Voltage-gated Ion Channel Drugs Flashcards
Ion channels are targets for…
Anesthetics
Heart failure drugs
Anti-arrhythmic drugs
Anti-hypertensives
Anti-convulsants
Anti-diabetics
Insecticides
Plant/animal toxins
Excitatory ion channels
Na
Ca
(Depolarization)
Inhibitory ion channels
K
Cl
(Hyperpolarization)
Properties of voltage-gated ion channels
Ion selectivity
Large opening to small changes in voltage
Fast activation
Many variants - may be specific to particularly tissue/organ
Types of voltage-gated Ca channels
N-type - neurons, release NT
L-type - cardiac cells, AP in cardiac cells
**Manipulated for drug specificity
Ion current depends on …
Fraction of channels open
Driving force for ion movement (electrochemical potential)
Inactivation of ion channels
Spontaneous closure (inactivation) —> intracellular domain of channel plugs the pore
Unplugged during repolarization
Modulated receptor hypothesis
Channel proteins can exist in 3 (+?) functional states
> dependent on membrane potential
(I.e. closed, open, inactivated)
Use/state dependence
Effect of drug depends on channel’s activity (state)
Mechanism of use/state dependence
Drug may enter channel more readily when open
Drug may preferentially bind a particular state
Actions of ion channel drugs
- Block the channel (physical block or pore or prevent key intramolecular mvt)
- change in gating behavior (change probability of gate opening)
Voltage-gated Na channel drugs
Modulation of excitability
- local anesthetics block initiation/propogation of AP (block action of nocioceptors)
Increasing conc of anesthetic (Na blocker) causes…
Increasing threshold for excitation
Slowing of impulse conduction
Decreased rate of rise of AP
Decreased amplitude of AP
Failure to generate AP
Mechanism of Na-channel blocking local anesthetics
Physically plug membrane channel pore from inside
Na-channel local anesthetic binds strongly to the…
Inactivated state
(Prolonging refractory period)
pH dependence of Na channel blockers
Local anesthetics are weak bases
Non-ionized form penetrates membrane
Ionized form binds the channel
**needs to act from inside channel*
HIGHLY pH dependent
Local anesthetic exhibit strong use dependence
Enter membrane through open channels
Bind more strongly to O and/or I state
Class I antiarrhythmic drugs
Block voltage gated Na channels
Use dependence - bind strongly to O and/or I states - block high frequency excitations (tachy, premature beats)
Binding rate of anti-arrhythmias
For drug that unbinds rapidly - strong activity at high rate of depolarization (tachy)
Not enough time to unbind > accumulation of block
Lidocaine
Binds inactive state of Na channel
Unbinds rapidly - only tachycardic activity
Quinidine
Binds open state
Unbinds slowly - block remains between beats; affects normal rates
Grayanotoxins
Toxin in plants (rhododendron, Azalea)
Stabilized open conformation of Na channel
Toxic to grazing animals, MAD HONEY (raw honey from bees near these plants > human toxin)
Increased intracellular Ca —>
Contraction in muscle cells
Secretion/release
Modulation of enzyme activity
Cardiac muscle Ca channel opener
beta-adrenergic receptors in cardiac muscle
Indirect mechanism of Ca channel openers
- Activation of adenylyl cyclase —> phosporylation of Ca channels
- Alpha subunit of G protein binds to Ca channels
Classes of Ca channel antagonists
Phenylalkylamines (verapamil)
Dihydropyridines (nifedipine)
Benzothiazepines (diltiazem)
**all act from inner side of channel
Use dependence of Ca channel antagonists
Nifedipine > binds resting state
Verapamil > binds open state
Diltiazem > binds inactivated state
**empirically determined
Cardiovascular implications of Ca channel antagonism (dec inward current)
Decreases SA node pacemaker rate
Decreased AV node conduction velocity
Reduced cardiac muscle contractility
Vascular smooth muscle relaxation
Cardiac actions of Ca channel agonists
Slow SA/AV nodal conduction velocity (slow HR; nodal AP propagation depends on slow, inward current of Ca; terminate supraventricular tachycardias via partial AV block)
Reduce force of contraction
Verapamil/diltiazem have strong cardiac effects
Vascular smooth muscle actions of Ca channel antagonists
Smooth muscle depends on Ca influx for resting tone/contraction
Blocking Ca entry > generalized arteriolar dilation > drop in BP
Nifedipine = most potent vasodilator (stronger affinity to Ca channel in VSMCs vs cardiac muscle cells)
Unwanted effects of Ca channel agonists
Relaxation of off-target smooth muscle
Headache/flushing (humans)
Constipation
AV block + negative inotropic effects
Cantharidin
Blister beetle toxin > increases opening of Ca channels
Blister beetles sometimes found in hay (esp alfalfa)
Horses especially susceptible > die within 24-72 h
Sheep/cattle often exposed, rarely ill
