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Block 1 > Week 7 Random > Flashcards

Week 7 Random Flashcards

1
Q

Peripheral nervous system subivisions

A

SENSORY (somatic & visceral)

GSA = external body (ex. touch, pain, temp, or pressure)

SSA = hearing, equilibrium, and vision

GVA = internal organs (strech, pain, temp) * not aware

GVA = taste, smell

MOTOR (somatic & visceral)

GSE = motor of skeletal muscle

SVE =

GVE = sympathetic & parasympathetic (cardiac muscle, smooth muscle, and glands)

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2
Q

CSN composition

PNS composition

A

CNS consist of spinal cord and brain

PNS includes nerve fibers and ganglia

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3
Q

Two types of nerves associated with PNS

A

Cranial (12) all different

Spinal (31) similar with composition but different targets

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4
Q

Component

A

Refers to whether the fiber is motor or sensory and somatic, visceral or special.

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5
Q

Spinal nerve components

A

General Sensory (GSA) : touch, feel

Viscerosensory (GVA) : streech recepotrs in blood vessels

Somatomotor (GSE) : muscle moving

Visceromotor (GVE) : vasoconstriction, sweat gland muscle, arrector pili

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6
Q

Components abbreviations, names, and function

(SSA)

(GSA)

(GVA)

(SVA)

(GVE)

(GSE)

(SVE)

A

Special somatosensory (SSA) (vision and balance/hearing)

General somatosensory (GSA) (skin etc.)

General viscerosensory (GVA) (gut, heart, etc.)

Special viscerosensory (SVA) (taste and smell)

Visceromotor (GVE) (autonomic)

Somatomotor (GSE) (muscles from somites)

Branchiomotor (SVE) (muscles from branchial arches)

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7
Q

Where do cranial nerves come from? Types?

A

Brain and brainstem

Some are motor, some are sensory, and others are mixed

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8
Q

Formation of spinal nerves

A

Spinal nerves are made from the ventral and dorsal roots of the spinal cord.

Some nerves travel alone (intercostals)

Some nerves merge with adjacent spinal nerves and form a plexus (cervical, brachial, lumber and sacral)

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9
Q

How do you know which side of the spinal cord are you looking at?

A

Dorsal root has ganglion

Dorsal horn externs further than anterior

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10
Q

Where do motor fibers originate?

A

Grey matter

* sensory synapse may be in the gray matter

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11
Q

Name of a fiber that comes out of the spinal cord

A

Rootlet

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12
Q

What rootlets form

A

Dorsal or ventral root that merges to form spinal nerve

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13
Q

Does the segmental nature of the cord and the rootlets give you an idea that each of the spinal nerves is destined to innervate a particular are of the body?

Is the whole plan well organized and evident during early development?

A

Yes

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14
Q

What does the spinal nerve branches into?

What are the functions of these branches?

A
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15
Q

How is the afferent neurons divided?

A

Peripheral process (toward the organ)

Central process (toward the spinal cord)

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16
Q

Function of dorsal ramus vs. ventral ramus?

A

Dorsal ramus = motor and sensory to skin of the back and the true back muscles (muscle that do something with back, not necessarily muscle in a back)

Ventral ramus = everything else

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17
Q

Which type of PNS has ganglia?

A

GVE (parasymphatetic / symphatetic)

* sensory fibers do not have ganglia

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18
Q

Where cell bodies are located for sensory, visceromotor, and somatomotor?

A

Sensory = Dorsal root ganglion (DRG)

Visceromotor = lateral horn (intermediate grey) T1-L2 symp and S2-4 for para

Somatomotor = ventral horn

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19
Q

Spinal nerves vs. Splanchnic nerve

A

Spinal nerves do not supply the body cavities, only body wall structures.

Splanchnic nerves and the vagus supply cavities.

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20
Q

Communicating rami

A

Fibers that connecte spinal nerve and sympathetic chain.

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21
Q

How efferent neuron can be activated?

A

By afferent neuron

By control from CSN

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22
Q

Dermatome

A

Skin innervated by a single spinal nerve (specifically the cutaneous branch).

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23
Q

Examples of dermatomes

A

C2 - back of head

T4 - nipple

T10 - belly

L1 - back legs

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24
Q

Myotome

A

The group of muscles that a single spinal nerve root innervates

Pattern of innervations to muscle innervation from a single spinal nerve

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25
Q

Level loss

A

In spinal injury all control is lost below the level.

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26
Q

Periopheral Nerves vs. Spinal Nerves

A

Nerve that comes off the plexus (periferal) = multiple combinations of spinal nerves

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27
Q

How many neurons are in parasymapthetic / sympathetic division?

A

2

Preganglionic

Postganglionic

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28
Q

Location of ganglion for sympathetic vs. parasympathetic

A

Near organ = parasympathetic

Near spinal cord = sympathetic

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29
Q

Which autonomic division is connected to body wall (dermatome)?

A

Sympathetic

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30
Q

Origin of sympathetic

A

T1-L2

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31
Q

Origin of parasympathetic

A

1st neuron in the CNS brainstem

sacral spinal cord S2-4

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32
Q

Parasympathetic innervations

A

Only innervates viscera in body cavities, glands in the head, the eye and erectile tissues.

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33
Q

Where do GSA fibers have their nuclei?

A

DRG

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34
Q

Function of Sympathetic Chain

A

Allows communication with CSN

Spinal nerves are inserted with

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35
Q

Where are the cell bodies located for the cutaneous branches of nerves?

A

GSA

GVE

GVA?

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36
Q

Are there overlaps between dermatomes?

A

Yes there is (ignore)

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37
Q

Herniated disk

A

A herniated disc is a condition in which the annulus fibrosus (outer portion) of the vertebral disc is torn, enabling the nucleus (inner portion) to herniate or extrude through the fibers.

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38
Q

Contusion

A

a region of injured tissue or skin in which blood capillaries have been ruptured; a bruise

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39
Q

Most important role of symphatetic division?

A

Control of vasculature

Other: decrease gastric motility / smooth muscle / hair follices

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40
Q

What is the name of the nerve that goes to the body cavity?

A

Splanchnic nerve

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41
Q

Which branches do not contain parasympathetic nerves?

A

Branches of spinal branches

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42
Q

What are seven types of cells found in nerve system?

A

NEUROEPITHELIUM (neutral tube)

Neuroblast -> Neruon

Astroblast -> Protoplasmic Astrocyte

Astroblast -> Fibrous Astrocyte

Oligodendroblast -> Oligodendrocyte

Neuroepithelium -> Epithelium of Choroid Plexus

Neuroepithelium -> Ependyma cells

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43
Q

Ganglion vs. Nucleus

A

Ganglia (group of neurons outside the CNS)

Nucleus (group of neurons within the CNS)

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44
Q

How many neurons are in a human?

A

10^9

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45
Q

Functions of Neurons

A
  1. receive and integrate stimuli from many sources simultaneously
  2. translate stimuli to membrane potential
  3. propagate this membrane potential
  4. translate this electrical message into neurotransmitter
  5. deliver neurotransmitter to target cells
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46
Q

Two types of pigmentations in neurons

A

Lipofuscin: golden brown, probably represents old age (found more in older neurons)

Melanin: a brown black, represents old neurotransmitter? But function not know for sure.

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47
Q

Prominent structures in neurons

A

Perikaryon (cell body)

Large nucleus with owl-eye nucleolus

nissil bodies = rER

microtubules / neurotubules (24nm)

intermediate filaments / neurofilaments (10nm)

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48
Q

How many axons can be in a neuron?

A

Only 1

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49
Q

Term that describes impulses in axon

A

Axonal transport

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50
Q

Five axon components

A

Contains neurofilaments/neurotubules

  1. Axon Hilloc (no nissl bodies)
  2. PInitial Segment (between axon hillock and myelination; site of action potential initiation)
  3. Axon Proper
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51
Q

Two types of transport in axon

A

Anterograde transport (kinesin)

Retrograde transport (dynein)

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52
Q

Site of protein synthesis in neuron

A

Cell body

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53
Q

Dendrites

A

Increase surface area (dendritic spines) increased during young age later decreased

Lack golgi

Synthesize message

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54
Q

2 unique characteristics of neurons?

A

Need trophic stimuli (need signal from other cells to survive)

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55
Q

Types of synapses

A

Axosomatic synapse (synapse with body)

Axodendritic synapse (on dendrite)

Axoaxonic synapse (contacting another axon terminal)

Axospinous synapse (ending on dendritic spine)

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56
Q

Classification neurons by processes

A

Multipolar (many dendites; most abundant; pryamidal cells - cerebellum; Purkinje cells - cerebrum)

Bipolar (single dendrite opose axon; sensory; retina, olfactory mucosa; inner ear)

Pseudounipolar (split axon; no dendrites; DRG and cranial ganglia)

Unipolar (short single axon and no dendrite; photoreceptors - rods/cones)

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57
Q

Classification of neurons by function

A

Motor Neurons: excite or inhibit

Sensory Neurons

Interneurons: chaining neurons; interaction

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58
Q

Classificaiton of neurons by postsynaptic neurotransmitter

A

Cholinergic - acetylcholine / parasympathetic postganglionic

 Adrenergic - epinephrine / sympathetic postganglionic
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59
Q

Names, function, and location of neuroglial cells

A

Fibrous (Astrocytes) | White Matter | Framework & BBB

Protoplasmic (Astrocytes) | Gray Matter | Framework & BBB

Oligodendrocytes | CNS Myelined Nerves | Myelination

Microglia | CNS | Immunity

Ependymocytes (Ependyma) | Ventricle & Central Canal lining | CSF absorption and circulation

Tanycytes (Ependyma) | 3rd Ventricle flood | CSF-> Hypophysal-portal system transport, monitor CSF

Choroidal epithelial cells (Ependyma) | Suface of choroid plexus | CSF production and secretion

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60
Q

What is glia cells?

A

Supporting cells in the CNS

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61
Q

Astrocytes

A

largest glial cells

long branched cytoplasmic processes with vascular end feet cover pia mater, blood vessels, and cell bodies

specific intermediate filaments = glial fibrillary acidic protein

protoplasmic - in gray matter, low [GFAP]

fibrous - in white mater, high [GFAP]

can divide

respond to injury by forming gliosis (similar to fibrosis)

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62
Q

Glia limitans

A
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63
Q

What junction connect endothelial cells in CNS?

A

Tight (BBB)

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64
Q

Oligodendrocytes

A

Most numerous

Myelination in CSN

Can myelinate several axons

Schmidt-Lanterman clefts maintain the membrane forming the mylein

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65
Q

Myelination PNS vs. CNS

Schwann cells vs. Oligodendrocytes

A

CNS (oligo) | PNS (schawnn)

Neuroepithelium | Neural crest

No close association | Close association

Oligo provides multiple axons | Wrapped around one

Inhibit axonal growth | participate in the regenration of injury

astrocyte foot is present in Node of Ranvier | Cytoplasm is trapped in the Node of Ranvier

BOTH INCREASE VELOCITY

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66
Q

Microglia

A

Derived from monocytes

Smallest and least numerous

Phagocytic during injury

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67
Q

What 4th ventricle connects to?

A

Central canal

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68
Q

Ependyma chracteristics

A

Line ventricles

More than “simple cuboidal epithelium”

Connected by macula adherence and zona adherence

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69
Q

Four ventricles

A

2 latteral

3rd and 4th

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70
Q

Tanycytes

A

No basement membrane

Long processes go into brain and terminate near blood vessels and hypothalamic cells (neurosecretory).

Conntected by tight junctions.

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71
Q

Ependymal cells attachement

A

Attached by desmosomes

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72
Q

Choroid Plexus

A

capillary tufts push up ependyma into the brain ventricles

made up of simple cuboidal cells upon BM responsible for **production and maintenance of CSF **

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73
Q

Schmidt-Lanternman clefts

A

Allow oligodendrocytes / schwann cells to get nutrients through the “jelly wrap” to the axon that it is myelinating

Communication

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74
Q

Nerve Regeneration

PNS vs. CNS

A

Schwann cells are capable of mitosis with the subsequent production of a basal lamina and therefor are key to peripheral nerve regeneration. Astrocytes produce gliosis.

Endoneurium Is Not Present in the CNS. Oligodendrocytes Do Not Proliferate. In trauma, astrocytes DO proliferate and form scar tissue

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75
Q

Why CSF circulates?

A

Because it is under the pressure

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76
Q

Meninges

A

Scalp

Skull

Dura mater

Subdural space

Arachnoid membrane

Subarachnoid space

Pia mater

Brain

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77
Q

Cells in cerebral cortex

A

Layer 1 = molecular

Layer 2 = granular

Layer 3 = Pyramindal external (small)

Layer 5 = Pyramidal internal (large)

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78
Q

Cerebellum

A
  1. Molecular layer
  2. Purkinje cells
  3. Granule cells
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79
Q

Spinal cord structure

A
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80
Q

Nerve structure (histology)

A

Axon wrapped in endoneurium

Fassicle wrapped with perineurium

Nerve wrapped with epineurium

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81
Q

How to tell peripheral nerve from connective tissue?

A

Wavy

Node of Ranvier

Schwann cells hug axon

Fibroblasts do are not covered by layers

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82
Q

Synonym to visceral

A

Autonomic

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83
Q

Where does paraympathetic does not innervate?

A

Skin

Adrenal medulla

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84
Q

Two types of motor neurons

A

**Somatic **(skeletal muscle) (motor neurons in ventral horn of spinal cord or equivalent area of brainstem)

Autonomic (cardiac muscle, smooth muscle, glands)

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85
Q

Parts of PNS

A

Sensory Neurons

Motor Neurons

Enteric Nervous System

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86
Q

Basic Unit of the Autonomic Nervous System

A

First Neuron

preganglionic synapse

Second Neuron

postganglionic synapse

Effector cell

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87
Q

Different pathways in PNS

A
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88
Q

Are synapses always 1:1 relays?

A

No

Allows for things like systemic verses local responses, or strengthening the intensity of a response.

89
Q

Dorsal root vs. Autonomic ganglia

A

DRG: no synapse; sensory

AG: synapse; motor

90
Q

Sympathetic vs. Parasymphatetic effect

A

Sympathetics often have more systemic effects too because of their association to the adrenal medulla and the principal of divergence.

91
Q

Where do parasympathetic fibers come from?

A

Cranial nerve III, VII, IX, X

S2-4

92
Q

Where do Sympathetic fibers originate?

A

T1-L2 Lateral horn

93
Q

Two locations where sympathetic neurons can synapse?

A

chain (paravertebral) ganglia

prevertebral/(preaortic) ganglia

94
Q

Destination of sympathetics

A

To the body wall

(T1T4) To the head: travel up in sympathetic chain “superior cervical”

(T1T12) To thoracic cavity: from cervical (cardiopulmonary plexus) thoracic ganglia (splanchnic nerves to heart/esophagus)

(T1T12) To lumber cavity: The Greater, Lesser and Least thoracic Splanchnics (prevertebral); pass throguh diapghgram “thoracic”

(L1L2) To lumber cavity: preaortic ganglia (Celiac, superior mesenteric, aorticorenal, inferior mesenteric) “lumbar”

(T1L2) To pelvic cavity: from lumbar by hypogastric nerves (most) others by sacral ganglion “sacral splanchnics”

(T8L1) To adrenal gland: traveling on the greater or lesser thoracic splanchnic

95
Q

Which direction the splanchnic nerves travel?

A

Antero-medial

96
Q

Name postganglionic cells in adrenal gland

A

Chromaffin cells

97
Q

Sensory fibers from viscera

Functions?

A

Reflexes

Pain

98
Q

How visceral afferent travel?

A

With parasympathetics (reflexes - autonomic, malaise)

With sympathetic (reflexes, localizable pain * often referred)

99
Q

Referred Pain

A

Referred pain means that pain from an organ is felt in a different part of the body.

100
Q

Mechanism of referred pain

A

Convergence of viscerosensory and somatic sensory fibers on the same dorsal horn cell causes pain to be felt in the skin or muscle.

101
Q

Modulators of autonomic system

A

Brainstem cardiovascular and respiratory centers

The hypothalamus

The cingulate cortex

The amygdala

102
Q

Epigenetics

A

Heritable traits (changes in phenotype) that do not involve changes to the underlying DNA sequence (changes in genotype).

103
Q

General examples of epigenetics

A
  1. Cellular differentiation (Cell fate is maintained by differential methylation of the DNA.)
  2. X-inactivation (random DNA methylation, XIST RNA binding, and chromatin remodeling during implanation)
  3. Metabolic imprinting (exposure during pre-natal and neo-natal periods e.g. grandparents in Europe, agouti mouse)
  4. Genomic imprinting (some genes are expressed from only a single copy parent speicifc origin Beckwith-Wiedmann, Prader-Willi, and Angelman)
104
Q

Genomic Imprinting mechanism

A

In all somatic cells the paternal chromosome (inherited from the father) can be distinguished from the maternal chromosome (inherited from the mother) due to differential markings.

Marking occurs during gametogenesis. It is initiated by differential methylation of specific sites (imprinting control regions; ICR) and maintained by regulatory RNA binding and chromatin remodeling. ICRs are methylated on only one of the two chromosomes.

The differential marking is maintained in all somatic cells throughout life, but is erased in the germline cells, then reestablished during gametogenesis.

105
Q

Genome imprinting and IVF

Genome impringing and cloning

A

Increased prevalence of AS and BWS in pregnancies conceived by **IVF **(genomic imprinting errors, not new mutations)

Genomic imprinting errors common in clones (mice)

106
Q

Beckwith-Wiedemann syndrome

A

Disorder of growth characterized by **large size for gestational age, large tongue, abdominal wall defects, and predisposition to **embryonic tumors (e.g. Wilms tumor, neurofibromas).

two active copies of IGF-2 gene and/or no active copy of CDKN1C

IGF-2 expressef from paternally inherited chromosome

CDKN1C expressef from maternally inherited chromosome

Controlled by methylations at DMR1/2 sites

60% cases due to loss of methylation @ DMR2

10% cases due to mutatin @ CDKN1C

20% cases due to paternal uniparental disomy

107
Q

Prader-Willi Syndrome vs. Angelman

A

PWS: short stature, hypotonia, small hands and feet, obesity, mild to moderate mental retardation, and hypogonadism.

AS: severe mental retardation, seizures, and ataxic gait.

70% caused by the same deletion (3-4Mbs)

PWS region- 5 genes; active only on the paternally derived chromosome.

AS gene- UBE3A; active only on the maternally derived chromosome.

* maternal nondisjunctions occur more often

108
Q

Diagnostic technique for Prader-Willi syndrome

A

methylation-sensitive restriction enzyme analysis

109
Q

Which structures only receive input from sympathetic

A

piloerector muscles

sweat glands

most blood vessels

110
Q

What is an exception from two neuron rule?

A

Adrenal medulla

111
Q

Function of chromaffin cells

A

Rlease “neurotransmitter” epinephrine into blood stream

Epinephrine and norepinephrine

112
Q

Neurotransmitters of ANS

Types?

Location where they are secreted?

Name for neurons?

Where are they found else?

A

Acetylcholine

all preganglionic neurons

para postganglionic neurons

muscle

“cholinergic”

also in CNS

Norepinephrine

symp postganglionic

exceptions: sweat glands (ACh) and chromaffin cells (Epi/Nore)

“noradrenergic”

also in CSN

**Epinephrine **

Chromaffin cells

also in CSN

Dopamine

postganglionic sympathetic neuroeffector junctions in the kidney

“dopaminergic”

also in CSN

113
Q

General types of neurotransmitter receptors in the ANS

A

Cholingergic (Ach)

Adrenergic (Epi)

114
Q

Types of cholindergic receptors

Subtypes

Drugs acting on these

A

Nicotinic (ligand gated)

Subtypes: Ganglionic NN and Muscle NM

Low dose stimulation; high dose blocking

Curarae blocks NN and NM

Muscarinic Receptors (GPCR)

Subtypes: M1-M5

Odd: Formation of IP3 (+) Ca2+ and DAG => PKC

Even: K+ channels activation (hyperpolarization) inhibit Adenylyl cyclase (decrease cAMP)

Muscarine activates Atropine blocks

115
Q

Types of adrenergic receptors

Location and functions

A

Alpha (IP3->Ca++ and DAG activate PKC)

a1 receptors (smooth muscle & glandular tissue | sm contraction)

a2 receptors (presynaptic neuron | inhibit norepinephrine release)

Beta (+ adenylyl cyclase and + cAMP)

b1 receptors (heart | increase rate and contractillity)

b2 (smooth muscle | sm relaxation)

b3 (adipocytes | lipolysis)

116
Q

“Computations” in ganglia

A

Divergence and convergence allow for integration of neural input and modulation of end organ responses, as opposed to all-or-none responses, which you see with somatic motor neurons and the neuromuscular junction (NMJ)

117
Q

Neuromuscuar junction vs. autonomic synapse

Where is neurotransmitter released from?

Receptor location?

Fibers connection?

A

Nerve terminal | Varicosities

End plate of cell | Distributed across entire plate

One muscle receives input from one motor neuron | Signal from multiple postynaptic neurons

Quick and all-or-none | Slow and modulatory

118
Q

EPSP

IPSP

A

excitatory postsynaptic potential

inhibitory postsynaptic potential

119
Q

Where parasympathetic and symphatetic stimulations produce the same response?

A

Salivary glands

120
Q

Sympathetic Flight of flight response in

Eye

Heart

Blood Vessels

GI

Bladder

Skeletal muscle

A

Eye: Pupil open; distant focus

Heart: Increased rate & force of contraction

Blood vessels: Constriction

GI: Decreased motility, sphincters constricted

Bladder: Bladder wall relaxed, internal sphincter contracted

Skeletal Muscle Stimulate glycogenolysis

121
Q

Sympathetic and Parasympathetic effect on Heart

A

SA node

Sympathetic activation of β1 adrenergic receptors has a positive chronotropic effect (increases heart rate)

Parasympathetic activation of M2 muscarinic receptors has a negative chronotropic effect (decreases heart rate)

AV node

Sympathetic activation of β1 adrenergic receptors has a positive dromotropic effect (increases conduction velocity)

Parasympathetic activation of M2 muscarinic receptors has a negative dromotropic effect (decreases conduction velocity)

Ventricular muscle

Sympathetic activation of β1 adrenergic receptors has a positive inotropic effect (increases contractility)

Parasympathetic activation of M<strong>2</strong> muscarinic receptors antagonizes sympathetic responses. In the absence of sympathetic tone, parasympathetic activation has little or no effect on the ventricles.

122
Q

Sympathetic and Parasympathetic effect on Blood vessels

A

α1 adrenergic receptors cause vascular smooth muscle contraction and constriction of blood vessels.

β2 adrenergic receptors cause relaxation of vascular smooth muscle and dilation of blood vessels.

123
Q

Where parasympathetic has effect on blood vessels?

A

the face, tongue, genitals and urinary trac

124
Q

Sympathetic and Parasympathetic effect on Adrenal Medulla

A

Sympathetic stimulation by preganglionic neurons that synapse directly with chromaffin cells in the adrenal medulla causes the release of epinephrine and norepinephrine into the circulation.

125
Q

Sympathetic and Parasympathetic effect on Lungs

A

Sympathetic activation of β2 adrenergic receptors causes relaxation of bronchial smooth muscle and dilation of the airways.

Parasympathetic activation of muscarinic receptors causes contraction of bronchial smooth muscle and constriction of the airways & stimulation of secretion of bronchial glands

126
Q

Sympathetic and Parasympathetic effect on Pupil

A

Sympathetic activation of α1 adrenergic receptors

Contracts iris radial muscles, dilating the pupil (mydriasis).

Parasympathetic activation of muscarinic receptors

Contracts iris circular muscles, constricting the pupil (miosis)

127
Q

Sympathetic and Parasympathetic effect on Eye

A

Sympathetic activation of β2 adrenergic receptors

Relaxes ciliary muscles allowing the lens to focus on far object

Stimulates ciliary epithelium secretion of aqueous humor

Parasympathetic activation of muscarinic receptors

Contracts ciliary muscles

Causing the lens to focus on near objects.

Increasing outflow of aqueous humor through trabecular meshwork into canal of Schlemm

128
Q

Sympathetic and Parasympathetic effect on Stomach and Intestines

A

Sympathetic activation of

β2 and α2 receptors decreases motility and tone

α receptors contracts sphincters

Parasympathetic activation of muscarinic receptors

increases gut motility and tone

relaxes sphincters

stimulates glandular secretion

129
Q

Autonomic regulation of the gut can involve enteric neurons

A
130
Q

Sympathetic and Parasympathetic effect on Urinary Bladder

A

Sympathetic activation (promotes filling)

α adrenergic receptors contract the internal sphincter muscle

β adrenergic receptors relax the detrusor muscle

131
Q

Sympathetic and Parasympathetic effect on Salivary Gland

A

Sympathetic activation

α receptors cause a weak increase in potassium and water secretion

β receptors cause a weak increase in amylase secretion

Parasympathetic

activation of muscarinic receptors causes a pronounced increase in potassium and water secretion.

132
Q

Sympathetic and Parasympathetic effect on Skin

A

Sympathetic activation

α receptors **contract pilomotor muscles **muscarinic receptor activation by **acetylcholine **released from postganglionic sympathetic fibers causes generalized sweating

133
Q

Organ vs. Predominant responce of ANS

A
134
Q

Two types of synapses?

A

Electrical (heart) and chemical

135
Q

Citeria for neurotransmitter identification

A

Presence (at terminal)

Release (due to depolarization and Ca2+ dependent)

Identity of action (control of posynaptic neuron inh/stim)

Removal (mechanism for removal from synaptic cleft)

136
Q

Nonadrenergic noncholinergic (NANC) transmission

A

Evidence that chemical transmission at some neuroeffector synapses (e.g., gut) does not involve either norepinephrine or acetylcholine.

Most neurons actually release multiple substances

Can act as modulators

adenosine 5’-triphosphate (ATP)
vasoactive intestinal peptide (VIP)
neuropeptide Y (NPY)
leutinizing hormone releasing hormone (LHRH)
5-hydroxy tryptamine (5-HT or serotonin)
nitric oxide (NO)
gamma-amino butyric acid (GABA)
substance P
•dopamine

137
Q

Lifecycle of neurotransmitter

A
  1. Synthesis
  2. Storage
  3. Release
  4. Receptor interaction
  5. Disposition
138
Q

Ach cycle

A

ACh is synthesized from Acetyl CoA and choline by the enzyme choline acetyltransferase

ACh is transported into vesicles by the vesicle-associated transporter (VAT)

ACh is released when Ca2+ influx into nerve terminal facilitates vesicular fusion by docking proteins

synaptosome associated proteins (SNAPs)

vesicle-associated proteins (VAMPs)

bind to nicotinic or muscarinic receptors on the postsynaptic membrane

be broken down by acetylcholinesterase (AChE) into choline and acetate

Choline can then be recycled by transport back into the presynaptic nerve terminal by the Na+-dependent choline transporter (CHT)

139
Q

SNARE proteins used in ACh transport

A

VAMPs (vesicle associated membrane proteins)
osynaptobrevin

SNAPs (synaptosome associated proteins)
syntaxin
SNAP 25

140
Q

Drugs affecting cholinergic transmission

Synthesis

Stroage

Release

Deposition

A

synthesis – hemicolinium inhibits the Na+-dependent choline transporter (CHT)

storage – vesamicol inhibits the vesicle-associated transporter (VAT)

release – botulinum toxin blocks exocytosis by modifying vesicle docking proteins:

synaptasome associated proteins (SNAPs)

vesicle-associated membrane proteins (VAMPs)

disposition – neostigmine inhibits acetycholinesterase

141
Q

Receptor agonists and antagonists for cholinergic receptors

A
  • *agonists**
  • *ACh** – nicotinic (N) and muscarinic (M) receptors
  • *nicotine** – nicotinic receptors
  • *bethanacol** – muscarinic receptors
  • *antagonists**
  • *trimethaphan** – neuronal nicotinic receptors (NN)
  • *d-tubocurarine** – muscle nicotinic receptors (NM)
  • *atropine** – muscarinic receptors
142
Q

NE cycle

A

Tyrosine is taken up into the presynaptic nerve terminal by a Na+-dependent amino acid transporter (A) where it is then converted to DOPA by the rate limiting enzyme tyrosine hydroxylase.

DOPA is then converted to dopamine by the enzyme DOPA decarboxylase (also called dopamine decarboxylase).

Dopamine is then transported into vesicles by the vesicular monoamine transporter (VMAT). The predominant adrenergic neurotransmitter released depends on what enzymes are present in the vesicles.

In the presynaptic nerve terminal of most postganglionic adrenergic neurons in the ANS, dopamine is converted to norepinephrine by dopamine beta-hydroxylase.

In chromaffin cells, norepinephrine is converted to epinephrine by phenylethenolamine N-methyltransferase (PNMT).

Once released into the synaptic cleft, norepinephrine (NE) can either
bind to pre or postsynaptic adrenergic receptors
be taken up by the presynaptic nerve terminal or other cells (extraneuronal)
diffuse out of the cleft

  • *Neurotransmitter** taken up by the presynaptic nerve terminal can be
  • *Transported** back into vesicles by the VMAT, or
  • *Metabolized** by monoamine oxidase (MOA)

Neurotransmitter taken up extraneuronally can be metabolized by MAO and COMT

Neurotransmitter not taken up is metabolized primarily by COMT found in the liver

143
Q

Drugs affecting adrenergic transmission

Synthesis

Stroage

Release

Deposition

A

synthesis – α-methyltyrosine inhibits tyrosine hydroxylase

storage – reserpine inhibits the vesicular monoamine transporter (VMAT)

  • *release** – bretylium, guanethadine, and clonidine
  • *bretylium inhibits** the nerve action potential preventing Ca2+ influx
  • *guanethadine** is taken up into nerves by the NET. It then gets concentrated in the synaptic vesicles, displacing endogenous sympathetic neurotransmitters.
  • *clonidine** inhibits catecholamine release by activating α2 receptors on the presynaptic nerve terminal.

disposition

  • *entacapone inhibits** catechol-O-methyl transferase (COMT)
  • *pargyline inhibits** monoamine oxidase (MAO)
  • *cocaine** and amphetamines inhibit neuronal reuptake by the norepinephrine transporter (NET)
144
Q

Adrenergic Transmission Agonists & Antagonists

A

α agonists
-oxymetazoline – α1 and α2 receptors
-phenylephrine – α1 receptors
-clonidine – α2 receptors
-
α antagonists
-phentolamine – α1 and α2 receptors
prazosin – α1 receptors
yohimbine – α2 receptors
-
β agonists
isoproterenol – β1 and β2 receptors
dobutamine - β1 receptors
terbutaline – β2 receptors
-
β antagonists
propranolol – β1 and β2 receptors
metoprolol – β1 receptors

145
Q

Chatecholamines

Definition?

Two moieties?

A

Class of compounds that include the endogenous neurotransmitters and hormones released by adrenergic neurons in the sympathetic nervous system.

Catechol (benzene ring with hydroxyls at the 3 (meta) and 4 (para) positions) and ethylamine

146
Q

Sympathomimetics

A

Exogenous compounds that imitate the functional responses produced by endogenous catecholamines

147
Q

Sympatholytics

A

exogenous compounds that block the functional responses to endogenous catecholamines or sympathomimetics

148
Q

What needs to be understand to understand response to a catecholamine?

A

Type of receptor

Type of tissue

The signaling pathway activated by receptor

Are the effects direct and/or indirect

149
Q

4 molecular types of

responses to catecholamines

their effect

types of membrane protein

A

[Gq] a1: (+) PLC = sm contraction

[Gi/o] a2: (-) Ca++ = inhibit neurotranmitter AND (-) AC = inhibit sm contract

[Gs] b: (+) AC => cardiac contractility, sm relaxation, glycogenolysis

[Gs] D1/5 (+) cAMP => sm relxation

150
Q

a1 receptors

location

signaling mechanism

response

A
  • *blood vessels**
  • *eye** (iris radial muscle)
  • *bladder** (sphincter muscle)
  • *skin** (piloerector muscles)
151
Q

a2 receptors

location

signaling mechanism

response

A

Some vascular smooth muscle (-) AC => Vasoconstriction

Central and peripheral presynaptic nerve terminal (+) Gi/o inhibition of presynaptic Ca++ channels => inhibition of neurotransmitter release

152
Q

b1 receptors

location

signaling mechanism

response

A

heart Gs (+chronotropic, +dromotrophic, +inotropic, +lusitropic)

kidney Gs (+renin secretion from JG-cells)

153
Q

b2 receptors

location

signaling mechanism

response

A

Cardiac muscle (Gs) => (+) HR and contracitility

Smooth muscle (vascular, airway, gastrointestinal, bladder (detruser), uterus) => Relax smooth muscle

Liver => Increase glycogenolysis

154
Q

b3 receptors

location

signaling mechanism

response

A

adipose tissue (Gs) => lipolysis

155
Q

D1 D5 receptors

location

signaling mechanism

response

A

vascular smooth muscle

Gs

smooth muscle relaxation

156
Q

D2-4 receptors

location

signaling mechanism

response

A

central nervous system

Gi (-) AC

CNS control of motor movement and regulation of prolactin secretion

157
Q

Can you find multiple adrenergic receptors in one cells type?

Can adrenergic molecules have multiple effects?

Is there a further subclassification for adrenergic receptors?

A

Y

Y

Y

158
Q

Classes of sympathomimetics

A

Direct (acting compounds produce their effects by directly activating adrenergic receptors. Endogenous catecholamines belong to this class)

Indirect (acting compounds produce their effects by increasing the availability of endogenous catecholamines. This can be achieved by: inhibiting reuptake, stimuating release, inhibiting metabolism)

Mixed (both)

159
Q

Direct sympathomimetics

Molecular charactersitics?

Modulation of activity?

A

Direct acting sympathomimetics will have substitutions on at least 2 of the following 3 positions:

the meta position on the benzene ring,

the para position on the benzene ring, or

the beta carbon of the ethylamine side chain, and it must be a hydroxyl.

Large substitutions on the terminal nitrogen tend to promote β adrenergic receptor activity.

Small substitutions tend to promote α adrenergic receptor activity

Hyroxyl substitutions on the 3 and 5 positions of the benzene ring tend to enhance β2 adrenergic receptor selectivity.

160
Q

Indirect Sympathomimetics

Molecular charactersitics?

Chirality issue

Structure vs. location of the effect

Metabolism

A

Indirect acting sympathomimetics will have no or only 1 substitution at either the meta or para postion of the benzene ring or the beta-carbon of the ethylamine side chain.

Both D and L might be active. (e.g. Amphetamine+)

b carbon increase CNS effects

COMT not metabolize if either 3 or 4 hydroxyl is missing

161
Q

Imadazolines

A

Imadazolines are a class of sympathomimetics that contain an imidazole moiety. Many of these compounds are potent α agonists used as vasoconstrictors in topical over the counter nasal and ophthalmic preparations.

OTC

162
Q

Therapeutic use of Norepinephrine

A

a1>a2 b1>>b2

  • therpeutic use (limited) hypotension (shock)
  • cardivascular responses (a1/b1): (+) heart contractility b1; (-) reflex rate (+) vasocontrction a1; (+) s&d pressure
  • smooth muscle (a1) not much effect on airway, gut, uterus not many receptors; (+) radial muscle in iris mydriasis; (+) bladder sphincter contraction
163
Q

Therapeutic use of Epinephrine

A

a1=a2 b1=b2

  • therapeutic use: bronchospasm, anaphylatic shock, cardiac arrest, open angle glaucoma, local anesthetic (adjunct)
  • cardiovasuclar resposnes (b1/b2) low dose similar to isorpoterenol (b1b2) high dose similar to norepinephrine (a1/b1)
  • smooth muscle (a1 and b2 effects)

airways = significant dialation (b2)

gut = transient decrease in motility (b2)

bladder = relaxation of detrusor muscle (b2)

contraction of sphincter muscle (a1)

uterus relaxation (b2)

164
Q

Therapeutic use of Dopamine

A

D1-5 > b > a

  • therapeutic use = cardiogenic short; heart failure
  • cardivascular resposnes (D1/5, b1, and a1 effects)

D1/5 activation increasing blood floow and urin production

intermediate doses activate b1 receptors icnrease CO

high dose activation a1 casuing vasoconstriction and increasing BP

  • central effects

controlling motor movememnt in basal ganglia; inhibits prolactin secretion in the anterior pituitary

165
Q

Therapeutic use of Isoproterenol

A

β1=β2=β3

  • therapeutic use = bradycardia (heart block, cardiac arrest), bronchospasms
  • cardiovascular responses (β1 and β2 effects)

increase in cardiac output due to increased heart rate and contractility (β1)
vasodilation of most vascular beds (β2)
increase in systolic and pulse pressure, decrease in diastolic pressure, slight decrease in MAP

other smooth muscle responses (β2 effects)
airways – significant dilation
gut – transient decrease in motility
bladder – relaxation of detrusor muscle (promotes filling)
uterus – relaxation

166
Q

Difference in effects of

Norepinephrine

Epinephrine

Isoproterenol

A
167
Q

Therapeutic use of Dobutamine

A

b1>b2

therapeutic uses – cardiogenic shock, acute heart failure

mechanism of action

(+) dobutamine – selective activation of β1 receptorsa a1 antagonist

(-) dobutamine – α1 agonist

pharmacologic responses
•increased cardiac output (β1) primarily through an increase in contractility
•increase in systolic and pulse pressure (little change in diastolic pressure) increase in MAP

168
Q

Therapeutic use of Terbutaline

A

mechanism of action – selective activation of β2 receptors

pharmacologic responses – smooth muscle relaxation, especially

airwaysotherapeutic uses – obstructive airway diseases, acute bronchospasms, preterm labor

169
Q

Therapeutic use of Oxymetazoline

A
  • *mechanism of action** – selective activation of α receptors (α1 and α2)
  • *pharmacologic responses** – smooth muscle contraction, especially vascularo

therapeutic uses – nasal decongestant

170
Q

Therapeutic use of Phenylephrine

A

omechanism of action – selective activation of α1 receptors

pharmacologic responses – smooth muscle contractionotherapeutic uses – vasopressor, nasal decongestant, mydriatic

other α1 selective agonists – midodrine, methoxamine, metaraminol

171
Q

Theraputic use of Clonidine

A

mechanism of action – selective activation of α2 receptors

pharmacologic responses – reduced sympathetic tone (central effect), inhibits NE release

therapeutic uses – hypertension, reducing sympathetic responses associated with withdrawal, analgesic adjuvant

other α2 selective agonists – α-methyldopa, guanfacine, guanabenz, dexmedetomidine

172
Q

Amphetamine

A

mechanism of action – indirectly acting sympathomimetic; stimulates the release of neurotransmitters (central and peripheral

pharmacologic responses
•increased cardiac output
•vasoconstriction - increases systolic, diastolic, and mean arterial pressure
•contraction of urinary bladder sphincter
•CNS stimulation

therapeutic uses – narcolepsy, attention deficit hyperactivity disorder (ADHD), appetite suppression, enuresis, incontinence

toxicity
•CNS effects - restlessness, dizziness, tremor, irritability, anxiety, delirium, paranoia, hallucinations
cardiovascular effects – severe hypertension,

173
Q

Therapeutic use of Ephedrine

A

mechanism of action – mixed acting sympathomimetic: stimulates release of NE, also causes direct activation of α and β receptors

pharmacologic responses – vasoconstriction, positive inotropy, bronchodilation, CNS stimulationo

therapeutic uses – bronchodilator, nasal decongestant, mydriatic, narcolepsy

174
Q

Therapeutic use of Phenylzine

A

mechanism of action
•blocks catecholamine metabolism by inhibiting monoamine oxidase (MAO)

therapeutic uses
•depression
•Parkinson’s disease

pharmacologic responses
•enhance neurotransmission at catecholaminergic synapses

175
Q

Factors that may affect drug transport across membrane

A

Lipid-water partition coefficient

size of the molecule

concentration gradient

pH

active vs. passive transport

paracellular transport

176
Q

4 ways of transporting drug across barriers

A

Paracellular tranport

Facilitated diffusion

Diffusion

Drug transporters

177
Q

Two major superfamilies of transporters

A

ATP-binding cassette (ABC) transporters

Active tranport; 49 genes in seven families ABCA-ABCG

P-glycoprotein; CFTR

Solute carrier trasnporters (SLC)

Facilitated transporters and ion-coupled secondary active transporters; 300 different proteins

Serotonin transporter (SERT); dopamine transporter (DAT)

178
Q

Perfusion

A

is the process of a body delivering blood to a capillary bed

179
Q

How drug can be metabolized?

A

Active/inactitve

Oxidations/Hydrolytic/Conjugative

180
Q

Example of drug target? (SERT inhibitor)

Example of drug resistance?

Example of Drug-Drug Interactions?

A

fluoxetine (Prozac®)

P-glycoprotein

cyclosporine A inhibits OATP transporters, which is at the same time a substrate of CYP3A4

181
Q

Cytochrome enzyme types

A

Phase 1 “oxygenases”

Phase 2 “transferases”

Other “dehydrogenases”

182
Q

CYP (cytochrome 450 gene) proteins

charactersitics

A

57 genes, 18 families, 43 subfamilies

families 1,2,3 are responsible for drug metabolism

Rates of metabolism are slow

Overlapping specificity

Competition leads to ADR

SNPs present

CYP3A4/5 family with most enzymes

183
Q

Cytochrome P450 Nomenclature

A

CYP2D6

CYP = cytochrome P450

2 = genetic family

D = genetic sub-family

6 = specific gene

genetical not functional

184
Q

Major cytochrome P450 isoenzymes that are responsible for metabolism of drugs in humans

A

CYP1A2

CYP3A

CYP2C9

CYP2C19

CYP2D6

185
Q

Polymorphic distribution of CYP2D6 vs. treatment

A
186
Q

Grapefruit Juice and CYP

A

Potent inhibitor of intestinal cytochrome CYP3A4

Can lead to increase in bioavailability in serum drug levels

187
Q

Inducers of CYP3A

A

Carbamazepine
Rifampin
Rifabutin
St. John’s wor

It is a medicinal herb with antidepressantproperties and potential antibacterial and anti-inflammatory properties.

Neurotransmitter re-uptake inhibition Involving 5-HT, dopamine, oradrenaline And possibly GABA and glutamate.

188
Q

What is the function of CYP3A?

Where is it found?

A

In GI tract and liver

Metabolism of:
–Most calcium channel blockers
–Most benzodiazepines
–Most HIV protease inhibitors
–Most HMG-CoA-reductase inhibitors
–Cyclosporine
–Most non-sedating antihistamines
–Cisapride

189
Q

CYP3A inhibitors

A

Ketoconazole
Itraconazole
Fluconazole
Ritonavir
Cimetidine
Clarithromycin
Erythromycin
Troleandomycin
Grapefruit juice

190
Q

CYP2D6

Allele in populations?

What does it metabolize?

Inhibitors?

A

Absent in 7% caucasians, 1-2% non-caucasians

Metabolize: codeine, b-blockers, tricyclic antidepressants

Inhibited by: Fluoxetine (Prozac), Haloperidol, Paroxetine (Paxil), Quinidine

191
Q

CYP2C9

Allele in populations?

What does it metabolize?

Inhibitors?

A

Absent in 1% caucasians and african americans

Metabolism: NSAID (including COX-2), S-warfarin, phenytoin

Inhibites: Fluconazole

192
Q

CYP2C19

Allele in populations?

What does it metabolize?

Inhibitors?

A

Absent in 20-30% asians, and 3-5% caucasians

Primary metabolism of:
–Diazepam
–Phenytoin
–Omeprazole

Inhibited by:
–Omeprazole
–Isoniazid
–Ketoconazole

193
Q

CYP1A2

Allele in populations?

What does it metabolize?

Inhibitors?

A

Induced by smoking tabaco

•Catalyzes primary metabolism of:
–Theophylline
–Imipramine
–Propranolol
–Clozapine

•Inhibited by:
–Many fluoroquinolone antibiotics
–Fluvoxamine
–Cimetidine

194
Q

Drug-Disease Interactions

A

Liver disease
Renal disease
Cardiac disease (hepatic blood flow)
Acute myocardial infarction?
Acute viral infection?
Hypothyroidism or hyperthyroidism?

195
Q

Ion Trapping

A

Altering pH to keep or remove compound from serum

196
Q

Bioavailability

Definition?

A

The fraction of the admnistered dose that reaches the systemic circulation

Higher absorption => (+) Bioavailability

F = AUCrouter/AUCIV=AUCP.O./Dose

197
Q

Pharmacokinetics vs. Pharmacodynamics

A

PK: What your body does to the drug (change in [c] as the drug moves in a body)

PD: What tyhe drug does to your body

198
Q

AUC

A

Are Underneath the Curve

199
Q

Volume of distribution

A

Vd=Total Mass Absorbed / Cplasma

200
Q

Parasympathomimetics

A

exogenous compounds that imitate functional responses associated with parasympathetic stimulation

201
Q

Cholinomimetics

A

exogenous compounds that imitate functional responses produced by acetylcholine (ACh) at cholinergic receptors

202
Q

Cholinergic Antagonists

A

compounds that block cholinergic transmission at involving muscarinic receptors (antimuscarinics), neuronal nicotinic receptors (ganglionic blockers) or the neuromuscular junction (neuromuscular blockers).

203
Q

Four things to understand for cholinomimetics

A

the type of cholinergic receptor involved

the type of cell and/or tissue involvedo

the signaling pathway activated by that receptoro

whether or not the effects or direct or indirect

204
Q

Mechanism of cholinergic receptors

A
205
Q

Effects of cholinergic receptors

A
206
Q

NM receptors

location?

Signalling mechanism?

Structure?

Response?

A

Muscle

Ligand gated

4 different subunits

Muscle contraction

207
Q

Nn receptors

location?

Signalling mechanism?

Structure?

Response?

A

Parasympathetic ganglia, adrenal medulla, CNS

ligand gated

composed of alpha and beta isofrom

neuronal excitation

208
Q

M1 M3 M5 receptors

location

signalling mechanism

A

Gq

sm (vessels, airways, eye, gut, bladder) / contraction

endothelial cells (blood vessels) / relax blood vessels

exocrine gland (salivary, sweat, airway, gut) / stimulate secretion

CNS

209
Q

M2 and M4 receptors

A

Gi aCyclase / K+ channels

cardiac muscle (M2) -chrono -dromo -iso

CNS (M4)

210
Q

Two types of cholinomimetics

A

Direct/Indirect

211
Q

Types of Direct Acting cholinomimetic

A

Akaloids

Choline Esters

Methyl substitution on β carbon (orange) of methacholine and bethanecol

  • reduces potency at nicotinic receptors
  • limits hydrolysis by cholinesterases

The carbamic acid ester group (green) of carbachol and bethanecol limits hydrolysis by cholinesterases.

212
Q

Types of indirect acting cholinomimetics

A

Indirect acting cholinomimetics work by inhibiting cholinesterase breakdown of endogenous ACh.

Acetylcholinesterase (AChE) – “true cholinesterase”

AChE contains two important sites at catalytic center
Anionic site – interacts electrostatically with charged nitrogen and methyl groups of ACh
Esteratic or esteric site – serine that combines via hydroxyl group with electrophilic carboxyl residue of the acetyl group of ACh

Steps:

Binding of ACh to anionic site
Cleavage of ACh at the ester linkage releasing choline
Reaction with water yielding acetic acid

Butyrylcholinesterase (BuChE) – “pseucocholinesterase”

213
Q

How AChE inhibitors can block ACh hydrolysis?

Effects?

A

Two types:

Interfering with anionic site, or

Interfering with esteratic site

Effects:

Low levels – increase skeletal muscle activity (fasciculations)

High levels – neuromuscular blockade

Increased ganglionic transmission

Complex cardiovascular responses

CNS effects

214
Q

Types of indirect acting cholinomimetics

A

Mono- or bis-quaternary amines – edrophonium

Carbamates – neostigmine, physostigmine

Organophosphates:

  • echothiophate – used clinically
  • parathion, malathion, diazinon used as insecticides
  • Form “irreversible” covalent bond with the esteratic site of cholinesterases
  • Pralidoxime or 2-PAM (2-pyridine aldoxime methyl chloride) can be used to “regenerate” cholinesterase. Used to treat organophosphate poisoning
  • Cholinesterase interaction with organophosphates can undergo “aging”, preventing reversal by 2-PAM.
215
Q

Bethanacol

Therapeutic use

Effects

Mechanisms of action

A

therapeutic use
•postoperative and neurogenic ileus
•postoperative urinary retention
•
effects – causes smooth muscle contraction (GI and urinary tract)
o
mechanisms of action –
•muscarinic agonist – activates M1 and M3 receptors
•negligible effect at nicotinic receptors

216
Q

Pilocarpine

Therapeutic use

Effects

Mechanisms of action

A

therapeutic use
•Glaucoma
•Sjögren’s syndrome, xerostomia

effects
•contracts sphincter and ciliary muscles of the eye facilitating aqueous humor outflow (glaucoma)
•stimulates salivary gland and tear duct secretions (Sjögren’s)

mechanisms of action – muscarinic agonist (primarily M3 receptor)

217
Q

Nicotine

Therapeutic use

Effects

Mechanisms of action

A

therapeutic use
•medical – smoking cessation
•non-medical – smoking, insecticides
effects
•activates NN receptors in central nervous system
•activates NN receptors on postganglionic sympathetic and parasympathetic neurons
•activates NM receptors at the neuromuscular junction

mechanisms of action – agonist at NM and NN receptors

218
Q

Neostigmine

A

therapeutic use
•treatment of myasthenia gravis
•postoperative and neurogenic ileus
•postoperative and neurogenic urinary retention

effects
•generalized parasympathetic stimulation

mechanisms of action – reversible cholinesterase inhibitor

Block 1 (25 decks)

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