Pharmacology Exam 3

How is ACh stored in vesicles?

"quanta" packaging (1000 to 50000 ACh molecules in each vesicle)

What is the enteric nervous system (ENS)?

-extensive network of interconnected sensory and motor interneurons within gastrointestinal wall that can control gut function independently of CNS -characterized by presence of complex intrinsic neural network that includes myenteric plexus and submucosal plexus -extensively innervated by nonadrenergic-noncholinergic (NANC) nerve fibers -sensory and motor interneurons also influenced by CNS through input from sympathetic and parasympathetic subdivisions

What are chromaffin cells?

-in adrenal medulla and are analogous to ganglionic neurons -innervated by sympathetic preganglionic fibers

What are the types of efferent/motor axons?

-somatic: to skeletal muscle -visceral: to cardiac muscle, smooth muscle, exocrine glands

How many muscarinic receptor subtypes are there?

5 (M1-M5)

What types of receptors are adrenergic receptors?

G-protein coupled receptors -specificity in response following adrenergic receptor activation caused by G protein-mediated effects

What are other characteristics and functions of ACh?

-arise from parasympathetic ganglia and project to target cell, tissues and organs -also primary neurotransmitter released from postganglionic PSNS neurons -binds and activates muscarinic receptors (M)

What are the non-adrenergic and non-cholinergic neurotransmitters (NANC)?

-ATP -vasoactive intestinal polypeptide (VIP) -neuropeptide Y (NPY) -serotonin (5-HT) -substance P -calcitonin gene-related peptide (CGRP) -nitric oxide (NO) many of same molecules/substances identified as cotransmitters in ANS nerves also released from NANC nerve endings

What is Dopamine?

-D1 receptor agonist -low dose IV administration promotes vasodilation of numerous vascular beds -moderate infusion rates: activates beta1 receptors which leads to increased cardiac contractility, heart rate, cardiac output -high infusion rate: activates alpha1 receptors which leads to vasoconstriction and increased peripheral vascular resistance (also remains as agonist at cardiac beta1 receptors)

How does synaptic NE/NE synaptic activity elimination occur?

-NE metabolized by enzyme catechol-O-methyltransferase (COMT) -NE transported back into postganglionic sympathetic nerve terminal by active NE transporter (NET) -NE diffuses away from synaptic cleft and is metabolized in plasma/liver or excreted in urine

Where are nicotinic (Nn) receptors found?

-Postganglionic neurons in autonomic ganglia (intramural, prevertebral, paravertebral) -adrenal medullary chromaffin cells to mediate neurotransmission from preganglionic SNS neurons to adrenal medullary chromaffin cells -distributed in CNS and non-neuronal tissues

What are the primary ANS neurotransmitters of the sympathetic systems?

-acetylcholine: primary neurotransmitter released from preganglionic neurons at sympathetic ganglionic sites; also released from preganglionic neurons at parasympathetic ganglionic sites -norepinephrine: predominant neurotransmitter released from postganglionic SNS neurons

What is Dobutamine?

-act as beta2 and alpha1-adrenergic receptors -relative selectivity for beta1-adrenergic receptors (subserving changes in myocardial activity rather than cardiac rate) -increases myocardial contractility, cardiac index, and stroke volume -treats low cardiac output flow states (CHF/dilated cardiomyopathy) -modest agonistic effect at alpha1-adrenergic receptors make it less effective treatment for isoflurane-induced hypotension

How does ATP mediate responses?

-activate purinergic receptors (adenosine P1 receptors and P2X and P2Y receptors)

What are organs with only sympathetic innervation?

-adrenal medulla -peripheral blood vessels -pilomotor muscles -sweat glands

What are ATP, neuropeptide Y and vasoactive intestinal polypeptide (VIP)?

-cotransmitter molecules released from postganglionic fibers at target tissues -ATP and NE stored in same vesicles and released together -can also be released with ACh from postganglionic PSNS fibers at target tissues and organs -similar to sympathetic nerves because cotransmitter and ACh can be stored in same vesicle and released together or stored in separate vesicles and regulated as individual entities

What is the parasympathetic nervous system?

-craniosacral system -parasympathetic nerves originate from cell bodies in brainstem and sacral sections of spinal cord -long preganglionic and short postganglionic axons -preganglionic axons leave CNS by way of cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), X (vagus) and several sacral spinal nerves -preganglionic axons synapse in diffuse parasympathetic ganglia residing close to intramural ganglia (pelvic viscera)

What is acetylcholinesterase (AChE)?

-enzyme that hydrolyzes/inactivates acetylcholine into choline and acetate when ACh is in the synaptic space -located in close proximity to synaptic cleft

How is catecholamine regulated in the cytoplasm?

-inactivation by neuronal mitochondrial enzyme monoamine oxidase (MAO) -transportation of NE into granules by vesicular monoamine transporter

Describe selectivity of adrenergic receptor agonists

-individual endogenous catecholamine/sympathomimetic drug may exhibit higher affinity/selectivity for one or more adrenergic receptor subtypes -selectivity for agonist not absolute -higher concentrations of given drug/catecholamine may interact/activate other subtype/class

What is dopamine?

-neurotransmitter released by postganglionic SNS neurons that is immediate metabolic precursor to norepinephrine -bind to and activates dopaminergic receptors (D)

What is dual ANS innervation?

-organs and tissues innervated by both sympathetic and parasympathetic arms of ANS -heart and urinary bladder -dual ANS is functionally antagonistic -basal physiological function of organs weighted toward PSNS or SNS regulation

What is the function of EPI in arterial blood regulation?

-potent cardiac stimulant and vasoconstrictive agent -reverse marked hypotension and cardiac irregularities associated with anaphylactic shock -potent renal vasoconstrictor (decreased renal blood flow at high doses) -addition to local anesthetics delays removal of anesthetic from site of injection

What is Isoflurane?

-potent vasodilator -causes reduction in peripheral vascular resistance (main mechanism for blood pressure decrease) -cardiac output preserved at low dose isoflurane -higher doses reduces cardiac output with depressant eefcts on myocardial contractility

What is the function of Neuropeptide Y?

-released with NE from sympathetic nerves -agonist at Y1 and Y2 neurokinin receptors -modulates sympathetic neurotransmission at pre- and postsynaptic sites

What are the three mechanisms that explain desensitization?

-sequestration of receptors to prevent interaction with ligand -down-regulation ; disappearance of receptors by destruction/decreased synthesis -inability to couple to G-protein because receptor is phosphorylation on cytoplasmic side

What types of vesicles do cholinergic nerve terminals contain?

-small membrane-bound vesicles where ACh is stored -large vesicles that contain biological substances

What are the types of afferent/sensory axons?

-somatic: from skin, retina, membranous labyrinth -visceral: from thoracic and abdominal organs, olfactory epithelium, taste buds

What is the sympathetic nervous system?

-thoracolumbar system -short and long postganglionic axons -preganglionic axons leave spinal cord by way of 1st thoracic through 3rd or 4th lumbar spinal nerves -preganglionic axons pass through ventral root and enter paravertebral sympathetic ganglion chain (sympathetic trunk)

What influences the pharmacologic interactions between agonists and adrenergic receptors?

-tissue distribution of adrenergic receptors -number of adrenergic receptors expressed at specific sites -interactions between sympathetic and parasympathetic nervous systems at target sites -pathophysiological/disease states -background level of sympathetic nerve activity -levels of endogenous catecholamines/sympathomimetic drugs

What is the number of neurons in the autonomic nervous system?

-two peripheral neurons -preganglionic neuron: cell body in CNS and axon innervates postganglionic neuron -postganglionic neuron: cell body in peripheral structure (ganglion)

What is the function of NE in arterial blood regulation?

-used in clinically hypotensive situations -induces marked artery and vein constriction -potent vasoconstrictor of renal vascular beds

What is Ephedrine?

=noncatecholamine drug that acts as agonist at alpha1, beta1 and beta2 receptors -induce NE release from postganglionic sympathetic nerve terminals -low doses: produces transient increase in mean arterial pressure, cardiac index, and stroke volume (activates cardiac beta1 and vascular beta2-adrenergic receptors) -higher doses: induces marked/sustained increase in mean arterial pressure (likely activates vascular alpha1-adrenergic receptors)

What are the 5 types of dopaminergic receptors?

D1, D2, D3, D4, D5

What are sympathomimetic drugs?

Drugs that mimic pharmacological and physiological actions of endogenous catecholamines E or NE (direct acting adrenergic agonists are an example) -effectiveness of drugs depends on similarity of chemical structure to NE and EPI

What type of receptors are muscarinic receptors?

G-protein coupled receptors

What is Albuterol?

Inhaled B2 agonist -Bronchodilator -used in cats and horses to alleviate bronchospasm/cough -inhaled/oral -aerosolized formulation used to improve hypoxemia in anesthetized horses

What happens after NE molecule release from adrenergic nerve endings?

NE binds to and activates adrenergic receptors located on postsynaptic cells -can also activate presynaptic adrenergic receptors located on postganglionic nerve terminal from which catecholamine was released

What endogenous catecholamines are secreted by adrenergic neurons?

NE, EPI, and dopamine

What are the 3 selective beta2-adrenergic receptor agonists that act on the respiratory sysstem?

Terbutaline, Albuterol, Clenbuterol

What is the function of chromaffin cells?

When stimulated by acetylcholine, they synthesize and release norepinephrine and epinephrine into the bloodstream

How is NE release from postganglionic SNS neurons augmented?

activation of presynaptic beta2-adrenergic receptors

What are EPI, NE, and phenylephrine?

additional sympathomimetics that increase arterial blood pressure

What does norepinephrine bind to?

adrenergic receptors (alpha and beta)

What are the two types of alpha-adrenergic receptors and what are their subtypes?

alpha1 and alpha2 subtypes: alpha1A, alpha1B, alpha1D, alpha2A, alpha2B, alpha2C

What are the three primary beta-adrenergic receptor types?

beta1, beta2, and beta3

What are mixed-acting adrenergic agonists?

capability to directly activate adrenergic receptors and increase NE release from adrenergic nerve terminals

What synthesizes and releases EPI and NE?

chromaffin cells of adrenal medulla

What is the terminal enzymatic step in catecholamine synthesis in postganglionic SNS neurons and in some CNS neurons?

conversion of dopamine to NE

What is the function of the autonomic nervous system?

coordinates bodily functions to ensure homeostasis -cardiovascular and respiratory control -thermal regulation -gastrointestinal motility -urinary and bowel excretory functions -reproduction -metabolic and endocrine physiology -fight or flight response changes in level of afferent and efferent activity in sympathetic and parasympathetic nerves occur primarily independent of conscious/voluntary control

How are adrenergic agonists classified?

direct-acting, indirect-acting, mixed-acting

What drugs are used for hypotension treatment?

dopamine, ephedrine, dobutamine

Where do NE and EPI act as agonists?

endogenous catecholamines at alpha- or beta-adrenergic receptors (adrenoreceptors)

What is choline acetyltransferase (ChAT)?

enzyme that synthesizes ACh from acetyl-CoA and choline in cholinergic nerve cytoplasm

What is the primary catecholamine released by the adrenal medulla?

epinephrine

How is choline transported?

from extracellular space to the neuronal membrane by sodium-dependent membrane choline transporter (CHT)

How are neuro- and co-transmitters in adrenergic nerve endings released?

from granules in nerve endings initiated by calcium-dependent action potential

What are neurons in PSNS characterized by?

high rates of ACh

When does catecholamine synthesis terminate?

in some neurons and select peripheral postganglionic sympathetic neurons it terminates with dopamine

What are synaptosomal nerve-associated proteins (SNAPs)?

interact with VAMPs to facilitate fusion with plasma membrane

What kind of receptors are nicotinic (Nn) receptors?

ligand-gated ion channels and contain 5 homologous subunits

How does the PSNS affect bronchial smooth muscle?

maintains baseline airway tone and activates bronchial muscarinic receptors which leads to bronchial smooth muscle contraction

What are indirect-acting adrenergic agonists?

mediate physiological response that involves increasing synaptic levels of endogenous catecholamines

Where does dopamine act as an agonist?

metabolic NE precursor at dopaminergic receptors

What is the adrenal medulla?

modified sympathetic ganglion that contain Nn receptors (nicotinic)

What receptors does ACh bind to?

muscarinic (M) and nicotinic neuronal (Nn) receptors

What are cholinergic fibers?

nerve fibers that synthesize and release and ACh

What are adrenergic fibers?

nerve fibers that synthesize and release norepinephrine

What are direct-acting adrenergic agonists?

neurotransmitter and drug bind directly to and activate adrenergic receptors

What receptors are involved in ANS regulation?

nicotinic and muscarinic receptors -named according to alkaloids nicotine and muscarine identified as receptor agonists

What is the number of neurons in the somatic nervous system?

one neuron whose cell body is located in CNS and axons extends uninterrupted to skeletal muscle

What parasympathetic nerves use vasoactive intestinal polypeptide as a cotransmitter?

parasympathetic nerves of the salivary glands

What parasympathetic nerves release ATP as a cotransmitter?

parasympathetic nerves of the urinary bladder

Where are muscarinic receptors located?

postsynaptic target sites innervated by postganglionic parasympathetic nerves (heart, glands, urinary bladder, GI tract)

What are the alpha2-adrenergic receptors?

primary presynaptic receptors that mediate an autoregulatory response to inhibit transmitter release at select postganglionic SNS nerve terminals when activated

What is desensitization?

prolonged exposure of adrenergic receptor to specific agonist reduces responsiveness of receptors, leads to progressive attenuation in capacity of tissue to facilitate physiological responses

What are vesicle-associated membrane proteins (VAMPs)?

proteins along vesicle membranes that align ACh-containing vesicles

What occurs after nicotinic receptors are activated?

rapid increase in cellular permeability to selective cations (Na+ and Ca2+) -cell membrane depolarization -excitation of postganglionic ANS neurons -excitation of adrenal medullary chromaffin cells -excitation of skeletal muscle fibers

What does activation of beta2-adrenergic receptors cause in respiratory physiology?

receptors present in bronchial smooth muscle activated by beta2-agonists results in bronchial smooth muscle relaxation and bronchodilation

What is a G-protein-mediated effect?

results in specificity in intracellular response profiles following specific muscarinic receptor activation

What is Clenbuterol?

selective beta 2 agonist -approved for use in horses as bronchodilator -parenterally/orally as uterine relaxant (dystocia) -contraindicated in food producing animals (toxicity in humans reported)

What is the function of nicotinic muscle (Nm) receptors?

signal transmission at neuromuscular junction (somatic nervous system)

What does the somatic nervous system innervate?

skeletal muscle

What does the autonomic nervous system innervate?

smooth muscle (blood vessels, GI tract, bladder), cardiac muscle, glands

What is the peripheral nervous system?

spinal and cranial nerves that carry electrical signals (action potentials) -axons carrying action potentials toward CNS: afferent -axons carrying action potential away from CNS: efferents

What are postganglionic-cholinergic fibers?

subgroup of postganglionic SNS neurons that release ACh which binds and activates muscarinic receptors

What is the general visceral efferent nervous system?

sympathetic nervous system (SNS) and parasympathetic (PSNS), enteric nervous systems

What axons are responsible for involuntary control?

visceral efferent and afferent axons part of the autonomic nervous system -smooth muscle, cardiac muscle, some glands, and physiological life support functions

What is Terbutaline?

β2 agonist that is used as bronchodilator -commonly used for small animals -administered parentally/orally -at usual doses, little effect on cardiac (beta1) receptors -no alpha-adrenergic activity