Pharmacology and Toxicology
Week 2
Dr. Mark Dallas
Voltage and Ligand- gated ion Channels
% of drugs that are major families;
- Ion channels [18%] // Nuclear Receptors [16%] // Kinases [3%] // GPCR’s [33%] //
Other [30%]
Ionic Homeostasis; plasma membrane charged, repels charged ions [ion channels with
established concentration gradients]
Potassium Channels;
- Most diverse, 70 different genes encoding K+ channels
- Α subunits in human genome
- Regulate cell excitability through different medialities.
o Frequency and shape of action potential
o Secretion of hormones
o Secretion of neurotransmitters
o Membrane potential
- α-subunit;
o intracellular C/N terminus, 6 TMD’s,
predominant influx of K+, TMD4 +ve
[voltage sensing domain], 4 x α-subunits
= pore.
o Families [all homologous or a mix] – to
maximize absorption.
- Drug: Minoxidil
o Opens K+ channels
o Causes hyperpolarization in smooth muscle cells, muscle relaxation and
vasodilation
o Indication; used to treat hypertension in combination with diuretic and β-
adrenoreceptor blocker.
Sodium Channels;
- First member of the ion superfamily to be discovered
- Voltage gated sodium selective ion
channels present in the membrane of
excitable cells
- Compromise of pore forming α-subunit,
encoded by at least 10 genes
- α-subunit;
, Pharmacology and Toxicology
Week 2
Dr. Mark Dallas
o intracellular C/N terminus, 6TMD, interconnection between 4 [forms 1 pore],
TMD 4 is voltage sensing
- Drug: Lidocaine;
o Blocks voltage gated sodium channels [NaV1.5/1.7/1.9]
NaV1.x
[Na] = Sodium / [V] = voltage / [1] = subfamily / [x] = subtype
o Primary target is NaV1.5 [main cardiac sodium channel]
o Indication; ventricular arrhythmias, after myocardial infarction, local
anesthesia.
Calcium Channels;
- Ca2+ voltage gated ion channels present in membrane of excitable cells
- Ca2+ channels form hereto-oligomeric complexes [α-1 subunit pore forming and
provides extracellular binding sites for all agonists/antagonists]
- 3 families exist;
1. High voltage activated dihydropyridine sensitive [L-Type, Cav1.x]
2. High voltage activated dihydropyridine insensitive [Cav2.x]
3. Low voltage activated [Cav.3.x]
- Drugs gabapentin and pregabalin can bind to pores α2-δ1 // α2-δ2
- α-1 subunit;
o 6 TMD x 4, intracellular N/C
terminus, TM4 voltage sensitive
o Low voltage activated exists on
alpha-1 subtypes.
o High voltage activated require;
γ-subunit [intracellular
C/N, 4 TMD]
α2δ-subunit [extracellular
subunit with 3 domains]
β-subunit [intracellular
subunit with 4 domains]
- Drug: Verapamil
o Blocks voltage gated calcium channels [L-type]
o Blocks calcium influx in myocardial and vascular smooth muscle cells. Leads
to reduction in cardiac and vascular smooth muscle contraction = dilation in
coronary and systemic arteries
o Indication; supraventricular arrhythmias, angina, hypertension [dose and
preparation dependent]
Channelopathies;
1. Epilepsy; [hyperexcitable disease of CNS] Na+ / Ca2+ / K+ channels
2. Diabetes; K+ / KATP channels
3. Ataxia [motor control]; K+ / Ca2+ channels
Week 2
Dr. Mark Dallas
Voltage and Ligand- gated ion Channels
% of drugs that are major families;
- Ion channels [18%] // Nuclear Receptors [16%] // Kinases [3%] // GPCR’s [33%] //
Other [30%]
Ionic Homeostasis; plasma membrane charged, repels charged ions [ion channels with
established concentration gradients]
Potassium Channels;
- Most diverse, 70 different genes encoding K+ channels
- Α subunits in human genome
- Regulate cell excitability through different medialities.
o Frequency and shape of action potential
o Secretion of hormones
o Secretion of neurotransmitters
o Membrane potential
- α-subunit;
o intracellular C/N terminus, 6 TMD’s,
predominant influx of K+, TMD4 +ve
[voltage sensing domain], 4 x α-subunits
= pore.
o Families [all homologous or a mix] – to
maximize absorption.
- Drug: Minoxidil
o Opens K+ channels
o Causes hyperpolarization in smooth muscle cells, muscle relaxation and
vasodilation
o Indication; used to treat hypertension in combination with diuretic and β-
adrenoreceptor blocker.
Sodium Channels;
- First member of the ion superfamily to be discovered
- Voltage gated sodium selective ion
channels present in the membrane of
excitable cells
- Compromise of pore forming α-subunit,
encoded by at least 10 genes
- α-subunit;
, Pharmacology and Toxicology
Week 2
Dr. Mark Dallas
o intracellular C/N terminus, 6TMD, interconnection between 4 [forms 1 pore],
TMD 4 is voltage sensing
- Drug: Lidocaine;
o Blocks voltage gated sodium channels [NaV1.5/1.7/1.9]
NaV1.x
[Na] = Sodium / [V] = voltage / [1] = subfamily / [x] = subtype
o Primary target is NaV1.5 [main cardiac sodium channel]
o Indication; ventricular arrhythmias, after myocardial infarction, local
anesthesia.
Calcium Channels;
- Ca2+ voltage gated ion channels present in membrane of excitable cells
- Ca2+ channels form hereto-oligomeric complexes [α-1 subunit pore forming and
provides extracellular binding sites for all agonists/antagonists]
- 3 families exist;
1. High voltage activated dihydropyridine sensitive [L-Type, Cav1.x]
2. High voltage activated dihydropyridine insensitive [Cav2.x]
3. Low voltage activated [Cav.3.x]
- Drugs gabapentin and pregabalin can bind to pores α2-δ1 // α2-δ2
- α-1 subunit;
o 6 TMD x 4, intracellular N/C
terminus, TM4 voltage sensitive
o Low voltage activated exists on
alpha-1 subtypes.
o High voltage activated require;
γ-subunit [intracellular
C/N, 4 TMD]
α2δ-subunit [extracellular
subunit with 3 domains]
β-subunit [intracellular
subunit with 4 domains]
- Drug: Verapamil
o Blocks voltage gated calcium channels [L-type]
o Blocks calcium influx in myocardial and vascular smooth muscle cells. Leads
to reduction in cardiac and vascular smooth muscle contraction = dilation in
coronary and systemic arteries
o Indication; supraventricular arrhythmias, angina, hypertension [dose and
preparation dependent]
Channelopathies;
1. Epilepsy; [hyperexcitable disease of CNS] Na+ / Ca2+ / K+ channels
2. Diabetes; K+ / KATP channels
3. Ataxia [motor control]; K+ / Ca2+ channels
