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Pharm > Voltage-gated Ion Channel Drugs > Flashcards

Voltage-gated Ion Channel Drugs Flashcards

1
Q

Ion channels are targets for…

A

Anesthetics
Heart failure drugs
Anti-arrhythmic drugs
Anti-hypertensives
Anti-convulsants
Anti-diabetics
Insecticides
Plant/animal toxins

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2
Q

Excitatory ion channels

A

Na
Ca
(Depolarization)

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3
Q

Inhibitory ion channels

A

K
Cl
(Hyperpolarization)

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4
Q

Properties of voltage-gated ion channels

A

Ion selectivity
Large opening to small changes in voltage
Fast activation

Many variants - may be specific to particularly tissue/organ

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5
Q

Types of voltage-gated Ca channels

A

N-type - neurons, release NT

L-type - cardiac cells, AP in cardiac cells

**Manipulated for drug specificity

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6
Q

Ion current depends on …

A

Fraction of channels open

Driving force for ion movement (electrochemical potential)

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7
Q

Inactivation of ion channels

A

Spontaneous closure (inactivation) —> intracellular domain of channel plugs the pore

Unplugged during repolarization

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8
Q

Modulated receptor hypothesis

A

Channel proteins can exist in 3 (+?) functional states
> dependent on membrane potential

(I.e. closed, open, inactivated)

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9
Q

Use/state dependence

A

Effect of drug depends on channel’s activity (state)

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10
Q

Mechanism of use/state dependence

A

Drug may enter channel more readily when open

Drug may preferentially bind a particular state

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11
Q

Actions of ion channel drugs

A
  1. Block the channel (physical block or pore or prevent key intramolecular mvt)
  2. change in gating behavior (change probability of gate opening)
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12
Q

Voltage-gated Na channel drugs

A

Modulation of excitability

  • local anesthetics block initiation/propogation of AP (block action of nocioceptors)
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13
Q

Increasing conc of anesthetic (Na blocker) causes…

A

Increasing threshold for excitation
Slowing of impulse conduction
Decreased rate of rise of AP
Decreased amplitude of AP
Failure to generate AP

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14
Q

Mechanism of Na-channel blocking local anesthetics

A

Physically plug membrane channel pore from inside

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15
Q

Na-channel local anesthetic binds strongly to the…

A

Inactivated state

(Prolonging refractory period)

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16
Q

pH dependence of Na channel blockers

A

Local anesthetics are weak bases

Non-ionized form penetrates membrane
Ionized form binds the channel

**needs to act from inside channel*
HIGHLY pH dependent

17
Q

Local anesthetic exhibit strong use dependence

A

Enter membrane through open channels
Bind more strongly to O and/or I state

18
Q

Class I antiarrhythmic drugs

A

Block voltage gated Na channels
Use dependence - bind strongly to O and/or I states - block high frequency excitations (tachy, premature beats)

19
Q

Binding rate of anti-arrhythmias

A

For drug that unbinds rapidly - strong activity at high rate of depolarization (tachy)

Not enough time to unbind > accumulation of block

20
Q

Lidocaine

A

Binds inactive state of Na channel

Unbinds rapidly - only tachycardic activity

21
Q

Quinidine

A

Binds open state
Unbinds slowly - block remains between beats; affects normal rates

22
Q

Grayanotoxins

A

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)

23
Q

Increased intracellular Ca —>

A

Contraction in muscle cells

Secretion/release

Modulation of enzyme activity

24
Q

Cardiac muscle Ca channel opener

A

beta-adrenergic receptors in cardiac muscle

25
Q

Indirect mechanism of Ca channel openers

A
  1. Activation of adenylyl cyclase —> phosporylation of Ca channels
  2. Alpha subunit of G protein binds to Ca channels
26
Q

Classes of Ca channel antagonists

A

Phenylalkylamines (verapamil)

Dihydropyridines (nifedipine)

Benzothiazepines (diltiazem)

**all act from inner side of channel

27
Q

Use dependence of Ca channel antagonists

A

Nifedipine > binds resting state
Verapamil > binds open state
Diltiazem > binds inactivated state

**empirically determined

28
Q

Cardiovascular implications of Ca channel antagonism (dec inward current)

A

Decreases SA node pacemaker rate
Decreased AV node conduction velocity
Reduced cardiac muscle contractility
Vascular smooth muscle relaxation

29
Q

Cardiac actions of Ca channel agonists

A

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

30
Q

Vascular smooth muscle actions of Ca channel antagonists

A

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)

31
Q

Unwanted effects of Ca channel agonists

A

Relaxation of off-target smooth muscle

Headache/flushing (humans)

Constipation

AV block + negative inotropic effects

32
Q

Cantharidin

A

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

Pharm (10 decks)

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