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Week 2 Flashcards

1
Q

What is the definition and significance of drug biotransformation?

A
  • Definition: chemical alteration of a foreign chemical within a living organism, usually by enzyme-mediated reactions
  • Significance: the goal is to make drugs more soluble (or more polar) in order to be eliminate the drug
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2
Q

What is the role and significance of Phase I biotransformation reactions in drug elimination?

A
  • Role: They are oxidation, reduction, and hydrolysis reactions that “unmask” drugs
  • Significance: these reactions break down drugs into smaller metabolites
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3
Q

What are the 3 types of Phase I biotransformation reactions and what do they do?

A
  • Oxidation: CYP P450 are important oxidative enzymes occurring in the ER of liver cells; susceptible to induction and inhibition
    • RH (active drug) + O2 + NADPH + H+ → ROH (polar drug metabolite) + H2O + NADP+
  • Reduction: favors certain chemical groups (ex: nitro group); carried out by CYP enzymes
  • Hydrolysis: uses water to break the parent drug into smaller pieces; carried out by CYP enzymes (ex: esterases)
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4
Q

What is the role and significance of Phase II biotransformation reactions in drug elimination?

A
  • Role: addition of side chains through “synthetic” or “conjugation” reactions
  • Significance: these reactions add side chains, making them too large for diffusion or polar for elimination
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5
Q

What are the two main types of Phase II reactions and how do they work? What are the other four kinds of reactions possible?

A
  • Glucuronidation: many side-groups (i.e. hydroxyl group) can be glucuronidated by UDPGA (uridine diphosphate glucuronic acid) to become more polar
  • Glutathione Conjugation: glutathione readies drugs for excretion by binding to an intermediate (when glutathione is used up, necrosis of liver occurs)
  • Sulfation
  • Acetylation
  • Methylation
  • Glycine conjugation
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6
Q

What are enzyme inducers and there impact on drug biotransformation.

A
  • Inducers are drugs or substances that act on enzyme
  • Induce DNA transcription of CYP enzymes, leading to increase in metabolite elimination
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7
Q

What are enzyme inhibitors and impact on drug biotransformation.

A
  • Inhibitors are drugs that compete for the same binding site on the enzyme
  • Inhibitors reduce enzyme activity (ex: warfarin is not metabolized after patient consumes grapefruit juice – inhibitor – leading to increased risk of bleeding out)
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8
Q

What is the impact of drug biotransformation on…

  • disease
  • species differences
  • age
  • hormones
  • genetics
  • diet
A
  • Genetics: CYP mutations can cause to ultrarapid or poor metabolism of active drugs, leading to differing active drug concentrations across patients
    • Another example is rapid and slow acetylator allelic variances
  • Disease: diseases that affect liver
  • Species Differences: cats do not have glucuronyl transferases
  • Age: human babies under 1yo have reduced levels of glucuronyl transferases
  • Hormones: thyroid disease causes changes in metabolism
  • Diet: grapefruit acts as inhibitor to warfarin
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9
Q

What are the factors (6) that impact hepatic clearance and the significance of those factors on drug elimination.

A
  • First pass effect: only fraction of drug reaches bloodstream after oral intake (bioavailability)
  • Hepatic blood flow: increased blood flow increases clearance
  • Free drug: binding of drug to plasma proteins (ex: albumin) → less free drug to be excreted
  • Enzyme inhibitors/inducers: P450 inducers can increase excretion
  • Enterohepatic Recirculation: estrogen is often glucuronidated in liver → bile duct → sugar is cleaved by gut bacteria in GI → estrogen is re-circulated in body
  • Extraction Ratio: value close to 1 suggests efficient clearance by an organ; value close to 0 suggests inefficient clearance
    • E = (Ca – Cv) / Ca
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10
Q

What is

  • glomerular filtration
  • tubular secretion
  • tubular reabsorption

and how do they impact renal elimination of drugs?

A
  • Glomerular filtration: free drug passively diffused into renal tube
    • Limited by size
    • Creatinine is used as measure of renal function (not reabsorbed or secreted)
  • Tubular reabsorption: lipid-soluble drugs renter bloodstream (can be passive/active)
    • Acidifying urine (aka: vitamin C) causes acidic drugs to be reabsorbed and vice-versa for basic drugs
  • Tubular secretion: active transport (or secretion) from blood to tubules after glomerulus with saturation kinetics
    • Para-aminohippuric acid (PAH) is used as measure since it is completely filtered and secreted
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11
Q

How does addition of probenecid to penicillin treatment help?

A

When treating infection, probenecid is given with penicillin in order to prevent active transport of penicillin (never filtered)

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12
Q

What are 2 ways that drug interactions impact drug biotransformation and elimination

A
  • Some drugs act as inducers, increasing other drug metabolites
  • Some drugs act as inhibitors, decreasing other drug metabolites
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13
Q

How does drug elimination and biotransformation changes that occur across the lifespan….

  • Infants
  • Children
  • Geriatrics
A
  • Infants
    • Biotransformation: glucuronidation and CYPs are underdeveloped
    • Elimination: glomerular filtration rate (GFR), secretion, reabsorption, not developed until 1yo
  • Children
    • Biotransformation: high ratio of water : fat causing faster drug clearance
  • Geriatrics
    • Biotransformation: hepatic blood flow decreases
    • Elimination: decreased GFR
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14
Q

Compare/contrast one-compartment versus two-compartment models of pharmacokinetics.

A
  • One-compartment model: drug is absorbed and eliminated in body as one system
  • Two-compartment model: drug is absorbed into blood and distributed into tissues (2 rate constants)
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15
Q

What is the difference in time-response between oral versus intravenous drug administration.

A

Oral administration (PO) has later onset of action (aka “lag time”).

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16
Q

What is the difference in Area Under the Curve (AUC) between PO and IV in the context of bioavailability.

A

PO has less AUC compared to IV because IV is injected directly into blood, therefore having less bioavailability

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17
Q

Define zero order and first order rates of elimination.

A
  • Zero order: A fixed amount of drug is eliminated per unit of time (constant rate)
    • Example: alcohol
  • First order: the amount of drug eliminated is proportional to concentration of drug (linear rate)
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18
Q

Describe/define “steady state”.

A
  • Steady state (Cpss): rate of drug degradation = rate of drug entering plasma
    • Depends on half-life, but does not depend on dose, dosing rate, or dosing frequency
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19
Q

How/when is “steady state” achieved with intermittent versus continuous dosing?

A
  • Intermittent dosing: Cpss achieved by administering drug at trough, which is the minimum concentration a drug is effective
    • Extending dose intervals will increase concentration fluctuations (requires more drug at each dose)
  • Continuous dosing: Cpss achieved by administering concentration of drug that matches drug elimination
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20
Q

Apply pharmacokinetic principles to make predictions about:

  • how dose affects duration of action
  • how changes to clearance
  • or volume of distribution

affect half-life, etc.

A
  • Lower dose → lower drug concentration → low duration of action
  • Increasing Vd → increases half-life because greater [drug] in body requires elimination (50% of present drug is eliminated each half-life)
  • Increasing Clearance → lowers half-life because less [drug] in body requiring elimination (50% of present drug is eliminated each half-life)
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21
Q

Apply knowledge from ADME lectures to describe elements that can alter a drug’s pharmacokinetic properties.

ADME: Absorption, Distribution, Metabolism, Elimination

A
  • Absorption
    • Increased absorption → increased Vd → increased half-life
  • Distribution
    • Increased tagging → increased reservoirs → decreased [drug plasma] → increased Vd → increased half-life
  • Metabolism (biotransformation)
    • Increased hepatic blood flow → increased biotransformation → Increased polarity → increased plasma solubility → increased elimination
  • Elimination (clearance)
    • Increased renal blood flow → increased secretion → increased elimination
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22
Q

Describe the physical structure and properties (4) of the plasma membrane. 


A
  • Phospholipid bilayer: phosphate and glycerol pointing out, FAs pointing in
  • Properties:
    • Highly impermeable
    • Provides specificity for molecules
    • Allows for signal amplification
    • Cholesterol adds stability
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23
Q

Describe the features of a membrane protein that cause it to be stable in the cell membrane.

A
  • 20 non-polar AA alpha-helix with side chains pointing outwards for single pass TM protein
  • Multi-pass TM protein alpha-helices can be partially non-polar due to alignment with other alpha-helix subunits
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24
Q

Describe why cells require transport proteins and the advantages afforded to the cell in having 
these proteins. 


A
  • Specificity of transport.
  • Allows for specific localization of function of protiens.
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25
Q

What is passive and active transport?

A
  • Passive: goes with concentration gradient
  • Active: requires energy moving larger molecules or moving against concentration gradient
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26
Q

What is the difference between primary and secondary active transport?

A
  • Primary: directly uses ATP
  • Secondary: uses concentration gradient energy of another molecule, but not directly using ATP (ex: GLUT1)
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27
Q

What are gap junction channels?

A
  • Six alpha-helices on each cell connecting two cells, allowing diffusion between cytosols without interacting with ECM
  • Non-specific diffusion
  • Good for electrical conductance
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28
Q

What is the general structure of ion channels?

A
  • Four TM domains with intracellular or extracellular subunits which can block the channel
  • Na+ and Ca++ have one alpha subunit, while potassium has four
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29
Q

Give an example of a pump and how it creates a concentration gradient?

A
  • Na+/K+ ATPase creates concentration gradient close to K+ equilibrium potential ~-70mV
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30
Q

What are the three major types of cell surface receptors.

A
  • Ion Channels
  • GCPRs
  • Catalytic Receptors
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31
Q

What are the two types of ion channels.


A
  • Ligand-gated: Nicotinic receptors require 2 molecules of ACh to let Na+ in
  • Voltage-gated: Na+ voltage gated channel
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32
Q

Describe GCPRs.

A
  • 7 TM spanning protein
  • N-terminus is on ECM
  • C-terminus is on ICM
  • No ligand is bound → G protein is not interacting with receptor → G protein binds to TM portion → GTP replaces GDP on G protein → G protein subunits go off and act on effectors (i.e. adenylyl cyclase)
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33
Q

What are catalytic receptors? Give two examples.

A
  • Single-pass TM alpha-helix
  • Binding by ligand causes conformational change (aka: dimerization)
  • Example 1: tyrosine kinase receptor binds insulin
  • Example 2: ANP and BNP protein floats around when volume in heart (by stretch of right atrium) is too large; binds on nephron to NPR-A or NPR-B, induces a conformational change and dimerization, catalyzing intracellular hydrolysis of GTP to cGMP. This increases Na+ excretion and therefore water secretion
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34
Q

What is membrane potential and how is it measured?

A
  • Membrane potential: voltage difference across the membrane created by the concentration gradient of ions (primarily Na+ and K+)
  • Measured by voltage clamp
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35
Q

What is electrochemical equilibrium?


A

When the chemical and electrical gradients are equal in magnitude.

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36
Q

Describe the roles of the various ATPases and other transport proteins in maintaining the sodium, potassium gradients across the plasma membrane.

A

Na+/K+ ATPase creates concentration gradient (~-70mV).

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37
Q

What is equilibrium potential of an ion and how it is influenced by ion concentrations?

A
  • Ion concentrations differences between intracellular and extracellular (voltagemembrane) equals equilibrium potential
    • Determined by concentration gradient of that ion across a membrane
    • Equilibrium potential is reached when channel is no longer in flux
    • Each ion has its own equilibrium potential
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38
Q

What are typical ion gradients found across the plasma membrane of a typical cell and how 
they are sustained. 


A
  • Sodium is higher outside cell
  • Potassium is higher inside cell
  • Calcium is higher outside cell
  • Chloride is higher outside cell
  • All are sustained through ATPases
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39
Q

What are the equilibrium concentrations of sodium, potassium, chloride, and calcium?

A
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40
Q

What are the differences in voltage gated channels of K+ and Na+?


A
  • Voltage gates
    • K+ channel has one gate and opens slowly
    • Na+ channel has two gates
      • M gate or activation gate (faster) closes at resting potential and opens with depolarization
      • H gate or inhibition gate (slower) opens in resting state and closes at depolarization
      • Lag time between gates closing at depolarization allows sodium to rush in
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41
Q

What is refractory period and why the action potential exhibits this 
property. 


A
  • When the cell hyperpolarizes (more – than resting potential), the sodium channels are deactivated
  • Puts a limit on frequency of action potentials
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42
Q

Define/describe efficiacy.

A

the ability to produce a response

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43
Q

Define/describe affinity.

A
  • The ability of a drug to bind to a receptor
    • KD is where 50% of receptors are saturated
    • Affinity = 1/KD
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44
Q

Define/describe agonist.

A

has affinity and efficacy

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45
Q

Define/describe antagonists.

A

has affinity but no efficacy

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46
Q

Define/describe potency.

A
  • A comparative term to compare drugs that work through the same mechanism (same maximal effect, shape of curve, and slope)
    • A more potent drug has lower KD
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47
Q

Define/describe desensitization.

A
  • GPCR is uncoupled from receptor as result of chronic exposure to agonists
    • When GS is no longer bound to TM portion of GCPR → B-ARK phosphorylates receptor → Arrestin binds receptor, “tagging” it for destruction
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48
Q

Define/describe tachyphylaxis.

A

Unexpected physiological response due to desensitization (in presence of agonists).

49
Q

Define/describe down-regulation.

A

decrease in number of expressed receptors on cell-membrane (in presence of agonists).

50
Q

Define/describe supersensitization.

A

increased response of the receptor due to chronic exposure to antagonist

51
Q

Define/describe upregulation.

A

increased number of receptors on cell-membrane (in presence of agonists)

52
Q

Define/describe graded dose-response curves.

A
  • Illustrates relationship between drug dose, receptor occupancy, and resulting magnitude of effect
  • X-axis: dose
  • Y-axis: graded response of individual to drug
53
Q

Define/describe quantal dose-response curves.

A
  • Determines therapeutic index
  • X-axis: dose
  • Y-axis: percent of population produces all-or-none response
54
Q

Define/describe therapeutic index (TI) with equation.

A
  • TI = (toxic dose TD50) / (effective dose ED50)
    • Want large TI
    • If TI is low (i.e. 2), doubling the dose would result in toxic/lethal effects
55
Q

Define agonists and list its three subtypes.

A
  • Definition: have affinity and efficacy
    • Full
    • Partial
    • Inverse
56
Q

What are the three types of agonists and how they affect the

  • shape
  • slope
  • position

on the dose-response curves.

A
  • Full: maximal response
    • Normal sigmoidal curve
    • Shift left and right depending on potency
  • Partial: sub-maximal response due to partial antagonist properties
    • Slope decrease because sub-maximal
  • Inverse: agent that binds to same receptor as agonist but induces a pharmacological response opposite to true agonist by suppressing constitutive activity
    • Negative slope
57
Q

Define antagonists (in terms of affinity and efficacy) and list the two subtypes.

A
  • Definition: have affinity but no efficacy
    • Competitive
    • Non-competitive
58
Q

What are the two types of antagonists and how they affect….

  • shape
  • slope
  • position

on the dose-response curves.

A
  • Competitive: binds reversibly to the same active site as agonist
    • Shape & Slope: same
    • Position: shifted right
  • Non-competitive: binds irreversibly to receptor permanently alters active site
    • Shape & Slope: sigmoidal and less steep
    • Position: shifted right
59
Q

Explain how drugs interact with the three subtypes of GCPRs and elicit different types of second messages and intracellular responses.

A
  • Gs – increase adenylyl cyclase → increase cAMP
  • Gi – decrease adenylyl cyclase
  • Gq – Increase phospholipase C → PIP2 → DAG & IP3 → increase Ca2++
60
Q

Explain how drugs interact with the Ligand Gated Ion Channel and elicit second messages and intracellular responses.

A
  • Ligand binds and open ion channel
  • Ach for Nicotinic (Na+) and GABA for (Cl-)
61
Q

Describe the Tyrosine Kinase Receptor and explain how it elicits second messages and intracellular responses.

A
  • Single TM
  • Signaling molecule binds to one receptor → dimerizes (moves closer together) → cross-phosphorylation → phosphorylated sites act as docking sites → intracellular messengers activated
62
Q

What are the two Intracellular Receptors and how do they elicit second messages and intracellular responses (give examples)?

A
  • Cytosolic: found in the cytosol but move to nucleus that can lead to transcription factor
    • Example: steroids
  • Nuclear: receptor found on nucleus that acts as transcription factor
    • Example
      • Steroid → crosses TM → attaches to cytosolic receptor → targeted to nucleus → attaches to nuclear receptor → acts as transcription factor
63
Q

Describe pharmacodynamic changes that occur with aging.

A
  • Changes in
    • [Drug at receptor]
    • Receptor numbers
    • Receptor affinity
    • Post-receptor alterations
  • Increased “sensitivity” to drugs (especially anti-cholinergics and CNS drugs)
64
Q

What are sarcomeres and their two acting components?

A
  • Sarcomeres – the functional contractile unit of muscle
    • More sarcomeres = more force (hypertrophy from going to the gym
  • Two Acting components
    • Myosin – thick
      • Surrounded by 6 actin filaments
    • Actin – thin
65
Q

What are the different lines/bands of the sarcomere?

A
  • Z-line – anchor of actin
    • Separate sarcomeres in series
  • A-band – length of myosin and includes overlap of actin
    • Does not change length
  • I-band – actin only
    • Shrinks during contraction
  • H-band – area where myosin filaments are not overlapped with actin filaments
    • Shrinks during contraction
  • M-line – anchor of myosin
66
Q

What is the organizational structure of muscles (smallest component to largest)?

A
  • Sarcomeres
  • Myofibril
  • Muscle Fiber/Cell
  • Fascicles
  • Muscle
67
Q

What is a myofibril?

A

multiple segments of sarcomeres in series

68
Q

What are Muscle Fibers/Cells?

A
  • Multiple myofibrils
  • Multinucleated
  • Each cell is surrounded by endomysium (connective tissue)
69
Q

What are Fascicles?

A
  • Bundles of muscle fibers
  • Fascicles are surrounded by perimysium (connective tissue)
70
Q

What is a muscle?

A
  • Bundles of fasciclesSurrounded by epimysium (connective tissue)
  • Forms tendon that attaches to bone
71
Q

What are the steps in the sliding filament hypothesis?

A
  1. Thick filaments remain constant and thin filaments slide over thick filaments
  2. Driven by ATP hydrolysis produced by myosin crossbridges in thick filament
  3. The crossbridges pull the actin filament toward the M-line because actin has a certain polarity (a plus-end and a minus-end).
    1. Outer-ends have positive charges whereas inner-ends have negative
    2. One outer end is attracted to opposite inner-end
  4. Myosin crossbridges can only produce force in one direction.
72
Q

Define the steps in excitation-contraction coupling in skeletal muscle.

A
  1. Action Potential Travels into T-tubules
  2. L-Type Ca++ Channels Open
  3. Direct Coupling Between L-Type Channel and RyR causes Ca++ release from SR
  4. Ca++ stimulates contraction – most of the Ca++ that actually stimulates contraction is from the SR (as opposed to the Ca++ coming in through the L-Type Ca++ channels)
73
Q

What is the role of the sarcolemma in excitation-contraction coupling.

A
  • Plasma membrane for muscle cells
74
Q

Describe the role of transverse tubules in excitation-contraction coupling.

A

transmit electrical signals/carries action potential throughout cell to allow for synchronous contraction

75
Q

Describe the role of the sarcoplasmic reticulum in excitation-contraction coupling.

A

acts as calcium storage in muscle cells

76
Q

Describe the role of calcium ions in excitation-contraction coupling.

A

bind to troponin C on actin, unblocking myosin binding site

77
Q

Describe the role of the L-type calcium channels in excitation-contraction coupling.

A

opened by action potentials causing conformational change, allowing Ca++ to enter cytosol

78
Q

Describe the role of the ryanodine receptor in excitation-contraction coupling.

A

release Ca++ from sarcoplasmic reticulum

79
Q

How is calcium-induced calcium release different than mechanical-induced calcium release?

A
  • Calcium Induced Calcium Release – in cardiac myocytes, RyRs are ligand-gated, requiring calcium to bind in order to release calcium
  • Mechanical Induced Calcium Release – in skeletal muscle, RyRs are voltage-gated, sensing conformational change in L-type calcium channel due to depolarization, releasing calcium
80
Q

What are the steps in the myosin ATPase cycle?

A

ATP binds → myosin head detaches from actin → ATP hydrolyzes on myosin head into ADP + Pi → myosin head goes back to cocked position (“recovery stroke”) → myosin cross-bridges with actin → phosphate group is released → power stroke (“working stroke”) causes filaments to slide past each other → ADP released (rate-limiting step) → ATP binds

81
Q

How does rigor mortis occur in regards to actin-myosin binding?

A

muscle stiffness that occurs due to low [ATP], causing myosin to remain attached to actin

82
Q

How does myosin ATPase cycle relate to force generation and contractile velocity in muscle?

A
  • Contractile velocity – ADP release step is considered the “detachment limited model”
    • Myosin head cycling is limited by how fast myosin motors can detach
  • Force generation – the more myosin heads interacting with actin, the greater the force
83
Q

How are intracellular calcium levels maintained by the SERCA pump and plasma membrane pumps?

A

SERCA pump uses ATP hydrolysis on SR and NCX/NKX (sodium-calcium/sodium-potassium exchange) system on sarcolemma compete for Ca++ reuptake

84
Q

How does calcium activate the actin thin filament with the three different toponin molecules and tropomyosin in skeletal muscle?

A
  • Troponin C – binds calcium, causing conformational change allowing actin to bind to myosin
  • Troponin I – covers the myosin binding site
  • Troponin T – binds tropomyosin and TnC
  • Tropomyosin – string-like protein that binds actin molecules
85
Q

What is the cooperative effect?

A

Cooperative effect – as one actin site opens and binds to myosin, more actin can bind to myosin

86
Q

Define the structural, enzymatic, and functional features of the three major categories (fast-glycolytic, fast-oxidative-glycolytic, and slow-oxidative fiber types) of skeletal muscle fiber types.

A
87
Q

What are the steps in muscle repair?

A
  1. Degeneration Phase: Injured fibers undergo rapid necrosis and degeneration – due to influx of Ca++ and activation of proteolysis
  2. Inflammatory Phase: Necrotic fibers activate an inflammatory response – invasion by inflammatory cell populations
  3. Regeneration Phase: Satellite cell (muscle stem cell) activation allows for regeneration of fibers – controversial how they are activated to differentiate into a muscle cell
    1. Can be altered by sarcopenia – muscle atrophy due to aging
  4. Remodeling/Repair Phase: is characterized by a maturation of the regenerated fibers, remodeling of the extracellular matrix, recovery of functional performance of injured muscle.
88
Q

What are the four general features of muscle repair disruption in muscular dystrophy?

A
  • Dystrophin – connects extracellular matrix with sarcolemma membrane and associated cytoskeleton
    • Defect in Dystrophin gene causes MD
    • X-linked disease
  • Ca++ entry from extracellular fluid causes proteolysis – inducing muscle damage
  • Creatine Kinase – muscle breakdown causes leak out of muscle and becoming elevated in the blood
  • Myofibrils are replaced with fatty tissue.
89
Q

Define the force vs. velocity relationships in terms of maximum force, velocity, and power.

A
  • Velocity correlates with contractile properties of the tissue
    • Skeletal muscle cells designed for fast contraction
    • Smooth muscle cells designed for slow and sustained/prolonged contraction
90
Q

Define isometric force.

A

constant length that depends on overlap of thick and thin filaments (ex: flexing muscle)

91
Q

Define isotonic contraction.

A

constant load where weight affects speed of contraction and length of muscle fibers (ex: heavy bench press)

92
Q

Define preload.

A

sets the resting muscle tension/length

93
Q

Define afterload.

A

the load on the muscle that is sensed after contraction begins.

94
Q

What are the two phases of contraction.

A
  • Phase 1: Tension Development – build up of passive elastic forces not yet high enough to move the afterload
  • Phase 2: Muscle Shortening – when tension can overcome afterload → muscle shortens
95
Q

What is the Length-Tension Relationship?

A
  • Isometric force is dependent upon the length of the muscle
    • Optimal force, cross bridge overlap is also optimized, at rest
  • Passive tension – depends on length.
    • Isometric force to maintain length
  • Active tension – depends on cross-bridging overlap
96
Q

How does fatigue alter the contractile properties of muscle at the crossbridge level.

A
  • Repeated stimulations → reduction in ATP, incomplete relaxation, decrease in pH
  • Decrease in pH → reduces number of crossbridges because of decrease in ATP
  • No fatigue in NMJ activity → contraction stimulus remains unchanged
97
Q

What is temporal and spatial motor unit recruitment and how do they mediate the strength of contraction?

A
  • Spatial recruitment – increased number of motor neurons firing and increase in # of motor units contracting
  • Temporal recruitment – increased number of action potentials in a motor neuron enhancing the contraction of the muscle fiber within a motor unit
  • Order of recruitment: type I → type IIa → type IIb
98
Q

What are gap junctions and how do they work in cardiac myocytes?

A
  • Cross the intercalated disk
  • Electrical connection between two cardiac myocytes
  • Allows quick transmission of electrical signal between cells
  • Flow is bidirectional
99
Q

What are the steps of action in gap junction in cardiac myocytes?

A
  1. AP electrically stimulates the first cell – Na+ ions flow into the cell to depolarize
  2. Na+ also flows into the adjacent cell – they are attracted by the more negative ions in the adjacent cell as well as the low concentration of Na+ in the adjacent cell (down concentration gradient)
  3. The extracellular current is the capacitive current – the positive ions from inside repel the positive ions near the extracellular surface of the cardiac muscle cell – the positive extracellular ions move back toward the original cell (cell A)
100
Q

What is the relationship between the timing of the action potential and a twitch in cardiac muscle and explain why this prevents tetanic contraction.

A

APs in cardiac muscles are prolonged due to slow closing Ca++ channels → longer depolarizations of cardiac muscle → prolonged twitch/contraction

Due to longer repolarization phase → longer refractory periods → prevents tetanic contraction

101
Q

Describe the length tension relationship in cardiac muscle and how it differs from skeletal muscle.

A
  • Length-tension is related to the overlap between the thick and thin filaments. When this overlap is ideal you get maximum contraction because more crossbridges are able to interact with actin.
  • In skeletal muscle this ideal overlap occurs at resting muscle length.
  • In cardiac muscle you have to stretch it to get to the ideal overlap between the thick and thin filaments and maximum force.
    • This is because in cardiac muscle there is higher passive stiffness at rest.
    • This is a good thing because when you fill the chamber with more blood the force of contraction increases when the cardiac muscle is stretched.
102
Q

Describe the mechanisms through which inotropic interventions change cardiac contractility.

A
  • Increasing length
    • Produce same force with greater velocity
    • Produce greater maximal force
    • Increasing length does not change Vmax
  • Increasing contractility
    • If you increase calcium → more available actin → more myosin-actin binding → crosslinking bridge cycle occurs at a faster rate
    • Produce same force with greater velocity
    • Produce greater maximal force
103
Q

Describe the role of mutations of contractile proteins in cardiac muscle disease pathologies.

A
  • Mutations in Myosin Heavy-Chain (MHC) and LC and Myosin Binding Protein C
    • Dilated phenotype – reduced function and contractile activity
      • Myocytes undergo apoptosis/cell death
      • Expansion of the ventricular chamber and thinning of the septum as the myocytes continue to die
      • Fibrosis leads to necrosis and cell death
    • Hypertrophy phenotype – enhanced force and velocity of contraction
      • Increased septum size due to enhanced fibrosis and myofibrillar disarray
      • Enhanced Ca++ sensitivity, leading to arrhythmias
      • Alters energy balance because of higher ATP consumption
104
Q

Describe the distinguishing characteristics of multi-unit and unitary smooth muscles.

A
  • Multi-unit: Muscle fibers act independently of one another for fine control
  • Single-units (unitary): allows coordinated contraction of multiple cells (using gap junctions as well)
    • GI and Urinary Tracts
105
Q

Describe the differences in actomyosin regulation of smooth and skeletal muscle and indicate the structural similarities in their respective contractile units.

A
  • Activity in skeletal muscle is regulated by troponin C uncovering myosin binding sites on actin, whereas smooth muscle regulates MLCK and
  • Slow tension development – the kinase activity is slower than diffusion of Ca++ to troponin/tropomyosin in skeletal muscle
  • The smooth muscle system allows for a graded control of muscle tension – the percentage of myosin crossbridges activated is directly proportional to muscle tension
  • The response is more graded and not all-or-none like skeletal muscle, different amounts of Ca++ produce different levels of muscle tension
106
Q

Diagram the two intracellular pathways that control contraction and relaxation in smooth muscle.

A
  • Contraction using Myosin Light Chain Kinase (MLCK)
    • 4 Ca++ ions bind Calmodulin → activates MLCK → MLCK phosphorylates myosin regulatory light chain (RLC) → activating myosin
    • Is stretch-induced contraction and is not dependent on nerve stimulation
  • Relaxation via Latch Bridge Mechanism
    • The latch bridge occurs when there is an intermediate level of phosphorylation (and calcium) of the smooth muscle myosin regulatory light chain. Relaxation will occur when all of the RLC becomes dephosphorylated which will occur when the calcium levels drop to near baseline.
    • Reducing [Ca++] → inactivates MLCK
107
Q

Distinguish between electromechanical coupling and pharmacomechanical coupling.

A
  • Electromechanical Coupling
    • Voltage-gated L-type calcium channel can activate RyR by calcium-induced calcium release
  • Pharmacomechanical Coupling
    • GCPR can activate IP3, allowing IP3 to bind to SR receptor to release Ca++ from SR without depolarization
108
Q

Describe the plasticity phenotype of smooth muscle.

A

Phenotypic plasticity – smooth muscle cells can differentiate into a wide variety of phenotypes

109
Q

What is the impact of the plasticity phenotype of smooth muscle on disease conditions.

A
  • Migroproliferative - increasing the number of SMC in the plaque
  • Matrogenic –increasing the fibrosis of the plaque – secrete collagen
  • Inflammatory – enhancing the inflammatory response by interactions with immune cells (monocytes and T cells)
  • Osteochondrogenic – participation in the calcification of the plaques
  • Mesenchymal Stem Cell – differentiates into many cell types
110
Q

What is the importance of phenotypic plasticity of smooth muscle on disease progression?

A
  • Thought that smooth muscle participates in artherosclerosis
  • Calcification in plaque can be seen on CT
111
Q

What is the cardiac muscle force-velocity relationship?

A
  • The force velocity relationship is based on the concept that as the load the muscle is working against increases, the velocity of contraction decreases
  • In the absence of load, there is unloaded shortening velocity
  • In the presence of maximal load, the velocity is zero and you get isometric contraction.
112
Q

What is the equation of bioavailability?

A
113
Q

What are the equations for loading dose?

A
114
Q

What are the maintenance dose equations?

A
115
Q

What are the equations for Ke and half life?

A
116
Q

What is the clearance equation in terms of Vd and half life?

A
117
Q

What is the Ct equation in terms of C0?

A
118
Q

What are the equilibrium concentrations of Na+, Ca2+, Cl-, K+?

A

SPM (17 decks)

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