart ? |
SNS - BETA receptors - accelerates SA node + ectopic pacemaker + increases contractility
PSNS - M2ACh - decelerates SA Node, reduces atrial contractility |
|
|
Sympathetic / parasympathetic effects on the blood vessels? |
SNS - - skin/ splanchnic - alpha - constricts - skeletal muscle - beta 2 - relaxes
PSNS - no effect |
|
|
Sympathetic / parasympathetic effects on the blood vessels? |
SNS - - skin/ splanchnic - alpha - constricts - skeletal muscle - beta 2 - relaxes
PSNS - no effect |
|
|
Sympathetic / parasympathetic effects on the bronchiolar smooth muscle? |
SNS - relaxes - beta 2
PSNS - constricts - M3 |
|
|
Sympathetic / parasympathetic effects on male sexual function? |
SNS - ejaculation - alpha
PSNS - erection mACh |
|
|
What is the normal physiological response to noradrenaline ? |
Increased TPR --> increased MAP --> baroreceptors --> increased vagal tone --> bradycardia to compensate for high MAP |
|
|
What is the mechanism of neostigmine and physostigmine? |
Block Acetylcholinesterase - parasympathomimetic Ie prevent degradation of ACh --> prolonged effect Used clinically to reverse the function of paralysis during an operation ie rocuronium or vecuronium (non-depolarising) |
|
|
What is the mechanism of atropine? |
Blockade of mACh - non-selective, crosses BBB Blocks vagal tone to the heart --> increase the HR in heart block |
|
|
What is the MOA of tropicamide? |
Blockade of mACh Blocks PSNS --> Causes dilation of the pupil (Myadriasis) + Cycloplegia (loss of accommodation) due to paralysis of the ciliary muscle |
|
|
Example of an Alpha 2 adrenergic agonist? |
Clonidine - alpha 2 agonist centrally stimulates these receptors --> decreases TPR reduces the BP and causes increase drowsiness |
|
|
Example of Alpha blocker |
Alpha 1 prazosin |
|
|
Example of a Beta blocker? |
Propanolol - non-selective Atenolol 1>2 --> ie less bronchoconstriction |
|
|
Example of drugs that prevent reuptake of NA? |
Cocaine Tricyclic antidepressants |
|
|
Receptor types on end organs and their effects ... |
Back (Definition) |
|
|
What is denervation supersensitivity? |
Increase in receptor number following a prolonged period of inactivity --> ie denervated muscle has ++++ nACh |
|
|
What causes late, slow EPSP |
Peptides - working over minutes - modulates responsiveness of the post synaptic cell to subsequent primary excitatory presynaptic activity |
|
|
MOA Local anesthetics?
Name another molecule that works via this pathway. |
bock voltage gated Na channels - prevent action potentials --> at nerve axons
Also how tetrodotoxin of the puffer fish works |
|
|
How does Metyrosine work> |
Blocks uptake of choline which is required for ACh synthesis ie anticholinergic effects Used only for the treatment of phaeochromocytoma |
|
|
Drugs that affect NT storage in nerves? |
Reserpine - VMAT (used to transport dopamine into the vesicle) on vesicles - NA Vesamicol - VAT - on vesicles - ACh |
|
|
MOA Botulinum toxin? |
Prevents release of ACh vesicles - preventing transmission Massive anticholinergic effects N/V + eye signs++ --> dilated pupils , facial paralysis affect somatic nerves too |
|
|
MOA Amphetamines? |
Increased NA release from vesicles same as tyramine |
|
|
MOA Atropine? |
m ACh Recceptor antagonist |
|
|
MOA Bethanechol? Drug class? Similar Drugs? |
mAChR Agonist (Choline ester) More resistant to AChE but no effect on nAChR - ACh, methacholine Used mainly for treating functional urinary retention or GIT atony parasympthaomimetic |
|
|
MOA Tubocurarine ? History ? |
nAChR Antagonist at NMJ --> the prototypical non-depolarising muscle relaxant Initially used in South America on arrows to shoot prey --> Paralysis Developments --> cisatracurium, rocuronium - better profiles - quicker onset/offset etc |
|
|
MOA neostigmine? |
Inhibits acetylcholinesterase Ie - increases the effect of ACh Used in the reversal of paralysis during surgery |
|
|
What is context sensitive half life? Relevance with example. |
It is the half life of a drug following prolonged infusion. During an infusion the drug will distribute into other compartments --> when the infusion is stopped the only drug metabolised is the drug in the plasma --> as this decreases the the drug from the other compartments then re-enters the plasma -- ie PROLONGED effects Examples - TIVA --> propofol - short; Thiopentone - increases with longer infusion Also with midazolam Ketamine and etomidate also short |
|
|
Structure of the nAChR? |
pentamer with various subunits - alpha,beta (ganglia), alpha, beta, gamma, epsilon (NMJ) Both ligand gated cation channels |
|
|
MOA SUXAMETHONIUM? |
Binds to and activates nAChR - does not dissociate --> prolonged binding resulting desensitization and refractory to further depolarising -- hence flaccid paralysis following initial twitching |
|
|
Function of the detrusor? Trigone |
Detrusor - pushes urine out of the bladder Trigone - helps constrict the sphincter - preventing urinary flow |
|
|
What kind of drug is pilocarpine? |
Muscarinic agonist Works similar to muscarine --> alkaloid ie not a Choline ester like ACh, methacholine, etc |
|
|
What are the types of AChE inhibitors? |
1. Simple alcohols - Edrophonium - very short T1/2 2. Carbamates- neostigmine 3. Organophosphates - Insectisides - echothiophate + Parathion + Sarin gas (very potent) - LONG T1/2 |
|
|
Length of action of different types of AChE inhibitors ? |
Shortest Edrophonium < Neostigmine < Organophosphates (long, form covalent bonds, 100hrs) |
|
|
Affects of AChE inhibitors? |
Increase in ACh - increase in parasympathetic + CNS + nACh CNS: Alertness, convulsions, coma, resp. arrest PSNS: Miosis, increase GIT and urinary activity, bronchoconstriction Heart: combo of PSNS + SNS --> Bradycardia, HTN, high TPR, low CO NMJ: strengthens contraction although may result in fasciculation or depolarising blockade |
|
|
Clinical uses of Cholinomimetics? |
1. EYE - Glaucoma --> ie pilocarpine (mAChR agonist) or physostigmine (AChE antagonist) 2. GIT/urinary Atony - Bethanechol (mAChR agonist) or neostigmine (AChE antagonist) 3. Myasthenia Gravis - pyridostigmine (AChE antagonist) + atropine to inhibit excessive mAChR effects 4. Surgery - reversal of paralysis - neostigmine 5. Alzheimers - Donepezil, rivastigmine (AChE antagonists) - modest effect |
|
|
Signs and symptoms of acute nicotine toxicity? |
CNS -stimulant, convulsions, coma MSK - depolarisation - blockade and paralysis with respiratory arrest HTN and cardiac arrhythmia |
|
|
MOA of varenicline? |
Anti smoking drug partial agonist for nAChR causes insomnia, anxiety prevents the stimulant effect of smoking |
|
|
Signs of organophosphate poisoning?
Management? |
IE signs of ACh Excess ! - Inhibits AChE
mAChR effects 1st - miosis, salivation, sweating, bronchial constricction, vomiting, diarrhoea CNS - cognitive impairment, convulsions, coma MSK - Neuromusclular blockade at nACh due to depolarising blockage similar to SUX +
pralidoxime
Support vitals, decontaminate, atropine IV, benzos for seizures,
|
|
|
Where does belladonna come from? Effect? |
Atropine is found in the plant ATROPA BELLADONNA mAChR blocker - anti PSNS |
|
|
Examples of mAChR antagonists? |
Atropine (Hyoscyamine) - long action on the eyes Hyoscine + scopolamine, crosses BBB Quanternary - Tiotropium, Glycopyrrolate, poor absorption via GIT, poor CNS penetration Benztropine - parkinsons Tropicamide - eyes Glycopyrrolate |
|
|
Effects of mAChR antagonists? |
Limited CNS, Improves parkinsonism, Improves Motion sickness Mydriasis, cyclopegia (reduced near vision) --> worsens acute glaucoma; Dry eyes CVS: Tachycardia, short PR Resp: Bronchodilation and reduced secretion (Aim of tiotropium) GIT - Dry mouth, reduced secretions and motility Urinary - can cause retention Prevent sweating and may cause "Atropine fever" in children |
|
|
Give examples of clinically relevant mAChR antagonists. |
1. CNS - parkinsonism + Hyoscine for motion sickness 2. Opthal - examination (not fundoscopy) ie atropine 3. RESP - COPD - tiotropium - bronchodilation, Premed for OT - prevent bronchospasm (not really now) 4. CVS - unstable Sinus bradycardia -atropine 5. Antidiarrhoeal 6. Urinary incontinence - oxybutynin + solifenacin--> + botox 7. Cholinergic poisoning |
|
|
What is Pralidoxime ? |
Compound capable of regenerating acetylcholinesterase following organophosphate poisoning Only works at peripheral sites (cannot enter the CNS) |
|
|
Role of Dicyclomine? |
mACh M3 antagonist - used for IBS |
|
|
What is the structural basis of a symathomimetic AMINEs? examples? |
Amine - terminal 2x carbons between Ring with 2x OH (catechol) = potent drugs Ie - adrenaline --> catecholamine Metaraminol - Missing OH so not a catecholamine and less potent but ++ alpha effects |
|
|
Degradation of catecholamines?? |
COMT - catechol-O methyl transferase |
|
|
Different between adrenalin and NA and isoprenaline? |
NA - Missing CH3 group on amine
Isoprenaline - large 3 x CH2/3 groups on amine (++Beta) |
|
|
MOA of metaraminol? |
Alpha1 agonist Vasoconstriction via IP3 /DAG --> Activation of phospholipase C and increased Ca |
|
|
Effects of Noradrenaline on the CVS? |
Alpha1 ++ agonist - mainly Increased TPR -- increase MAP with normal reduction in HR due to baroreceptors |
|
|
Effects of adrenaline on CVS? |
Mixed alpha + beta Increase HR (beta 1) Increase BP (mainly due to HR) Decrease TPR - beta 2 receptors agonist |
|
|
Effects of isoprenaline? |
Mainly Beta 1 Increased HR High BP Fall in TPR |
|
|
Which are of the brain does clonidine affect to produce sedation and hypotension? |
Nucleus Coeruleus via presynaptic alpha 2 agonism NTS - for inhibition of SNS activity |
|
|
Applications of BETA BLOCKERS |
HTN Heart failure Angina Arrhythmia control Essential tremor Migraine Somatic expressions of stress |
|
|
Which beta blockers also have alpha blocking effects? ie are vasodilators. |
carvediolol labetalol |
|
|
Non selective beta blockers? |
propanolol sotalol timolol |
|
|
Which of the following is incorrect? 1. propanolol has high lipid solubility and therefore ++ CSN Side effects such as nightmares 2. Carvedilol is non selective with Alpha1 blockade 3. Most of the commonly used BB do not have symmathomimetic effects 4. Metoprolol has low first pass metabolism |
4. Metoprolol has low first pass metabolism - incorrect! low bioavailability |
|
|
true / false? There are 2 types of nAChR - N1 (NMJ) and N2 ganglia, CNS |
true |
|
|
Indications of mAChR antagonists? |
Atropine - bradycardia Asthma - ipratropium, tiotropium Benztropine - parkinsons, EPS Hyoscine + scopolamine - motion sickness, nausea Hyoscine n-butylbromide - buscopan - antispasmodic |
|
|
Location of mACh receptors? |
M1 - neural - stomach M2 - Cardiac - mainly atria M3 - glandular, viseral, bronchial SM M4/5 - CNS |
|
|
Side effects of anti-cholinergic? |
Dry mouth Blurred vision - pupillary dilation and cycloplegia (accommodation paralysis) Urinary retention Constipation CNS effects - hyperthermia, reduced sweating, Atropine in high dose becomes non-specific and block nACHR - hypotension (SNS ganglia) and paralysis (NMJ) |
|
|
Which of the following drugs do NOT have anti-ACh side effects? TCAs Ranitidine Chlorpromazine Antipsychotics ie olanzapine Frusemide |
None - they all have anti-ACh effects |
|
|
Alpha 1 intracellular signalling? |
IP3 + DAG --> increased Ca |
|
|
Signalling via Alpha 2 receptors? |
Inhibitory - inhibit cAMP |
|
|
Signalling via beta receptors |
both activate adenylyl cyclase and increase cAMP |
|
|
How does activation of beta receptors cause contraction in the heart and relaxation in SM????? |
B1/2 both activate adenylyl cyclase and increase cAMP. HEART --> cAMP activates PK-A which phosphorylates L type Ca channels and increases Ca influx --> contraction SM --> cAMP --> inhibits MYOSIN LIGHT CHAIN KINASE which usually phosphorylate SM myosin to allow contraction --> hence relaxation |
|
|
Describe the specificity of NA, Adr, Dobutamine and isoprenalin on beta and alpha adrenergic receptors. |
Adrenalin - A1= A2 > B1=B2 NA - A1= A2 + B1 >> B2 Isoprenaline - B1/B2 >>>> A1 = A2 Dobutamine - B1 > B2 >>>>> A1 = A2 |
