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Describe the steps for CHOLINERGIC TRANSMISSION
- 1. Ach is formed with Acetyle Co A (synthesized in the cell mitochondria) + choline that is brought intracellular.
- 2. Formed ACh is transported into a vesicle with the aid of vesicle associated transporter (VAT)
- 3. A “quanta” of ACh is stored in each vesicle (approx 1000-50,000 molecules)
- 4. Vesicles are concentrated at nerve terminal.
- 5. Held in place by protein.
- 6. Release (exocytosis) occurs when AP reaches the nerve terminal causing EC calcium to influx.
- 7. Ca causes vesicles to fuse with membranes and release ACh into the synapse.
- 8. ACh binds with N1 receptors (pre synaptic) and is hydrolyzed by AChe’s.
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Manipulation of ACh release. Name three ways
- 1. Botulinum toxin blocks binding of ACh vesicle to membrane.
- 2. Choline transport can be blocked from entering the cell (reducing ACh formation)
- 3. Hypocalcaemia reduces ACh release.
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Direct Acting Cholinergic Agonist, Acetylcholine – organic NT. activates which receptors?
- 1. Muscarenic
- 2. Nicotinic
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What is the most common method to increase / activate the PSNS?
1. Using an In Direct Acting Cholinergic Agent
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How does an In Direct Acting Cholinergic (Cholinomimetics) agent work?
- 1. It indirectly activates the PSNS by DECREASING the mechanism to terminate ACh.
- 2. Indirect acting agents produce their primary effects by inhibiting acetylcholinesterase.
- 3. By inhibiting ACHe's the endogenous acetylcholine concentration is INCREASED.
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh)have on the eye?
- 1. Contraction (miosis)
- 2. Contraction for near vision
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh) have on the heart?
- 1. Sinoatrial node - DECREASE heart rate (negative chronotropy)
- 2. Atria - DECREASE in contractile strength (negative inotropy), DECREASE in refractory period
- 3. Atrioventricular node - DECREASE in conduction velocity (negative dromotropy), increase refractory period
- 4. Ventricles - Small DECREASE in contractile strength
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh) have on the blood vessels?
1. Dilation (via EDRF), Constriction (high- dose direct effect)
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh) have on the lungs?
- 1. Bronchial muscles - Contraction (bronchoconstriction)
- 2. Bronchial glands - Stimulation
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh) have on the Gastrointestinal tract?
- 1. Motility is INCREASED
- 2. Sphincters are RELAXED
- 3. Secretion are STIMULATED
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh) have on the urinary bladder?
- 1. Detrusor - CONTRACTION
- 2. Trigone and sphincter - RELAXATION
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What effect does a direct-acting Cholinoceptor stimulants (e.g. ACh) have on the glands?
1. Sweat, salivary, lacrimal, nasopharyngeal- SECRETION
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What forms a bond (varying strength) and inhibits enzymatic degradation of ACh. Ultimately causes an increase in ACh.
1. Anticholinesterases
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Cholinesterase Inhibitor that is used to (treatment of MG) is quaternary amine (does not cross CNS). Short bond
1. Edrophonium
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Cholinesterase Inhibitors that is used to (treatment of MG, reversal of NDMR) is a quaternary amine (does not cross CNS) – intermediate covalent bond
1. Neostigmine
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Cholinesterase Inhibitors that has a prolonged covalent bond with acetylcholinesterase (AChE)
1. Organophosphate (insecticides) Sarine Nerve Gas
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Cholinergic Activation and Clinical Practice (Para sympathomimetic Agonist) for GLAUCOMA
1. Mechanism of action: Lower IOP by increasing aqueous outflow related to contraction of the ciliary muscle
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Cholinergic Activation and Clinical Practice (Para sympathomimetic Agonist) for GI/GU
- 1. Increased smooth muscle activity in the gut
- 2. increased secretions
- 3. reduction of sphincter tones
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Cholinergic Activation and Clinical Practice (Para sympathomimetic Agonist) for NMJ
1. Increase the concentration gradient of ACh in comparison to NDMR
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Cholinergic Activation and Clinical Practice (Para sympathomimetic Agonist) for Heart
1. Reduction in heart rate
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Cholinergic Activation and Clinical Practice (Para sympathomimetic Agonist) for CNS
- 1. tertiary amines will cross BBB
- 2. may reduce NV and motion sickness
- 3. can produce mild sedation.
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Name the two sets of receptors of the PSNS
- 1. Nicotinic
- 2 Muscarinic
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If an anticholinergic is given it will block at the N2 (at the NMJ) and cause what reaction?
1. Muscle relaxation
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Blockade of M receptors produce side effects commonly seen antimuscarinic drugs:
- 1. Atropine
- 2. Scopolamine
- 3. Glycopyrulate
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Can the drug atropine, a tertiary amine, cross the blood brain barrier?
- 1. Yes,
- 2. quat amines do not cross the BBB.
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How does Atropine (cholinergic antagonist) affect the CNS
- 1. Mild dedative effect
- 2. May reduce Parkinsons Tremor
- 3. Dilates pupils - may influence CNS evaluation
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How does Atropine (cholinergic antagonist) affect the CV
- 1. Blocks vagal tone leads to tachycardia
- 2. may block coronary dilation and coronary flow
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How does Atropine (cholinergic antagonist) affect the lungs
1. Mild to moderate bronchodilation
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How does Atropine (cholinergic antagonist) affect the GI
1. Reduced GI motility
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Increased cholinergic activity (insecticide or nerve agents) leads to increased PSNS activity can be a
1. Cholinergic Crisis
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During a cholinergic crisis which receptors are effected
- 1. Nicotinic
- 2 Muscarinic
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Treatment for a Cholinergic Crisis
- 1. Antimuscarinics are the best method to treat CNS and “peripheral” symptoms (brady, salivation, ect).
- ATROPINE THE BEST CHOICE
- 2. No effective anti Nicotinic available. Must use 2-PAM Chloride or similar agent to help regenerate AChe’s
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Atropine (cholinergic antagonist) contraindications for use
- 1. Glaucoma
- 2. Elderly men with prostate enlargement
- 3. Gastric Ulcers
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Where does adrenergic transmission occur
1. ONLY in the POSTganglionic SNS
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Describe the steps for ADRENERGIC TRANSMISSION
- 1. Tyrosine is brought intracellular (like Choline). Binds with Dopa makes Dopamine.
- 2 Dopamine is transported into vesicle transporter (VMAT) and is converted to NE.
- 3. Norepi is stored in post synaptic nerve vesicles at the terminals.
- 4. Ca2+ helps with the release via exocytosis
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Termination for adrenergic transmission is carried out in three different ways, name them.
- 1. Reuptake -into the nerve terminal by NET or into perisynaptic glia or other cells
- 2. Dilution by diffusion from receptors - simple diffusion away from the receptor site (with eventual metabolism in
- the plasma or liver)
- 3. Metabolism by enzymes (MAO and COMT)
- 4. Norepi action is brief and termination is efficient
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Uptake vía active transport is done
- 1. Vesicle cytoplasm
- 2. Move norepi back into vesicle
- 3. 80 percent of Norepi is terminated through re-uptake
- 4. Uptake is the site of action for may drugs.
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What is the rate liming step for adrenergic transmission
1. THE CONVERSION OF TYROSINE TO DOPAMINE IS THE RATE LIMITING STEP TO CATACHOLAMINE DEVELOPMENT.
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Manipulation of Noriepi release, nome three ways.
- 1. Block the transport of Tyrosine - can be blocked with reserpine
- 2. Inhibit of VMAT protein that will block the conversion of Dopamine to NE
- 3. Block/inhibit NE transporter (carries NE back into cell after release). - cocaine, tricyclic antidepressants
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Adrenergic Agonists manipulate what
1. SNS
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Effects of the SNS are due to what
1. NE
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Name the two ways to manipulation of the SNS can occur
- 1. Agonizing directly: organic or synthetic catecholamine.
- 2. Indirect: reduce degradation of catecholamine.
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Adrenergic Receptor type Alpha 1 affects WHAT and effects WHAT
- 1. Receptor - Vascular smooth muscles
- 2. Effect - increase IP3, DAG
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Adrenergic Receptor type Alpha 2 affects WHAT and effects WHAT
- 1. Recptor - CNS
- 2. Effects - Decrease cAMP
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Adrenergic Receptor type BETA 1 affects WHAT and effects WHAT
- 1. Recptor - heart
- 2. Effects - increase cAMP
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Adrenergic Receptor type BETA 2 affects WHAT and effects WHAT
- 1. Recptor - Lungs
- 2. Effects - increase cAMP
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Adrenergic Receptor type DOPAMINE affects WHAT and effects WHAT
- 1. Recptor - renal
- 2. Effects - increase cAMP
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The receptor type that increases IP3, DAG
1. Alpha 1
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The receptor type that decreases cAMP
1. Alpha 2
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The receptors that increase cAMP
- 1. Beta 1
- 2. Beta 2
- 3. Dopamine
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What is meant by many drugs are "dirty"
1. Many drugs are “dirty” – they have affinity for more then one receptor and as such cause a variety of responses
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Example of receptor affinity norepi vs epi
- 1. Norepi: Equal alpha binding, B1 greater then b2
- 2. Epi: equal alpha binding, equal beta binding
- 3. Isoproterenol: pure beta, little to no alpha
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Endogenous Catecholamine's: "dirty"
- 1. Norepinephrine (NE): a1=a2 > B1
- 2. Epinephrine: a1=a2, b1=b2
- 3. Dopamine: low dose=dopa, mod=dose alpha, high dose=beta
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Direct Acting Sympathomimetic:
- 1. Phenylephrine – pure alpha 1 agonist
- 2. Clonidine – pure alpha 2 agonist
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Sympathomimetic Drugs, Ephedrine has
1. Mixed alpha and beta
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Sympathomimetic Drugs, indirect acting agents act by increasing NE in two ways, name them
- 1. Entering nerve cells and displacing NT leads to increased concentrations (amphetamines)
- 2. Reducing the termination of NT (MAOI)
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What will reduce turbulence in airways
1. Beta 2 agonist
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What effect does a sympathomimetic drug have on alpha 1 receptor
- 1. Tissue - most vascular smooth muscle (innervated) Action - contraction
- 2. Tissue - pupillary dilator muscle - Action - contraction (dilates pupil)
- 3. Tissue - pilomotor smooth muscle - Action - Erects hair
- 4. Tissue - Prostate - Contraction
- 5. Tissue - Heart - Action - Increases force of contraction
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What effect does a sympathomimetic drug have on alpha 2 receptor
- 1. Tissue - Postsynaptic CNS - Action - probably multiple
- 2. Tissue - Platelets - Action - aggregation
- 3. Tissue - Adrenergic and Cholenergic nerve terminals - Inhibits transmitter release
- 4. Tissue - Some vascular smooth muscle - Action - Contraction
- 5. Tissue - Fat Cells - Action - inhibits lipolysis
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What effect does a sympathomimetic drug have on beta 1 receptor
1. Tissue - Heart, juxtaglomerular cells -Action - Increases force and rate of contraction; and increases renin release
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What effect does a sympathomimetic drug have on beta 2 receptor
- 1. Tissue - Respiratory, Uterine, and Vascular smooth muscle - Action - Promotes smooth muscle relaxation
- 2. Tissue - Skeletal muscle - Action - Promotes potassium uptake
- 2. Tissue - Human liver - Action - Activates glycogenolysis
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Hypotension: From Sepsis – toxins leads to vasodilation. What is the best agent for treatment? Why?
1.
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Hypotension: Neurogenic –Loss of ANS control leads to loss of SVR (maybe hear rate). What is the best treatment? Why?
1.
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Hypotension: Cardiogenic – loss of contractile force/pump. What is the best treatment? Why?
- 1. Positive inotropic agent such as dopamine or dobutamine
- 2. The goal is tissue perfusion, not blood pressure
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Hypotension: Hypovolemic - loss of volume. What is the best treatment? Why?
- 1. Norepinephrine
- 2. Phenylephrine
- 3. Methoxamine
- All have the the vasoconstriction properties desired
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Anaphylaxis: Anaphylaxis commonly causes mast cell degranulation hypotension. Best choice? Why?
1. Epinephrine
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Adrenoceptor Antagonist will have what effect
- 1. Blockade or Antagonism of SNS receptors will reduce the outflow of the “fight or flight” response
- 2. Reduction in NT or BLOCKADE of a receptor will cause a reduced clinical effect
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Adrenoceptor Antagonists duration of action is dependent on
- 1. the half life
- 2. clearance of the drug
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Alpha Antagonists, blockade of alpha 1 receptors will
- 1. Decrease in SVR, orthostatic hypotension
- 2. Miosis (small pupils), nasal congestion
- 3. May see reflex tachycardia
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Phenoxybenzamine:
- 1. Covalent bond with alpha 1
- 2. Low oral bioavailability
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Generally, beta blockers, Beta Receptor Antagonist have
- 1. High oral absorption
- 2. Extensive first past effect
- 3. Rapid distribution with large Vd.
- 4. ½ lives approximately 3-10 hours
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What effects does the Beta Blockers have on the body, Pharmacodynamics: CardioVascular System:
- 1. Reduction in BP1.
- 2.Primarily via B1 rate control, but may also reduce renin release
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What effects does the Beta Blockers have on the body, Pharmacodynamics: Respiratory System:
1. Non selective B or B2 blockers can increase bronchiolar resistance
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What effects does the Beta Blockers have on the body, Pharmacodynamics: Ocular:
- 1. Reduces IOP
- 2. Decreases aqueous humor production.
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Specific agents: Propranolol "prototypical drug"
1. Non-selective drug
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Specific agents: Metoprolol:
1. selective B1 greater than B2
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Specific agents: Labtolol:
1. B1 > a1, may see bronchospasm. Less reflex tachycardia.
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