FFM2 - Mini I Flashcards
Pharmacology
Study of substances that will interact with living systems via chemical processes
Drug
Molecule that will bind to target to exert effect
Prototype drug
First form of a drug/medication
Is used to formulate alternative forms
Pharmacokinetics
What body does to drug
Pharmacodynamics
What drug does to body
Toxicology
Science of adverse effects of chemicals on body
Pharmacogenetics
Relationship between persons genetic makeup and response to specific drugs
What is main item that NBME tests on for medication names?
Generic names of medications
Mechanism of action
How drug works to produce change in body
Pharmacologic drug action
Consequences of drug-receptor combination
Pharmacologic effect
Results of drug action
Consequences of drugs own actions
Precaution
Used when medication use should be used with care and careful monitoring of patient
Contraindication
Specific circumstance where medication should NOT be used
Relative Contraindication
Caution needs to be used when 2 meds used together
Benefits outweigh risks
Absolute contraindication
Substance can cause life-threatening and should be avoided
Black box warning
Serious/life threatening risks associated with
Most serious medication warning from FDA
Therapeutic effect
Beneficial consequence of treatment
Adverse event
Harmful/abnormal result form medication
Pregnancy Risk Catagories
A
B
C
D
X
Which pregnancy risk catagories are adverse?
C
D
X
Affinity
Strength of interaction between drug and target
Potency
Amount of drug necessary to produce effect
EC50
Concentration drug needed to produce 50% of max effect
Efficacy
Largest effect achieved with drug, regardless of dosage
Agonist
Bind to receptor
Produce normal response
Antagonist
Bind to receptor
Compete and prevent binding by other molecules
Will block actions OF agonist
Full Agonist
Complete 100% activation of receptor
Partial agonist
Binding to receptor results in >0% but < 100% of activation even with high concentrations
Inverse agonist
Bind to receptor and will produce a response BELOW baseline response
Decreased concentration of drug
Competitive antagonist
Bind to same site
Lowers efficacy of medication
Decreases EC50 of medication
Noncompetitive anatgonist
Bind covalently to receptor
Permanent reduction of # of receptors
Irreversible
EC50 remains same; efficacy decreases
Selectivity
Degree to which drug acts on given site relative to other sites
Nonselective drug
Affects many different tissues producing range of effects
Selective drug
Affects single organ/system
Local effects of medication
Application to site of action
Systemic effects
Drug enters circulation and transported to cellular site of action
Routes of Administration:
Enteral
Oral, sublingual/buccal, rectal
Routes of Administration:
Paraenteral
IV/IA
IM
SubQ
Intradermal
Routes of Administration:
Other types
Oral inhalation
Intrathecal/intraventricular
Topical
Transdermal
Vaginal
Urethral
Absorption
Entering blood stream from site of administration
Distribution
Process which drug reversibly leave bloodstream and enters ECF and tissues
Metabolism
Biochemical changes to medication to facilitate elimination from body
Elimination
Irreversible removal of medication from body
Renal most common
Bioavailability
Extent to which medication reaches systemic circulation
Factors affecting Absorption
ph changes
Blood low
Presence/absence of transporters
First pass effect (Liver/GI metabolism)
Drug formulation
Factors affecting Distribution
CO and Blood flow
Permeability of capillaries
Degree of binding of drug to proteins in blood/tissue
Lipophilicity of medication
MW
Central compartment of body
Highly perfused organs
Heart/Liver/Kidneys
Peripheral compartment of body
Fat tissues
Muscle tissues
CSF
Instantaneous distribution within body
One-compartment
All fluids/tissues considered part of compartment
Delayed distribution within body
Some areas get medication faster than others…
Two-compartments
Distribution into high vascular organs then everywhere else more slowly
Metabolism of meds in 3 ways
1)
2)
3)
1) Active med to inactive med
2) Active med to active metabolite
3) Inactive med to active med
Volume of Distribution (Vd)
Fluid volume required to contain entire drug in body at same concentration as measured in plasma
Equation for Vd
Dose of drug/drug concentration
Factors affecting Vd
Drug MW
Lipophilic or hydrophilic
Ionization at pH
Protein binding
Disease states
Half Life (T1/2)
Time it takes to reduce plasma concentration by 1/2
Clearance (CL)
Volume of blood from which drug is cleared per unit of time
Equation of CL
CL(total) = CL(hepatic) + CL(renal) + CL (other)
Clearance is dependent on…
Half Life - t1/2
Volume of Distribution - Vd
Notable CYP-450 Interactions:
Inducers (8)
1) Carbamazepine
2) Chronic alcohol abuse
3) Modofinil
4) Nevirapine
5) Phenobarbital
6) Phenytoin
7) Rifampin
8) St Johns Wort
Notable CYP-450 Interactions:
Substrates (5)
1) Anto-epileptics
2) Oral contraceptives
3) Statins (EXCEPT FOR pravastatin)
4) Theophylline
5) Warfarin
Notable CYP-450 Interactions:
Inhibitors (16)
1) Acute alcohol overdose
2) Acetomenophen
3) Amniodarone
4) Chloramphenicol
5) Cimitidine
6) Clarithromycin
7) Erythromycin
8) Fluconazole
9) Grapefruit juice
10) Isoniazid
11) Ketoconazole
12) NSAID’s
13) Omeprazole
14) Ritonavir
15) Sulfonamides
16) Valporic Acid
Types of Tissues
Epithelial
Connective
Nervous
Muscular
Characteristics of Epithelium
Avascular
Packed cells with shape/arrangement associated with function
Cell characteristics of epithelium
Arranged as sheets or masses
Close to one another
Have intercellular junctions
Polarized
Rest on basal lamina
Polarization in epithelium
Distinct surface domains
Apical, Lateral and basal surfaces
Classification of cells:
1)
2)
Arrangement
Shape
Examples of Arrangement for cells
Simple
Stratified
Examples of Shape of cells
Squamous
Cuboidal
Columnar
Features of Simple Squamous cells
Width greater than height
One cell layer thick
Nucleus protrudes into lumen
Location of Simple Squamous cells
Lining of BV and Lymphatic vessels
Wall of Bowmans capsule
Covering of mesentery
Lining of respiratory spaces/alveoli in lungs
Function of Simple Squamous cells
Diffusion
Transportation in/out of lumen
Special terminology for certain simple squamous epithelia
Endothelium
Mesothelium
Endothelium
Simple Squamous cells lining blood vessels, lymph vessels, lining of heart (atria/ventricles)
Mesothelium
Simple Squamous cells lining walls and covering contents of body cavities (C/A/P)
Features of Simple Cuboidal cells
Width, depth and height all similar
One cell layer
Centrally located nuclei
Location of Simple Cuboidal cells
Wall of thyroid follicle
Walls of kidney tubules (DCT)
Surface of ovary (germinal epithelium)
Interior surface of tympanic membrane
Function of Simple Cuboidal cells
Absorption
Secretion
Conduction involving different metabolic processes
Features of Simple Columnar cells
Height greater than width
One cell layer
Nuclei seen near basement membrane
Location of Simple Columnar cells
Intestinal tract (stomach to rectum)
Gallbladder
Uterus/cervix
Kidney collecting ducts (lower portion of)
Inner ear
Larger glands and ducts
Function of Simple Columnar cells
Protection
Lubrication
Absorption
Secretion
Conduction involving different metabolic processes
Features of Stratified Squamous cells
Multilayered
Superficial layer is squamous
Can be keratinzied/nonkeratinized
Location of Stratified Squamous cells
Epidermis (K)
Lining of oral cavity (NK)
Lips
Lining of esophagus (NK)
Lining of vagina (NK)
Functions of Stratified Squamous cells
Barrier
Protection
Keratinized Stratified Squamous cells seen…
Dry environment
Non-keratinized Stratified Squamous cells seen…
Wet environment
Features of Stratified Cuboidal cells
Multilayered
Location of Stratified Cuboidal cells
Ducts of sweat glands
Larger ducts of exocrine glands
Anal canal
Functions of Stratified Cuboidal cells
Barrier
Conduit
Features of Stratified Columnar cells
Multilayered
Basal layer appears cuboidal
Superficial layer appears columnar
Location of Stratified Columnar cells
Largest ducts of exocrine glands
Anal canal
Conjunctiva of eye
Male urethra
Submandibular salivary gland
Function of Stratified Columnar cells
Barrier
Conduit
Features of Transitional Epithelium
Stratified
Upper cells domed shaped
Some cells are binucleated
Apical surface will stain more pink due to actin filaments
Location of Transitional Epithelium
Ureters
Urinary bladder
Renal calyces
Urethra
Function of Transitional Epithelium
Accommodation of distention
Another name for Transitional Epithelium
Urothelium
Features of Pseudostratified Epithelium
Appearance of being stratified but is NOT
Some cells do not reach free surface
Nuclei located at different distances from basal lamina
All cells rest on basement membrane
Location of Pseudostratified Epithelium
Upper Respiratory Tract
Epididymis
Ductus deferens
Middle Ear
Special features usually seen with Pseudostratified epithelium
Ciliated or Stereocilia
Goblet cells
Features of Basal Lamina
Acellular
Attachment site
Components synthesized and secreted by epithelial cells
Seen with PAS and Silver salts
Layers of Basal Lamina
1) Lamina Densa
2) Lamina Lucida
Features of Lamina Densa
Network of fine filaments
Features of Lamina Lucida
Clear space between base of cell and Lamina Densa
Cause by artifact
Functions of Basal Lamina
1)
2)
3)
Structure Attachement
Compartmentalization
Filtration
Function of Basal Lamina:
Attachement
Connection of epithelial cells to connective tissue
Function of Basal Lamina:
Compartmentalization
Separates connective tissue FROM nervous, epithelial, and muscular tissue
Function of Basal Lamina:
Filtration
Movement of blood filtrate within kidney
Negatively charged molecules in lamina lucida/collagen fibrils in lamina densa
Regulated via ion exchange and molecular sieve
Composition of Basal Lamina
Laminins
Collagens
Entactins/Nidogen
Proteoglycans
Functions of Laminins
Possess integrins
Link basal lamina to basal plasma membrane
Functions of Collagens
Type IV collagen
Short filaments
Structural integrity
Molecular sieve
Functions of Entactin/Nidogen
Link between laminins and Type IV collagen
Supports cell adhesion
Functions of Proteoglycans
Bulk of basal lamina
Protein cores
Attached to cores are negatively charges GAG’s
VERY EXTENSIVELY HYDRATED
Role in regulation of ions across basal lamina
Types of cell surface modifications
Microvilli
Cilia
Stereocilia
Lateral/Basal foldings
Features of Microvilli
Features of Stereocilia
Features of Lateral folds
Types of Junctional Complexes
Zonula Occludens
Zonula Adherens
Macula Adherens/Desmosomes
Gap Junctions
Features of Zonula Occludens
Features of Zonula Adherens
Features of Macula Adherens
Features of Gap Junctions
Features of Hemidesmosomes
Located on basal surface of plasma membrane
Connects basal PM to basal lamina
Locations with hemidesmosomes
Epithelia subjected to abrasion and mechanical shearing
Skin
Cornea
Mucosa of Oral cavity, Esophagus, and vagina
Composition of hemidesmosomes
Attachment plaque (plectin and BP230)
Plaque on cytoplasmic side
Intermediate filaments bind to attachment plaque
Integrins bind attachent plaque to ECM
Features of Focal Adhesions
Dynamic attachments
Link actin filaments to ECM proteins
Composition of Focal Adhesions
Actin filaments
Integrins
Laminin and Fibronectin
Role of Focal Adhesions
Attachment and migration of cells
CN-I
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Olfactory
- Sensory Nerve - sense of smell
- No motor function
- Cerebrum
CN-II
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Optic
- Sensory Nerve - sense of sight
- No motor function
- Cerebrum
CN-III
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Oculomotor
- No sensory function
- Motor function - controls 5/7 muscles of orbit/eye
- Midbrain
CN-IV
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Trochlear
- No sensory function
- Downward internal rotation of eye (Superior Oblique)
- Midbrain
CN-V
Name:
Sensory Function:
Motor Function:
- Trigeminal
- Sensory for facial sensations (pain, hot/cold)
- Motor function for muscles of mastication
- Motor function of myohyloid, anterior belly of digastric; tensor veli palantini; tensor tympani
- Pons
Muscles of mastication
Temporalis muscle
Massetter muscle
Lateral/Medial Pterygoid
CN-VI
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Abducens
- No sensory function
- Motor function for lateral deviation of eye (Lateral Rectus)
- Pons
CN-VII
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Facial
- Sensory function of taste on anterior 2/3 of tongue and sensation of ear
- Motor function of facial expressions (posterior belly of digastric; stapedius muscle)
- Pons
CN-VIII
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Vestibulocochlear
- Sensory function of hearing (cochlear) and balance (vestibular)
- No motor function
- Pons
CN-IX
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Glossopharyngeal
- Sensory function of taste on posterior 1/3 of tongue
- Sensory of pharynx, posterior portion of eardrum and ear canal
- Motor function of the stylopharyngeus muscle
- Medulla Oblongata
CN-X
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Vagus
- Sensory function of pharynx and larynx
- Motor function of pharynx, larynx, and palatal muscles
- Medulla Oblongata
CN-XI
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Spinal Accessory
- No sensory function
- Motor function of SCM and trapezius
- Medulla Oblongata
CN-XII
Name:
Sensory Function:
Motor Function:
Origin from brain:
- Hypoglossal
- No sensory function
- Motor function of the intrinsic and extrinsic muscles of the tongue
- Medulla Oblongata
Membrane potential
Differences in charges between 2 sets of ions
ICF or ECF:
Higher concentration of K+
ICF
ICF or ECF:
Higher concentration of Na+
ECF
ICF or ECF:
Higher concentration of Ca2+
ECF
ICF or ECF:
Higher concentration of Cl-
ECF
ICF or ECF:
Higher concentration of PO4(3-)
ICF
Nernst Equation
Na+, K+
~60 mV log (Concentration outside)/(Concentration inside)
Nernst Equation
Cl-
~60 mV log (Concentration inside)/(Concentration outside)
Pump Leak model
Pumps: Process using energy to move system away from equilibrium
Leaks:Process that drives a system towards equilibrium
Will excess Na+ outside cell change extracellular potential
No
Will excess K+ outside cell change extracellular potential
Yes
Goldman-Hodgkin-Katz Equation
It’s an estimation of Vm when no net current through membrane
Which way do ions move?
Na+
K+
- Na will move positive charge into cells to move the internal cell potential from -70 to +60 mV (Na+ equilibrium)
- K will move positive charge out of cell to move internal cell potential from -70 to -90 mV
Types of graded potentials
Depolarization
Hyperpolarization
Electrotonic conduction
Passive process
Localized
Graded process
Examples of Graded potentials
Pacemaker potential in heart
Post-synaptic potentials
EPSP
Excitatory Post Synaptic Potential
Will move to threshold
Na+ will enter
IPSP
Inhibitory Post Synaptic Potential
Will move to hyperpolarization
Chloride enters or K+ leaves
Types of Graded potential summation
1) Temporal summation
2) Spatial summation
Temporal Summation
1 synapse can fire multiple AP’s over time
May or may not actual action potential
Spatial Summation
Multiple synapses firing at various times intergrating at cell body to determine AP
Refractory Period
Period of time when cell is totally or partially inhibited from being able to respond to stimuli
Types of Refractory period
1) Absolute - NO AP can be generated bar none
2) Relative - able to achieve AP but requires larger amount of stimuli
Aqueous diffusion:
< 100 D
Small molecules
Passive
Nonselective
Lipid Diffusion
100 - 1500 D
Passive process
Non-selective
Facilitated diffusion
Passive process
Carrier-mediated
Confers selectivity
Able to be saturated
Competative
Bulk Transport
Passive process
<15000 but up to 16000 D
Non selective
Active Diffusion
Energy Dependent
Carrier dependent
Saturable
Competitive
Selective
Endocytosis/exocytosis
Require energy
Large molecules > 100,000 D
Efflux transporters
Decrease drug absorption
Influx transporters
Increase drug absorption
If pH > pKa…what is favored
Ionized H+ and A-
Unionized B and A-
Lipophillic
Uncharged or unionized molecule
If pH < pKa…what is favored
Unionized HA
Ionized BA+
Hydrophilic
Charged or ionized molecule
Ion trapping
Ionized forms of meds are more likely to undergo ion trapping - unionized forms will be readily reabsorbed back into system
Calculation of pH and pKa for water solubility
Absorption:
Sublingual
Absorption:
Oral
Small intestine transit time = 3-4 hrs
Absorption:
Rectal
Systemic and Local effects
Absorption:
Topical
Local effect
Absorption:
Transdermal
Systemic effect
Absorption:
Pulmonary (gases)
Systemic effects
Absorption:
IM
Systemic effect
Absorption:
IV
100% bioavailability; systemic effect
Absorption:
Pulmonary (aerosols)
Local effect
Absorption:
SubQ
Systemic effect
Absorption:
Intraarticular
Localized to tissue/organs
Delay systemic effect
Absorption:
Intrathecal
Used to bypass BBB
Administration of drugs through CSF
Absorption:
Intracardiac
Used for cardiac emergencies
Absolute bioavailability
(AUC oral)(Dose IV) / (AUC IV)(Dose oral)
F
Bioavailability
Absorption:
Intrapleural/intraperitoneal
Local effect
Decreased availability to system
Tmax
Time is takes for maximum [Drug] within plasma
Cmax
Max [Drug] reached in plasma AFTER administration of dose
MTC
Minimum Toxic concentration
MEC
Minimum effective concentration
Vd
(Drug Dose)(F) / CPo
CL total
CL hep + CL renal + Renal others
t 1/2
(0.7)(Vd) / CL
Steady State
Dose/CL
Loading Dose
(Css)(Vd) / F
Maintenance Dose
(Css)(CL)(infusion time) / F
CL
Rate of elimination / Plasma concentration
Dosing Rate
CL / Css
Distribution:
BBB
Distribution:
Placenta
Types of muscles
1)
2)
3)
Skeletal
Cardiac
Smooth
Sarcolemma of muscle types surrounded by…
Basal or external lamina
Composition of External Lamina
Collagen Type IV
Laminin
Perlecan
Composition of Skeletal Muscle Cells
- Long, multinucleated cells
- Long, oval nuclei seen at periphery of cells
- Nuclei underneath the sarcolemma
Origin of Skeletal Muscle
Mesodermal
Embryonic formation of skeletal muscles
1)
2)
3)
1) Mesenchymal myoblasts fuse and form myotubes (with many nuclei)
2) Myotubes differentiate into muscle fibers
3) Some don’t differentiate - satellite cells
Function of muscle Satellite cells
Form new muscle fibers after injury
Endomysium
Surrounds muscle fiber (single muscle cell)
Contents of endomysium
Small BV’s and small nerve branches
Composition of endomysium
Type I and type III collagen
Perimysium
Surround group of muscle fibers (fasicles)
Contents of Perimysium
Contains larger BV’s and nerves
Composition of perimysium
Type I collagen
Epimysium
- Sheath of DCT surrounding collection of fascicles
Contents of epimysium
Major vascular structures and nerves
Composition of epimysium
Type I collagen
Myotendinous junctions - meeting of what 2 structures
Muscle fibers and tendon
At transition of muscles and tendon of myotendinous junction, fibers seen
Collagen
Blood supply of skeletal muscles
High vascularity
Reason for high vascularity of skeletal muscles
High O2 req
High energy requirements
What are neurovascular bundles?
Where vasculature/nerves enter muscles
Function of Muscle Spindles
Stretch detection in the muscle fibers
Structure of Muscle Spindles
Connective tissue capsule surrounding fluid filled space
Space contains thin, non-striated fibers filled with nuclei (intrafusal fibers)
Function of intrafusal muscle fibers
Proprioception
Detect amount and rate of length change in muscle
Function of Golgi Tendon Organs
Detection of tension in tendons
Clinical Correlation:
Polymyositis
Inflammatory disease attacking endomysium of muscles
Clinical Correlation:
Polymyositis S/S
Loss of muscle tisse
Progressive SYMMETRICAL proximal muscle weakness
Clinical Correlation:
Dermatomyositis
Inflammatory disease affecting perimysium
Clinical Correlation:
Dermatomyositis S/S
Progressive SYMMETRICAL proximal muscle weakness along with cutaneous findings
A-bands
Comprised of H-band
Area where overlap of myosin and actin fibers occur
Will remain the same with contraction/relaxation
I-bands
Actin filaments
Area with shorten/expand with contraction/relaxation
Z-line
Beginning and ending of ONE Sarcolemma unit
H-band
Area within A band where myosin filaments do not overlap actin filaments
M-line
Area where mysoin attaches
Thick myofilaments
Myosin
Structure of myosin
2 heavy chains = thin, motor proteins with heads twisted together
4 light chains = Binding sites
Thin myofilament
Thin, helical actin filaments running between thick filaments
Regulation sites of thin filamaments
Tropomyosin
Troponin
Structure/Function of Tropomyosin
Coil of 2 polypeptide chains situated in a groove between 2 actin strands
Will block myosin from binding to actin filaments
Structure/Function of Troponin:
1) Troponin T
2) Troponin C
3) Troponin I
Troponin T = attaches to tropomyosin
Troponin C = Ca2+ binding site
Troponin I = regulates myosin/actin interaction
Function of accessory muscle proteins
Maintain efficiency of contraction
Maintain speed of contraction
Examples of accessory muscle proteins (8)
Titin
𝛼-actinin
Nebulin
Myomesin
C protein
Tropomodulin
Desmin/Vimentin
Dystrophin
Function of:
Titin
- Anchor thick filaments to Z line
- Will prevent excessive stretching of sarcomere
Clinical correlation:
Dilated cardiomyopathy
Mutation of TTN gene encoding titin
Function of:
𝛼-actinin
- Bundle thin filaments into parallel arrays
- Anchor thin filaments to Z line
Function of:
Nebulin
- Runs parallel to actin filaments
- Helps anchor 𝛼-actinin to actin filaments to Z line
- Regulate length of thin filament during muscle development
Function of:
Myomesin
- Myosin binding protein
- Holds thick filaments at M line
Function of:
C protein
- Myosin binding protein
- Holds thick filaments at M line
- Will form stripes on either side of M line
Function of:
Tropomodulin
- Small protein attached to free part of actin
- Maintain/regulate length of actin filament in sarcomere
- Affects length-tension relationship in contractions
Function of:
Desmin/Vimentin
- Intermediate fibers - form lattice around sarcolemma at Z line
- Attaches Z discs to one another and to sarcolemma
- Crosslink/stabilizes myofibrils
Function of:
Dystrophin
- Seen beneath cell membrane
- Links laminin and agrin of external lamina to actin filaments (thru membrane)
Clinical Correlation:
Muscular Dystrophy
- Disorder where organ/tissue wastes away
- Progressive weakness and wasting of muscles
- Links actin cytoskeleton to sarcoglycan complex
- Sarcoglycan complex links to external lamina/laminin
- Laminin links to collagen fibers for endomysium
- Impairment of dystrophin causes microruptures in cell membranes - cell death
Function of sarcoplasmic reticulum
Concentrate and sequester Ca2+
Consists of…
Longitudinal tubules with enlarged region at the end (terminal cisternae)
Terminal cisternae associated with
T-tubules
1 T-tubule flanked by 2 terminal cisternae
1 T-tubule with 2 associated flanking terminal cisternae are called…
a Triad
Membranes of T-tubules continuous with…
Muscle fiber membranes
Lumen of T-tubules continuous with…
ECF
Function of T-tubules
Allow AP to move rapidly from cell surface into interior fiber to reach terminal cisternae
Composition of cardiac muscle
- Striated, single nucleus (rare for 2)
- Elongated/branched cells bound to intercalated discs
- Contraction involuntary, vigorous, rhythmic
Origins of Cardiac muscle
- Splanchnic mesoderm cells
- Will form primitive heart tube
- Cells align into chainlike array
- Cells form complex junctions between intercalated discs
Structure of intercalated disc in Cardia muscle
Cells in one fiber branch and join cells of another fiber
Cardiac muscle fiber components
- Single nucleus (sometimes 2, rare)
- Contain myosin/actin filaments arranged in sarcomeres
- 40% of cell volume is mitochondria
- Store FA’s stored as TG’s in lipid droplets
Components of intercalated discs
- Gap junctions
- Desmosomes
- Fascia adherens
Function of ______ in Cardiac muscle:
Gap junctions
Ionic continuity between cells
Allows cells to act in multinucleated syncytium
Function of ______ in Cardiac muscle:
Desmosomes
Macula Adherens
Function of ______ in Cardiac muscle:
Fascia adherens
Ribbon-link structure to stabilize non-epithelial tissue
Anchors actin filaments
Organells of cells located in…
Juxtanuclear region
Granules located in atria
Atrial natriuretic factor (ANF)
Brain natriuretic factor (BNF/BNP)
Function of ANF and BNF
Inhibit renin secretion in kidneys
Inhibit contraction of vascular smooth muscle
Function of lipofuscin granules
Pigment seen in older cardiomyocyte cells
Composition of Smooth muscle
- Collection of spindle cells with one central nucleus
- NO STRIATIONS SEEN
- Slow, involuntary movements
Origin of smooth muscles
Smooth muscles found where in the body?
Everywhere!
Wall of BV and airways
GIT
Pupillary dilation
Lens shape
etc…
Regulation of smooth muscle contraction
Electrical signals
Chemicals
Hormones
Drugs
Response of SM depends on:
1)
2)
3)
1) Function of tissue
2) ° of innervation from ANS
3) Expression of receptors for chemicals/hormones
Smooth muscle cells attached to one another via…
Desmosomes
Gap junctions
Types of fibers seen in Smooth muscle
Think, thin and intermediate filaments
Function of:
Thin filaments
Attach to dense bodies
Function like Z disc (one sarcomere from one another)
Function of:
Dense bodies
- Contain 𝛼-actin for thin filament attachment
- Attachment sites for intermediate filaments and adhesive junctions
Function of:
Intermediate filaments
Desmin/vimentin
Arrangement of Smooth muscle in GIT
Sheets of opposing fibers
Form inner circular layer
Outer longitudinal layer
Peristalsis
Contraction of inner and outer opposing layers of smooth muscle
Arrangement of Smooth muscle in vasculature (BV)
Seen in tunica media of blood vessels
Contracts to narrow lumen of BV
Seen in which types of BV’s?
Medium arteries
Small arteries
Myoepithelial cells
- Seen in glands
- Share basal lamina of secretory/duct cells
- Contract to express contents from ducts out of gland
- Contraction mediated via calmodulin process
Myofibroblasts
- Possess vimentin
- Contain higher amounts of actin/myosin
- Capable of contractions
- Contract during wound healing
Excitation-contraction coupling
Events between generation of AP in skeletal muscle cell and release of Ca2+ from SR
First receptor to open to AP in skeletal muscle
Dihydropyridine receptors (DHPR)
Dihydropyridine is what types of receptor?
Voltage gated Ca2+ channels
How are DHPR arranged and where are they arranged?
1) Arranged in rows
2) On the T-tubule
What is the receptor associated with DHPR?
Ryanodine receptors
Describe Ryanodine receptors
Ca2+ release channels
How are Ryanodine receptors/channels opened?
1) AP signal in T-tubule causes conformational change in DHPR
2) Conformational change opens Ryanodine channels
3) Ca2+ released from SR
How is Ca2+ removed from intracellular concentration?
Ca2+ pump
Ca2+-ATPase pump
Other name for Ca2+-ATPase
SERCA
Sarcoplasmic endoplasmic reticulum calcium ATPase
How many molecules of Ca2+ does the SERCA pump back into the SR?
2 molecules of Ca2+ for every 1 ATP hydrolyzed
Steps to induce a contraction of muscle:
1) Troponin-tropomyocin complex covers myosin binding site on actin
2) Myosin is bound to ADP and Pi
3) AP signal is released to muscle membrane
4) Ca2+ released via RYN receptors/channels in SR
5) Ca2+ binds to Troponin-C; activates movement of tropomyosin from binding site
6) Myosin binds to binding site
7) Binding triggers conformational change in myosin head - power stroke occurs
8) ADP + Pi dissociate; ATP binds to myosin head
9) ATP binding causes detachment of myosin from actin; ATP immediately hydrolyzed to ADP + Pi
10) Myosin returns to resting state
Steps to allow for relaxation
1) Cycle continues AS LONG AS ATP/Ca2+ present at all times
2) Ca2+ re-sequestered in SR via SERCA
3) Ca2+ lvls drop; tropomyosin moves over myosin binding site on actin
What occurs when ATP is not available?
Myosin and actin will remain attached to one another - rigor mortis
What difference is there between Ca2+ binding in skeletal muscle and smooth muscle
- Ca2+ binding in skeletal muscle occurs with Troponin C
- Ca2+ bind in smooth muscle occurs with calmodulin
Sliding Filament Theory
Sliding part of actin past myosin generates muscle tension
Energy sources during muscle contraction
ATP
Creatine Phosphate
Carbs/Glycogen/Glucose
FA’s/TAG’s
Cells that generate AP in the heart
Pacemaker cells
Propagation of AP in the heart
SinoAtrial node
Difference between SR in skeletal muscle and cardiac muscle
Cardiac muscle SR is less dense and not as well developed
30% of heart is comprised of
Mitochondria
Why the high amount of mitochondria in the heart?
Increase ability for oxidative capacity and generation of ATP
Pacemaker cells able to undergo…
Spontaneous depolarization to generate AP
Reason for long duration of cardiac AP
Slow inward movement of Ca2+ thru voltage gated L type Ca2+ channels in sarcolemma
Composition of voltage gated L type Ca2+ channels…
5 subunits
𝛼1, 𝛼2, β, 𝛾, δ
Other name of 𝛼1 subunit
Dihydropyridine receptor
Amount of Ca2+ entering cardiac muscle cell…
Normally, small amount.
Absence of extracellular Ca2+
Duration of AP is shorter and unable to initiate contraction of heart
Ryanodine receptors in cardiac muscle - opens what kind of channel
Calcium gated calcium channel
Influx of Ca2+ initiates release OF Ca2+ from SR
Removal of excess Ca2+ from cardiac muscle cells
Through sarcolemma Na+/Ca2+ antiporter and Ca2+ pump
Type of NS stimulation on heart
Sympathetic NS
Types of Sympathetic receptors in cardiac muscle
β1 adrenergic
Sympathetic receptors are connected to which signaling pathway in cardiac muscle?
cAMP/PKA
↑ Ca2+ entry into cells
How often will myocardial ATP pool turnover?
Every 10 seconds
Which products produce 60-90% of the cardiac ATP generated?
Fatty Acid Oxidation
Differences between skeletal/cardiac muscle and smooth muscle
- Smooth muscle has no troponin
- Smooth muscles are not arranged in sarcomeres
Direct Entry of Ca2+ into Smooth muscle cell
- Enters via voltage-gated, ligand-gated, or mechanically gated channels
- Some cells (BV) have stretch activated channels
- Ca2+ entry induces Ca2+ release from SR
Second messenger Signaling of Smooth Muscle
- Chemical messenger binds to GPCR
- GPCR causes release of IP3
- IP3 binds to receptors on SR membrane
- Binding releases Ca2+ from SR
Release of Ca2+ for relaxation
- Removal of Ca2+ via Ca2+ pumps and exchangers
- Move Ca2+ into ECF and SR
Differences in Contraction in Smooth muscle vs Skeletal/Cardiac muscle
Smooth muscle have Pi associated with the myosin head AND with the MLC
Regulation of actin/myosin interaction in smooth muscle
Altering properties of myosin itself - phosphorylation of MLC
Phosphorylation of MLC =…
Activation of MLC binding to actin filaments
Enzyme that phosphorylates MLC
MLC Kinase
Activation of MLC Kinase due to
Ca2+-Calmodulin complex
Relaxation of smooth muscle due to which enzyme?
MLC Phosphatase
Function of MLC Phosphatase
Dephosphorylation of MLC
Latch State of myosin
Dephosphorylation of myosin while attached to actin
Control of Latch mechanism for smooth muscle
- MLCP dephosphorylation MLC
- Dephosphorylation during actin/myosin binding = latch state
- Cross bridge proceeds just MUCH slower
- Actin/Myosin complex has ↓ affinity for ATP
Latch mechanism is sustainable for
BV’s, spinchters, and hollow organs
Rationale for Latch mechanism
Prolonged contractions using minimal ATP
Types of smooth muscle
Single-unit
Multi-unit
Single Unit Smooth muscle seen
Walls of hollow viscera
Multiunit Smooth muscle seen
Iris of eye
Divisions of the ANS
1) Sympathetic NS
2) Parasympathetic NS
3) Enteric NS
Describe the Enteric NS
Located within the GIT
Connected to CNS via parasympathetic/sympathetic fibers
Neural plexuses of Enteric NS
Submucosal plexus
Myenteric plexus
Submucosal plexus:
Where:
Function
Between submucosa and circular muscle layer
Controls secretions and GI blood flow
Myenteric plexus:
Where:
Function
Between circular muscle and Longitudinal muscle layers
Controls motility, contractions, and relaxation
Parasympathetic system located where in spinal cord?
Cranial and sacral
Sympathetic system located where in spinal cord?
Thoracolumbar
Only NT transmitted in Parasympathetic system
Acetylcholine (ACh)
NT transmitted in Sympathetic NS
Norepinephrine
Acetylcholine (ACh)
Preganglionic fibers of Para/Sympathetic NS secreted…
Acetylcholine (ACh)
Receptor type in the Parasympathetic NS
(pre to post ganglion)
Nicotinic receptors in the post ganglion
(nAChR)
Receptor type in the Parasympathetic NS
(post ganglion to target tissue)
Muscarinic receptor
Receptor type in the Sympathetic NS
(pre to post ganglion)
Nicotinic receptors in post ganglion
EXCEPTION:
Receptor type in the Parasympathetic NS
(pre ganglion to target tissue)
Seen in adrenal medulla
There are no post receptor fibers
Targer Adrenal medulla tissue directly
Receptor type in the Sympathetic NS
(post ganglion to target tissue)
1) Regular target tissue = Adrenergenic
2) Exception to the rule: sweat glands (muscarinic)
Nerves types according to what NT they release
1) Cholinergic - ACh
2) Adrenergic - Nor/Epinephrine
Types of ACh receptors and their specific mechanism of function
(Ligand, Voltage, GPCR, etc)
Nicotinic (nAChRs)- Ligand gated ion channel
Muscarinic (mAChRs) - GPCR
Types of Adrenergic receptors and their specific mechanism of function
(Ligand, Voltage, GPCR, etc)
𝛼-adrenergic; β-adrenergic
GPCR
Long preganglionic fibers
Short post ganglionic fiber
Short pre ganglionic fiber
Long post ganglionic fiber
Cells in adrenal medulla affected by pre-ganglionic secretion of ACh?
Chromaffin cells
Muscarinic receptors:
Stimulatory
M1, M3, M5
Muscarinic receptors:
Inhibitory
M2, M4
Stimulatory muscarinic receptors activate which type of G protein
Gq
Inhibitory muscarinic receptors activate which type of G protein
Gi
Activation of Gq protein leads to…
Increased PLC and increased Ca2+
Activation of Gi protein leads to…
Inhibition of Adenylate cyclase (AC) and decrease in cAMP
Activation of Gs protein leads to…
Stimulation of Adenylate Cyclase
Increased production of cAMP
Adrenergic receptors
𝛼1, 𝛼2
β1, β2, β3
Adrenergic receptors:
Stimulatory
𝛼1 = stimulates Gq protein
β1, β2, β3 = stimulate Gs protein
Adrenergic receptors:
Inhibitory
𝛼2 = stimulates Gi protein
Post ganglionic innervation at which sites?
Smooth muscle
Cardiac
Secretory glands
↑ intracellular Ca2+ stimulates…
Contraction of smooth muscle
↑ cAMP stimulates…on smooth muscle
Relaxation
↑ cAMP on cardia muscle stimulates…
↑ HR and ↑ force of contraction
Sympathetic responses to CVS
↑ HR = SA/AV node, β1
↑ force = β1 on atrial/ventricular muscles
↑ dilation of BV in skeletal muscles - β
↓ dilation of skin BV -
CO
of heartbeats per minute
SV
Amount blood pumped by each ventricle with each contractionSV
EDV
End distolic volume - amount of blood left in ventricle after diastole/relaxation
ESV
End systolic volume - amount of blood left in ventricle after systole/contraction
Calculation of SV
EDV - ESV
normal should be around 70 mL
Calculation of CO
CO = SV - HR
MAP
Mean arterial pressure
Average arterial pressure during one contraction of heart
Calculation of MAP
DP + 1/3 (SP-DP)
CO x TRP
TPR
Total Peripheral Resistance
Total resistance of BV to blood flow thry them