8 - Na & Ca Channel Blockers Flashcards
Define affinity
How strongly a molecule binds to a receptor (stickiness)
Define potency
- Amount of a molecule required to achieve a defined biochemical effect (smaller dose = more potent drug)
- Also called IC50
Define efficacy
Maximum biological effect that a molecule can have upon binding to a receptor
What is the relative affinity and efficacy of antagonists?
High affinity, no efficacy
How is affinity measured?
Using radio-labelling, usually in a binding assay
How is potency measured?
Using inhibition assays
How is efficacy measured?
Using animal models
Can a molecule have high potency and low efficacy or vice versa?
Yes, don’t need a highly potent drug to have high efficacy
What are ion channels?
- Membrane proteins that are pores or gates that allow inorganic ions to pass
- Only method that inorganic ions can cross the membrane
What can trigger the opening and closing of ion channels?
- Voltage gradients
- Mechanical tension
- Ligands (endogenous or exogenous)
What happens during the opening or closing or a pore/gate?
The channel undergoes several conformational changes
What is the role of ion channels in non-excitable cells, such as hematopoietic cells?
Mediate cellular functions, such as intracellular biochemical responses
What is the role of ion channels in excitable cells, such as neuronal cells, muscle, and secretory cells?
Regulate membrane potential, usually for transmission of electrical signals
Do any drugs act directly on ion channels?
Yes, this causes a change in membrane potential
How do excitable cells produce and respond to electrical signals?
Through the movement of ions
What is resting membrane potential?
Voltage difference across the cell membrane
What happens if there are more cations on the outside of a cell?
Membrane will develop a negative charge on the inside of the cell, leaving an excess of negatively charged proteins
How does the Na+/K+ pump create a concentration gradient?
- Pumps 3 Na+ ions out of the cell and 2 K+ ions into the cell
- Uses ATP -> ADP as energy
- Change in ion concentration causes the development of a net voltage across the membrane (positive on outside and negative on inside)
What are leak channels and what do they do?
- Protein channels
- Allow Na+ or K+ to leak down their concentration gradients, from high to low concentration
- Na+ tends to leak into cell and K+ out of the cell (b/c of the Na+/K+ pump)
Are cell membranes more permeable to Na+ or K+? Why?
K+ b/c there are more K+ channels
When the cell is at rest, is more K+ entering or leaving the cell?
- At eq’m
- Some is entering b/c of charge gradient, and some is exiting b/c of concentration gradient
At equilibrium, what is the relative INTRACELLULAR concentration of various ions?
- High K+
- Low Na+, Ca2+, and Cl-
- High protein and DNA
What 2 components are required to maintain a stable resting membrane potential?
- Ion pumping
- Ion leaking
How can gated ion channels be opened or closed?
Depending on conditions of the cell (such as pressure, voltage, and presence of chemicals/ligands)
What happens when gated Na+ and K+ channels are opened?
- Na+ = more positive charge b/c more positive ions entering the cell
- K+ = more negative charge b/c more positive ions exiting the cell
What are the types of Na and K channels involved in neuronal action potentials?
- Na channels can be voltage activated or ligand activated
- K channels are voltage activated; some leak channels are always open
Describe an action potential of a neuronal cell
- Stimulus causes few Na+ channels to open, allowing Na+ to enter the cell and making the charge more positive
- When threshold is reached, more Na+ channels open and voltage increases even more
- At the peak, Na+ channels begin to close and K+ channels open
- Voltage drops due to K+ leaving the cell, and undershoots (hyperpolarization)
- K+ channels close, except leak channels, and cells resting membrane potential returns to resting state
What is the difference between myocardial action potentials and neuronal APs?
- Myocardial AP is self stimulating, w/ Ca2+ channels playing an important role
- Normally myocardial AP activation starts at one location of the heart (SA node) then spreads down to AV node, then bundle of His, then Purkinje fibers, leading to heart beat/contraction
What are the 3 important types of action potentials in the heart?
1) Pacemaker action potential (mostly by calcium influx) in SA and AV nodes
2) Conduction action potential passing around ventricles starting from bundle of His and Purkinje fibers
3) Muscle contraction AP to contract ventricles
Describe an action potential of a cardiac pacemaker cell
- Ca2+ leaking into cell through Ca(T)
- Cell reaches threshold and Ca(L) channels open, causing influx of Ca2+ (spontaneous depolarization)
- Ca(L) channels close at peak (end of depolarization phase)
- Kv channels open, causing influx of K+ (repolarization)
- Kv channels close
Describe an action potential of a cardiac non-pacemaker cell
- Na+ channels open and Na+ flows in (depolarization)
- Na+ channels close
- Cl- channels open and Cl- flows in
- Ca2+ and K+ channels open, Ca2+ flows in and K+ flows out
- K+ channels open and K+ flows out
- K+ channels close (repolarization)
What does each of the 5 classes of anti-arrhythmic drugs do?
- Class 1 agents interfere w/ Na+ channels
- Class 2 agents are anti-sympathetic NS agents (beta blockers)
- Class 3 agents affect K+ efflux
- Class 4 agents affect calcium channels and AV node
- Class 5 agents work by unknown mechanisms
What can cause extra heart beats? What is done to prevent this?
- When Na+ channels are too sensitive and open too early in Purkinje fibers
- Can use an anti-arrhythmic agent that prevents Na+ channels from opening too soon; but anti-arrhythmic agent must be at low concentration to allow normal Na+ channel function so heart beat doesn’t completely stop
What can a delayed repolarization trigger?
Early depolarization
What is the normal length of a cardiac action potential?
About 300 ms
What are the 2 types of Na channels?
nAChR (ligand; nicotinic acetylcholine receptor) and Nav (voltage)
Ligand-gated nicotinic acetylcholine receptors are the target for ____ drugs
Anesthetic
Voltage-gated Nav channels are the target for ____ drugs
Anti-arrhythmic and anesthetic
Where are nicotinic acetylcholine receptor found?
- Neuromuscular junction (where anesthetics and skeletal muscle relaxants bind to receptor)
- Ganglionic structures in symp and para nerves
- Sensory nerve endings
How is the nicotinic acetylcholine receptor opened? What enters and exits the gate?
- Opened through the binding of 2 acetylcholine molecule, causing a conformational change in the receptor
- Na+ and Ca2+ enter and K+ exits
- Following depolarization, acetylcholine molecules dissociate from the receptor and are enzymatically hydrolyzed by acetylcholinesterase
When does the fast opening of the Nav channels occur?
- Nerve axon’s action potentials
- Heart non-pacemarker conduction action potentials
What triggers the opening of the Nav channels?
Change in membrane voltage
What is the Na+ channel composed of?
Alpha subunit that forms the core/pore and 2 accessory beta subunits
What is the protein sensor in the alpha subunit of the Na+ channel? What does it do?
- A helix that carries 6 positive charges
- When helix is compressed, charge are close together and result in a self-limiting action that only allows ion channel to stay open for 0.5 ms
How do local anesthetics prevent transmission of a nerve impulse?
- They posses lipid-soluble hydrophobic aromatic groups and a charged, hydrophilic amine group
- Bind to sodium channels (ionized form), holding them in an inactive state
What is the rule for basicity of amines?
- Secondary > primary > tertiary for methyl amines
- Secondary > tertiary > primary when alkyl chains are attached (larger than methyl)
What 2 factors determine the basicity of an amine?
- Alkyl groups increase basicity by stabilizing positive charge on N by donating electrons inductively (through bonds), so it should be tertiary > secondary > primary
- In aqueous solution, increased alkyl substitution decreases ability of ammonium cation to form H bonds w/ water molecules, so tertiary amines are less able to stabilize positive charges, so should be secondary > tertiary ~= primary
Is a high or low concentration of local anesthetic needed to block all Na+ channels?
High, so it also blocks K+ and Ca2+ ion channels
Drugs w/ ____ log P give more resting state blocking
Higher
____ a local anesthetic and anti-arrhythmic drug
Lidocaine
Why is articaine given as an anti-arrhythmic instead of lidocaine? What is articaine given w/ and why?
- Methyl ester of articaine is readily hydrolyzed into carboxylic acid and is much less active and will have a difficult time crossing the cell membrane
- Given w/ epinephrine to constrict blood vessels
How is the amine of lidocaine metabolized?
By hepatic amidases
What is an important characteristic of an Na+ channel blocker as an antiarrhythmic drug?
- Must only block cardiac Nav channels for a short period (have fast onset and fast unblocking rate)
- Needs to selectively block channels during rapid cardiac rhythms, so desirable to have frequency-dependent blocking, not resting state blocking
Nav channel blockers w/ ____ molecule weights have faster onset & offset rate and are selective toward inactive states
Lower
What is the main difference between the structures of local anesthetics and anti-arrhythmic molecules?
Anti-arrhythmics have more robust amide linkages to increase half lives in plasma
What are the indications of Ca2+ channel blockers?
Treating hypertension, arrhythmias, and angina
What are the 3 main classes of Ca2+ channel blockers?
- Dihydropyridine
- Phenylalkylamine
- Benzothiazepine
What are the 3 main types of Cav channels?
1) L-type (long acting; responsible for phase 0 of pacemaker AP and phase 2 of non-pacemaker AP; regulates influx of Ca2+ into muscle cells)
2) N-type (short acting in neurons to promote NT secretion)
3) T-type (short acting transient channels; produces pacemaker AP in pacemaker cells in heart; must not be blocked)
What are some examples and structural features of L-type Cav channel blockers?
- Nifedipine has vascular effects
- Diltiazem and verapamil have vascular and myocardial membrane effects and bind to sites that are allosterically linked to nifedipine sites
What is the difference between orthosteric and allosteric?
- Orthosteric = primary, unmodulated binding site (site of endogenous ligand-receptor binding)
- Allosteric = secondary binding site that causes conformational change and receptor activity/inactivity
How do Ca2+ channel blockers actually “block” the channel?
Allosterically change the pore conformation that blocks Ca2+ from passing through
Which 2 Ca2+ channel blockers can be used together?
Diltiazem and nifedipine
Is it better to give nifedipine in a normal release or extended release tablet?
Extended release b/c this will prevent peaks and troughs over 24 h and will keep BP at normal levels
Describe the release of nifedipine from the ADALAT XL extended release tablet
- Tablet consists of a semi-permeable membrane surrounding an osmotically active core
- After ingestion, tablet outer coating is quickly dissipated, allowing water to enter tablet through a semi-permeable membrane
- Polyethylene oxide polymer swells in the osmotic later and expends against the active drug layer, forcing drug through the orifice in the active layer, releasing a constant dose of nifedipine as a fine suspension
What is the conformation of the dihydropyridine ring of nifedipine?
Shallow boat conformation, making it nearly planar
Why is the nitrogen of nifedipine unable to be protonated in aqueous solution?
Nifedipine has many resonance forms
Which isomer of nifedipine has the highest binding affinity? (Cis or trans)
3-cis-5-trans (cis is same side as double bond in the phenyl ring; trans is opposite side)
What are the major metabolizers of nifedipine?
- Esterase
- Ring oxidation by CYP 3A4
- Methyl oxidation
What are the major metabolizers of diltiazem?
- Esterase
- N-demethylation by CYP 3A4
- O-demethylation by CYP 2D6
What are the major metabolizers of verapamil?
- N-demethylation by CYP 3A4
- Multiple O-demethylation by CYP 2D6
