Week 7 Random Flashcards
Peripheral nervous system subivisions
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)
CSN composition
PNS composition
CNS consist of spinal cord and brain
PNS includes nerve fibers and ganglia
Two types of nerves associated with PNS
Cranial (12) all different
Spinal (31) similar with composition but different targets
Component
Refers to whether the fiber is motor or sensory and somatic, visceral or special.
Spinal nerve components
General Sensory (GSA) : touch, feel
Viscerosensory (GVA) : streech recepotrs in blood vessels
Somatomotor (GSE) : muscle moving
Visceromotor (GVE) : vasoconstriction, sweat gland muscle, arrector pili
Components abbreviations, names, and function
(SSA)
(GSA)
(GVA)
(SVA)
(GVE)
(GSE)
(SVE)
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)
Where do cranial nerves come from? Types?
Brain and brainstem
Some are motor, some are sensory, and others are mixed
Formation of spinal nerves
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)
How do you know which side of the spinal cord are you looking at?
Dorsal root has ganglion
Dorsal horn externs further than anterior
Where do motor fibers originate?
Grey matter
* sensory synapse may be in the gray matter
Name of a fiber that comes out of the spinal cord
Rootlet
What rootlets form
Dorsal or ventral root that merges to form spinal nerve
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?
Yes
What does the spinal nerve branches into?
What are the functions of these branches?
How is the afferent neurons divided?
Peripheral process (toward the organ)
Central process (toward the spinal cord)
Function of dorsal ramus vs. ventral ramus?
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
Which type of PNS has ganglia?
GVE (parasymphatetic / symphatetic)
* sensory fibers do not have ganglia
Where cell bodies are located for sensory, visceromotor, and somatomotor?
Sensory = Dorsal root ganglion (DRG)
Visceromotor = lateral horn (intermediate grey) T1-L2 symp and S2-4 for para
Somatomotor = ventral horn
Spinal nerves vs. Splanchnic nerve
Spinal nerves do not supply the body cavities, only body wall structures.
Splanchnic nerves and the vagus supply cavities.
Communicating rami
Fibers that connecte spinal nerve and sympathetic chain.
How efferent neuron can be activated?
By afferent neuron
By control from CSN
Dermatome
Skin innervated by a single spinal nerve (specifically the cutaneous branch).
Examples of dermatomes
C2 - back of head
T4 - nipple
T10 - belly
L1 - back legs
Myotome
The group of muscles that a single spinal nerve root innervates
Pattern of innervations to muscle innervation from a single spinal nerve
Level loss
In spinal injury all control is lost below the level.
Periopheral Nerves vs. Spinal Nerves
Nerve that comes off the plexus (periferal) = multiple combinations of spinal nerves
How many neurons are in parasymapthetic / sympathetic division?
2
Preganglionic
Postganglionic
Location of ganglion for sympathetic vs. parasympathetic
Near organ = parasympathetic
Near spinal cord = sympathetic
Which autonomic division is connected to body wall (dermatome)?
Sympathetic
Origin of sympathetic
T1-L2
Origin of parasympathetic
1st neuron in the CNS brainstem
sacral spinal cord S2-4
Parasympathetic innervations
Only innervates viscera in body cavities, glands in the head, the eye and erectile tissues.
Where do GSA fibers have their nuclei?
DRG
Function of Sympathetic Chain
Allows communication with CSN
Spinal nerves are inserted with
Where are the cell bodies located for the cutaneous branches of nerves?
GSA
GVE
GVA?
Are there overlaps between dermatomes?
Yes there is (ignore)
Herniated disk
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.
Contusion
a region of injured tissue or skin in which blood capillaries have been ruptured; a bruise
Most important role of symphatetic division?
Control of vasculature
Other: decrease gastric motility / smooth muscle / hair follices
What is the name of the nerve that goes to the body cavity?
Splanchnic nerve
Which branches do not contain parasympathetic nerves?
Branches of spinal branches
What are seven types of cells found in nerve system?
NEUROEPITHELIUM (neutral tube)
Neuroblast -> Neruon
Astroblast -> Protoplasmic Astrocyte
Astroblast -> Fibrous Astrocyte
Oligodendroblast -> Oligodendrocyte
Neuroepithelium -> Epithelium of Choroid Plexus
Neuroepithelium -> Ependyma cells
Ganglion vs. Nucleus
Ganglia (group of neurons outside the CNS)
Nucleus (group of neurons within the CNS)
How many neurons are in a human?
10^9
Functions of Neurons
- receive and integrate stimuli from many sources simultaneously
- translate stimuli to membrane potential
- propagate this membrane potential
- translate this electrical message into neurotransmitter
- deliver neurotransmitter to target cells
Two types of pigmentations in neurons
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.
Prominent structures in neurons
Perikaryon (cell body)
Large nucleus with owl-eye nucleolus
nissil bodies = rER
microtubules / neurotubules (24nm)
intermediate filaments / neurofilaments (10nm)
How many axons can be in a neuron?
Only 1
Term that describes impulses in axon
Axonal transport
Five axon components
Contains neurofilaments/neurotubules
- Axon Hilloc (no nissl bodies)
- PInitial Segment (between axon hillock and myelination; site of action potential initiation)
- Axon Proper
Two types of transport in axon
Anterograde transport (kinesin)
Retrograde transport (dynein)
Site of protein synthesis in neuron
Cell body
Dendrites
Increase surface area (dendritic spines) increased during young age later decreased
Lack golgi
Synthesize message
2 unique characteristics of neurons?
Need trophic stimuli (need signal from other cells to survive)
Types of synapses
Axosomatic synapse (synapse with body)
Axodendritic synapse (on dendrite)
Axoaxonic synapse (contacting another axon terminal)
Axospinous synapse (ending on dendritic spine)
Classification neurons by processes
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)
Classification of neurons by function
Motor Neurons: excite or inhibit
Sensory Neurons
Interneurons: chaining neurons; interaction
Classificaiton of neurons by postsynaptic neurotransmitter
Cholinergic - acetylcholine / parasympathetic postganglionic
Adrenergic - epinephrine / sympathetic postganglionic
Names, function, and location of neuroglial cells
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
What is glia cells?
Supporting cells in the CNS
Astrocytes
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)
Glia limitans
What junction connect endothelial cells in CNS?
Tight (BBB)
Oligodendrocytes
Most numerous
Myelination in CSN
Can myelinate several axons
Schmidt-Lanterman clefts maintain the membrane forming the mylein
Myelination PNS vs. CNS
Schwann cells vs. Oligodendrocytes
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
Microglia
Derived from monocytes
Smallest and least numerous
Phagocytic during injury
What 4th ventricle connects to?
Central canal
Ependyma chracteristics
Line ventricles
More than “simple cuboidal epithelium”
Connected by macula adherence and zona adherence
Four ventricles
2 latteral
3rd and 4th
Tanycytes
No basement membrane
Long processes go into brain and terminate near blood vessels and hypothalamic cells (neurosecretory).
Conntected by tight junctions.
Ependymal cells attachement
Attached by desmosomes
Choroid Plexus
capillary tufts push up ependyma into the brain ventricles
made up of simple cuboidal cells upon BM responsible for **production and maintenance of CSF **
Schmidt-Lanternman clefts
Allow oligodendrocytes / schwann cells to get nutrients through the “jelly wrap” to the axon that it is myelinating
Communication
Nerve Regeneration
PNS vs. CNS
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
Why CSF circulates?
Because it is under the pressure
Meninges
Scalp
Skull
Dura mater
Subdural space
Arachnoid membrane
Subarachnoid space
Pia mater
Brain
Cells in cerebral cortex
Layer 1 = molecular
Layer 2 = granular
Layer 3 = Pyramindal external (small)
Layer 5 = Pyramidal internal (large)
Cerebellum
- Molecular layer
- Purkinje cells
- Granule cells
Spinal cord structure
Nerve structure (histology)
Axon wrapped in endoneurium
Fassicle wrapped with perineurium
Nerve wrapped with epineurium
How to tell peripheral nerve from connective tissue?
Wavy
Node of Ranvier
Schwann cells hug axon
Fibroblasts do are not covered by layers
Synonym to visceral
Autonomic
Where does paraympathetic does not innervate?
Skin
Adrenal medulla
Two types of motor neurons
**Somatic **(skeletal muscle) (motor neurons in ventral horn of spinal cord or equivalent area of brainstem)
Autonomic (cardiac muscle, smooth muscle, glands)
Parts of PNS
Sensory Neurons
Motor Neurons
Enteric Nervous System
Basic Unit of the Autonomic Nervous System
First Neuron
preganglionic synapse
Second Neuron
postganglionic synapse
Effector cell
Different pathways in PNS
Are synapses always 1:1 relays?
No
Allows for things like systemic verses local responses, or strengthening the intensity of a response.
Dorsal root vs. Autonomic ganglia
DRG: no synapse; sensory
AG: synapse; motor
Sympathetic vs. Parasymphatetic effect
Sympathetics often have more systemic effects too because of their association to the adrenal medulla and the principal of divergence.
Where do parasympathetic fibers come from?
Cranial nerve III, VII, IX, X
S2-4
Where do Sympathetic fibers originate?
T1-L2 Lateral horn
Two locations where sympathetic neurons can synapse?
chain (paravertebral) ganglia
prevertebral/(preaortic) ganglia
Destination of sympathetics
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
Which direction the splanchnic nerves travel?
Antero-medial
Name postganglionic cells in adrenal gland
Chromaffin cells
Sensory fibers from viscera
Functions?
Reflexes
Pain
How visceral afferent travel?
With parasympathetics (reflexes - autonomic, malaise)
With sympathetic (reflexes, localizable pain * often referred)
Referred Pain
Referred pain means that pain from an organ is felt in a different part of the body.
Mechanism of referred pain
Convergence of viscerosensory and somatic sensory fibers on the same dorsal horn cell causes pain to be felt in the skin or muscle.
Modulators of autonomic system
Brainstem cardiovascular and respiratory centers
The hypothalamus
The cingulate cortex
The amygdala
Epigenetics
Heritable traits (changes in phenotype) that do not involve changes to the underlying DNA sequence (changes in genotype).
General examples of epigenetics
- Cellular differentiation (Cell fate is maintained by differential methylation of the DNA.)
- X-inactivation (random DNA methylation, XIST RNA binding, and chromatin remodeling during implanation)
- Metabolic imprinting (exposure during pre-natal and neo-natal periods e.g. grandparents in Europe, agouti mouse)
- Genomic imprinting (some genes are expressed from only a single copy parent speicifc origin Beckwith-Wiedmann, Prader-Willi, and Angelman)
Genomic Imprinting mechanism
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.
Genome imprinting and IVF
Genome impringing and cloning
Increased prevalence of AS and BWS in pregnancies conceived by **IVF **(genomic imprinting errors, not new mutations)
Genomic imprinting errors common in clones (mice)
Beckwith-Wiedemann syndrome
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
Prader-Willi Syndrome vs. Angelman
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
Diagnostic technique for Prader-Willi syndrome
methylation-sensitive restriction enzyme analysis
Which structures only receive input from sympathetic
piloerector muscles
sweat glands
most blood vessels
What is an exception from two neuron rule?
Adrenal medulla
Function of chromaffin cells
Rlease “neurotransmitter” epinephrine into blood stream
Epinephrine and norepinephrine
Neurotransmitters of ANS
Types?
Location where they are secreted?
Name for neurons?
Where are they found else?
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
General types of neurotransmitter receptors in the ANS
Cholingergic (Ach)
Adrenergic (Epi)
Types of cholindergic receptors
Subtypes
Drugs acting on these
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
Types of adrenergic receptors
Location and functions
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)
“Computations” in ganglia
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)
Neuromuscuar junction vs. autonomic synapse
Where is neurotransmitter released from?
Receptor location?
Fibers connection?
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
EPSP
IPSP
excitatory postsynaptic potential
inhibitory postsynaptic potential
Where parasympathetic and symphatetic stimulations produce the same response?
Salivary glands
Sympathetic Flight of flight response in
Eye
Heart
Blood Vessels
GI
Bladder
Skeletal muscle
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
Sympathetic and Parasympathetic effect on Heart
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.
Sympathetic and Parasympathetic effect on Blood vessels
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.
Where parasympathetic has effect on blood vessels?
the face, tongue, genitals and urinary trac
Sympathetic and Parasympathetic effect on Adrenal Medulla
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.
Sympathetic and Parasympathetic effect on Lungs
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
Sympathetic and Parasympathetic effect on Pupil
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)
Sympathetic and Parasympathetic effect on Eye
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
Sympathetic and Parasympathetic effect on Stomach and Intestines
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
Autonomic regulation of the gut can involve enteric neurons
Sympathetic and Parasympathetic effect on Urinary Bladder
Sympathetic activation (promotes filling)
α adrenergic receptors contract the internal sphincter muscle
β adrenergic receptors relax the detrusor muscle
Sympathetic and Parasympathetic effect on Salivary Gland
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.
Sympathetic and Parasympathetic effect on Skin
Sympathetic activation
α receptors **contract pilomotor muscles **muscarinic receptor activation by **acetylcholine **released from postganglionic sympathetic fibers causes generalized sweating
Organ vs. Predominant responce of ANS
Two types of synapses?
Electrical (heart) and chemical
Citeria for neurotransmitter identification
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)
Nonadrenergic noncholinergic (NANC) transmission
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
Lifecycle of neurotransmitter
- Synthesis
- Storage
- Release
- Receptor interaction
- Disposition
Ach cycle
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)
SNARE proteins used in ACh transport
VAMPs (vesicle associated membrane proteins)
osynaptobrevin
SNAPs (synaptosome associated proteins)
syntaxin
SNAP 25
Drugs affecting cholinergic transmission
Synthesis
Stroage
Release
Deposition
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
Receptor agonists and antagonists for cholinergic receptors
- *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
NE cycle
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
Drugs affecting adrenergic transmission
Synthesis
Stroage
Release
Deposition
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)
Adrenergic Transmission Agonists & Antagonists
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
Chatecholamines
Definition?
Two moieties?
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
Sympathomimetics
Exogenous compounds that imitate the functional responses produced by endogenous catecholamines
Sympatholytics
exogenous compounds that block the functional responses to endogenous catecholamines or sympathomimetics
What needs to be understand to understand response to a catecholamine?
Type of receptor
Type of tissue
The signaling pathway activated by receptor
Are the effects direct and/or indirect
4 molecular types of
responses to catecholamines
their effect
types of membrane protein
[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
a1 receptors
location
signaling mechanism
response
- *blood vessels**
- *eye** (iris radial muscle)
- *bladder** (sphincter muscle)
- *skin** (piloerector muscles)
a2 receptors
location
signaling mechanism
response
Some vascular smooth muscle (-) AC => Vasoconstriction
Central and peripheral presynaptic nerve terminal (+) Gi/o inhibition of presynaptic Ca++ channels => inhibition of neurotransmitter release
b1 receptors
location
signaling mechanism
response
heart Gs (+chronotropic, +dromotrophic, +inotropic, +lusitropic)
kidney Gs (+renin secretion from JG-cells)
b2 receptors
location
signaling mechanism
response
Cardiac muscle (Gs) => (+) HR and contracitility
Smooth muscle (vascular, airway, gastrointestinal, bladder (detruser), uterus) => Relax smooth muscle
Liver => Increase glycogenolysis
b3 receptors
location
signaling mechanism
response
adipose tissue (Gs) => lipolysis
D1 D5 receptors
location
signaling mechanism
response
vascular smooth muscle
Gs
smooth muscle relaxation
D2-4 receptors
location
signaling mechanism
response
central nervous system
Gi (-) AC
CNS control of motor movement and regulation of prolactin secretion
Can you find multiple adrenergic receptors in one cells type?
Can adrenergic molecules have multiple effects?
Is there a further subclassification for adrenergic receptors?
Y
Y
Y
Classes of sympathomimetics
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)
Direct sympathomimetics
Molecular charactersitics?
Modulation of activity?
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.
Indirect Sympathomimetics
Molecular charactersitics?
Chirality issue
Structure vs. location of the effect
Metabolism
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
Imadazolines
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
Therapeutic use of Norepinephrine
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
Therapeutic use of Epinephrine
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)
Therapeutic use of Dopamine
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
Therapeutic use of Isoproterenol
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
Difference in effects of
Norepinephrine
Epinephrine
Isoproterenol
Therapeutic use of Dobutamine
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
Therapeutic use of Terbutaline
mechanism of action – selective activation of β2 receptors
pharmacologic responses – smooth muscle relaxation, especially
airwaysotherapeutic uses – obstructive airway diseases, acute bronchospasms, preterm labor
Therapeutic use of Oxymetazoline
- *mechanism of action** – selective activation of α receptors (α1 and α2)
- *pharmacologic responses** – smooth muscle contraction, especially vascularo
therapeutic uses – nasal decongestant
Therapeutic use of Phenylephrine
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
Theraputic use of Clonidine
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
Amphetamine
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,
Therapeutic use of Ephedrine
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
Therapeutic use of Phenylzine
mechanism of action
•blocks catecholamine metabolism by inhibiting monoamine oxidase (MAO)
therapeutic uses
•depression
•Parkinson’s disease
pharmacologic responses
•enhance neurotransmission at catecholaminergic synapses
Factors that may affect drug transport across membrane
Lipid-water partition coefficient
size of the molecule
concentration gradient
pH
active vs. passive transport
paracellular transport
4 ways of transporting drug across barriers
Paracellular tranport
Facilitated diffusion
Diffusion
Drug transporters
Two major superfamilies of transporters
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)
Perfusion
is the process of a body delivering blood to a capillary bed
How drug can be metabolized?
Active/inactitve
Oxidations/Hydrolytic/Conjugative
Example of drug target? (SERT inhibitor)
Example of drug resistance?
Example of Drug-Drug Interactions?
fluoxetine (Prozac®)
P-glycoprotein
cyclosporine A inhibits OATP transporters, which is at the same time a substrate of CYP3A4
Cytochrome enzyme types
Phase 1 “oxygenases”
Phase 2 “transferases”
Other “dehydrogenases”
CYP (cytochrome 450 gene) proteins
charactersitics
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
Cytochrome P450 Nomenclature
CYP2D6
CYP = cytochrome P450
2 = genetic family
D = genetic sub-family
6 = specific gene
genetical not functional
Major cytochrome P450 isoenzymes that are responsible for metabolism of drugs in humans
CYP1A2
CYP3A
CYP2C9
CYP2C19
CYP2D6
Polymorphic distribution of CYP2D6 vs. treatment
Grapefruit Juice and CYP
Potent inhibitor of intestinal cytochrome CYP3A4
Can lead to increase in bioavailability in serum drug levels
Inducers of CYP3A
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.
What is the function of CYP3A?
Where is it found?
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
CYP3A inhibitors
Ketoconazole
Itraconazole
Fluconazole
Ritonavir
Cimetidine
Clarithromycin
Erythromycin
Troleandomycin
Grapefruit juice
CYP2D6
Allele in populations?
What does it metabolize?
Inhibitors?
Absent in 7% caucasians, 1-2% non-caucasians
Metabolize: codeine, b-blockers, tricyclic antidepressants
Inhibited by: Fluoxetine (Prozac), Haloperidol, Paroxetine (Paxil), Quinidine
CYP2C9
Allele in populations?
What does it metabolize?
Inhibitors?
Absent in 1% caucasians and african americans
Metabolism: NSAID (including COX-2), S-warfarin, phenytoin
Inhibites: Fluconazole
CYP2C19
Allele in populations?
What does it metabolize?
Inhibitors?
Absent in 20-30% asians, and 3-5% caucasians
Primary metabolism of:
–Diazepam
–Phenytoin
–Omeprazole
Inhibited by:
–Omeprazole
–Isoniazid
–Ketoconazole
CYP1A2
Allele in populations?
What does it metabolize?
Inhibitors?
Induced by smoking tabaco
•Catalyzes primary metabolism of:
–Theophylline
–Imipramine
–Propranolol
–Clozapine
•Inhibited by:
–Many fluoroquinolone antibiotics
–Fluvoxamine
–Cimetidine
Drug-Disease Interactions
Liver disease
Renal disease
Cardiac disease (hepatic blood flow)
Acute myocardial infarction?
Acute viral infection?
Hypothyroidism or hyperthyroidism?
Ion Trapping
Altering pH to keep or remove compound from serum
Bioavailability
Definition?
The fraction of the admnistered dose that reaches the systemic circulation
Higher absorption => (+) Bioavailability
F = AUCrouter/AUCIV=AUCP.O./Dose
Pharmacokinetics vs. Pharmacodynamics
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
AUC
Are Underneath the Curve
Volume of distribution
Vd=Total Mass Absorbed / Cplasma
Parasympathomimetics
exogenous compounds that imitate functional responses associated with parasympathetic stimulation
Cholinomimetics
exogenous compounds that imitate functional responses produced by acetylcholine (ACh) at cholinergic receptors
Cholinergic Antagonists
compounds that block cholinergic transmission at involving muscarinic receptors (antimuscarinics), neuronal nicotinic receptors (ganglionic blockers) or the neuromuscular junction (neuromuscular blockers).
Four things to understand for cholinomimetics
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
Mechanism of cholinergic receptors
Effects of cholinergic receptors
NM receptors
location?
Signalling mechanism?
Structure?
Response?
Muscle
Ligand gated
4 different subunits
Muscle contraction
Nn receptors
location?
Signalling mechanism?
Structure?
Response?
Parasympathetic ganglia, adrenal medulla, CNS
ligand gated
composed of alpha and beta isofrom
neuronal excitation
M1 M3 M5 receptors
location
signalling mechanism
Gq
sm (vessels, airways, eye, gut, bladder) / contraction
endothelial cells (blood vessels) / relax blood vessels
exocrine gland (salivary, sweat, airway, gut) / stimulate secretion
CNS
M2 and M4 receptors
Gi aCyclase / K+ channels
cardiac muscle (M2) -chrono -dromo -iso
CNS (M4)
Two types of cholinomimetics
Direct/Indirect
Types of Direct Acting cholinomimetic
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.
Types of indirect acting cholinomimetics
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”
How AChE inhibitors can block ACh hydrolysis?
Effects?
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
Types of indirect acting cholinomimetics
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.
Bethanacol
Therapeutic use
Effects
Mechanisms of action
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
Pilocarpine
Therapeutic use
Effects
Mechanisms of action
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)
Nicotine
Therapeutic use
Effects
Mechanisms of action
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
Neostigmine
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
