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67 Cards in this Set

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How do we inhibit depolarization of an ion channel?
1. block sodium channels = decreased sodium conductance

2. block calcium channels = decreased calcium conductance

3. open potassium channels = increased potassium conductance

4. open chloride channels = increased chloride conductance
Where are the sodium channels found that drugs like to affect?
1. autonomic ganglia --> nicotinic type I receptors

2. skeletal muscle motor endplate --> nicotinic type II receptors

3. cardiac fast fibers in atria and ventricles

4. CNS

5. sensory nerve fibers

6. Na channels coupled to 5-HT3 receptors in CTZ
SODIUM CHANNEL: Nicotinic type I receptor

Agonists and antagonists?
nicotinic type I receptors = autonomic ganglia


AGONISTS
ACh and nicotine
-- enhance Na conductance


ANTAGONISTS
trimethaphan, hexamethonium
-- ganglionic blocking drugs
SODIUM CHANNEL: Nicotinic type II receptors

Agonists and antagonists?
nicotinic type II receptors = skeletal muscle motor endplate

AGONISTS
ACh, nicotine, succinylcholine -- enhance Na conductance

ANTAGONISTS
d-tubocurarine (d-tc), pancuronium, Mg++
-- the -curiums and -roniums
SODIUM CHANNEL: cardiac fast fibers

Drugs that affect them and their classes?
CLASS IA DRUGS
procainamide
disopyramide
quinidine

CLASS IB DRUGS
lidocaine
-- only affects ventricles
SODIUM CHANNEL: CNS

Which drugs and MOA?
ANTIEPILEPTICS
phenytoin
carbamazepine
valproate

Inhibit spread of electrical signals by prolonging the state of inactivation of the sodium channel
SODIUM CHANNEL: sensory nerve fibers

Which drugs and MOA?
the cationic form of local anesthetic drugs
-- cocaine
-- procaine
-- lidocaine

Blocks Na+ conductance by binding to a site in the channel on the axoplasmic side (inside cell)
SODIUM CHANNEL: coupled to 5-HT3 receptors in CTZ

Effect of receptor binding and antagonist?
Induces nausea/emesis

Blocked by ONDANSETRON
6 different locations Ca channels are antagonized?
1. block heart and vascular smooth muscle (VSM) L-type channels

2. block channels in SM of GI

3. block channels in SM of uterus

4. block T-type channels in CNS

5. block NMDA receptors coupled to Ca channels

6. block internal Ca channels of SR
Drugs which block L-type Ca channels in heart and VSM?
nifedipine
diltiazem
verapamil
Drugs which block Ca channels in SM of GI?
diltiazem
verapamil

Al
Fe
What blocks Ca channels in SM of uterus
Mg++
Drug which blocks Ca channels in CNS?
ethosuximide
Drug which blocks NMDA receptors coupled to Ca channels?
KETAMINE
PHENCYCLIDINE ("angel dust")
-- prevent excitatory effects of glutamate to cause "dissociative" anesthesia and hallucinations

FELBAMATE
-- prevents seizures by blocking NMDA receptors
Drugs which blocks Ca channels in SR? Use of that drug?
DANTROLENE
-- prevents release of "trigger" Ca

1. DOC for tx of
-- neuroleptic malignant syndrome
-- anesthesia induced malignant hyperthermia

2. prevent spasticity caused by neuro diseases byt causes generalized muscle weakness b/c relaxes ALL skeletal muscle, not just spastic muscle
9 locations to affect K channels?
1. Muscarinic receptors at the SA node
2. 5-HT1A-receptors in the CNS
3. Vascular smooth muscle
4. Fast cardiac fibers
5. pancreatic -islet cells
6. GABA-B receptors coupled to K+-channels in the CNS
7. mu receptors
8. D2-receptors in the anterior pituitary
9. alpha2-adrenoceptors in the medulla
Muscarinic receptors at the SA node: agonists and antagonists?
Muscarinic receptors are coupled to a K-channel via G-protein

AGONISTS
ACh
pilocarpine
AChase inhibitors (indirect through increased ACh)

ANTAGONISTS
atropine et al.
pancuronium
quinidine
TCA’s
older antihistamines like diphenhydramine
Which drug affects 5-HT1A-receptors in the CNS?
buspirone is a partial agonist = antianxiety
Which drugs affect vascular smooth muscle K channels? Their MOA?
ARTERIAL VASODILATORS
hydralazine
minoxidil
diazoxide

activate ATP-modulated K-channels = hyperpolarization = relaxation = vasodilation
Which drugs affect K channels at fast cardiac fibers?
ANTIARRHYTHMICS

CLASS IA
procainamide
disopyramide
quinidine
-- all PROLONG repolarization (APD & ERP increased)
-- only quinidine actually widens the QRS and increases the Q-T interval


CLASS IB
lidocaine
-- ACCELERATES repolarization (APD decreased)

Amiodarone and sotolol
-- DELAY ventric repol by blocking K+ channels
-- APD, ERP and Q-T interval increase

Terfenadine
-- blocks K+ channels and DELAYS repol in ventricles
What is special about terfenadine?
Under normal circumstances terfenadine is completely metabolized by CYP450 to its active metabolite fexofenadine.

The macrolide erythromycin inhibits this CYP450, so terfenadine inhibits repolarization and can increase the Q-T interval enough to cause torsades de pointes = polymorphic ventricular tachycardia

CIDAPRIDE also causes torsades by partially inhibiting the K-repolarization current.
Which drugs affect K channels at pancreatic beta-islet cells to INCREASE insulin secretion? MOA?
the orally active hypoglycemics
-- tolbutamide
-- chlorpropamide
-- glypizide

Close K+-channels causing the cell to depolarize
-- depolarization opens voltage-sensitive channels
-- Ca++ flows in to activate PLC which increases IP3 which release more Ca++ from the SR
-- increased free intracellular Ca++ causes insulin secretion
Which drugs affect K channels at pancreatic beta-islet cells to DECREASE insulin secretion? MOA?
DIAZOXIDE opens ATP-regulated K+-channels to prevent depolarization and thus inhibit insulin secretion

THISZIDE DIURETICS and FUROSEMIDE also inhibit insulin secretion, but the MOA is unknown
Which drugs affect GABA-B receptors coupled to K+-channels in the CNS? MOA?
BACLOFEN
-- enhances GABA-mediated K+ conductance to hyperpolarize presynaptic terminals
-- thus reduces the release of an excitatory NT glutamate in the spinal cord.
Baclofen therapeutic use?
1. Baclofen used to tx spasticity assoc w/ cerebral palsy, multiple sclerosis and stroke.

2. Baclofen is as effective as BZ’s, but causes less sedation.

3. Baclofen also causes less of a decrease in muscle strength than does dantrolene
Which drugs affect K channels at mu receptors? MOA?
opiates (morphine)

hyperpolarizes neurons via mu receptors
Which drugs affect alpha2-adrenoceptors in the medulla? MOA?
CLONIDINE
-- hyperpol to inhibit peripheral sympathetic outflow
2 locations to affect chloride channels?
1. GABA-A receptors

2. Glycine receptors on Renshaw cells (spinal interneurons)
Which drugs enhances GABA-A chlorine channel effect?
GABA-A receptors = hyperpol = inhibition

1. ethanol
2. propofol
3. volatile anesthetics
4. BZs
-- increase freq of channel opening
5. Barbituates
-- increase duration of channel opening

6. valproate
-- increases [GABA] by increasing glutamic acid dehydrogenase and inhibiting GABA transaminase

7. gabapentin releases GABA from its neurons
Which drugs affect glycine receptors on Renshaw cells (spinal interneurons)?
Glycine released from Renshaw cells normally INHIBITS alpha-motor neurons

STRYCHNINE blocks glycine receptors in the spinal cord
-- no alpha motor neuron inhibition --> convulsions
Where might we find cAMP receptors coupled to adenyl cyclase via a G-protein?
1. B1-adrenoceptors
2. B2-adrenoceptors
3. D1-dopamine receptors
4. H2-histamine receptors
5. PGI2(prostacyclin) and PGE receptors
6. V2-AVP receptors
7. 5-HT1 receptors
B1-adrenoceptor cAMP denyl cyclase activation causes?
HEART
-- increased heart rate, contractility & impulse conduction
-- decreased APD and ERP

ADIPOCYTE
-- lipolysis
-- increased plasma ffa's

RENAL JG CELL
-- increased renin release
B2-adrenoceptor cAMP denyl cyclase activation causes?
LUNGS (bronchial SM)
relaxation = bronchodilation = increased FEV1

VSM
-- relaxation
-- vasodilation of arteries and veins

UTERUS
-- relaxation (inhibition of parturition)

LIVER
-- glycogenolysis via protein kinase activation of phosphorylase a

MAST CELL
-- decreased free intracellular calcium inhibits degranulation
D1 dopamine receptor cAMP denyl cyclase activation causes?
vasodilation in the kidney,

**blocked by D1- D2-receptor blockers like haloperidol
H2-histamine receptor cAMP denyl cyclase activation causes?
1. relaxation of VSM
-- direct and through NO
-- causes vasodilation

2. increased gastric acid secretion from oxynitic cells
PGI2 (prostacyclin) and PGE receptor cAMP denyl cyclase activation causes?
1. relaxation of vascular smooth muscle
-- vasodilation

2. decreased platelet aggregation
V2-AVP receptor (renal collecting duct)cAMP adenyl cyclase activation causes?
AVP (ADH) release increases water reabsorption
V2-AVP receptor inhibited by...?
-- PGE's
-- atrial natriuretic factor
-- lithium
-- demeclocycline
V2-AVP receptor potentiated by...?
chlopropramide
carbamazepine
5-HT1 receptor cAMP adenyl cyclase activation causes?
relaxation of vascular smooth muscle
-- causes sustained vasodilation
Which hormones activate adenyl cyclases?
ACTH
FSH
LH
glucagon
PTH
What are the phosphodiesterase inhibitors and what are they used for?
1. theophylline, aminophylline
-- bronchodilation
-- tx of neonatal apnea

2. papaverine
-- relaxation of s.m. in the corpus cavernosa
-- penile erection

3. dipyridamole
-- decreased platelet aggregation when used with aspirin

4. amrinone and milrinone
-- increased cardiac dp/dt
-- tx of terminal CHF
What is the effect of NO?
NO is produced tonically by the vascular endothelial cells

NO activates guanyl cyclase --> cGMP relases arterial/venous VSM (a kinase dephosphorylates the MLCs) and inhibits platelet aggregation
Which drugs affect signal transduction via cGMP? MOA?
THINK ANTIANGINAL DRUGS!!

NITRATE VASODILATORS (nitroglycerin)
Na NITROPRUSSIDE
-- both can convert to NO

ATRIAL NATRIURETIC FACTOR (ANF)
-- also decreases BP by activation of guanyl cuclase and increased [cGMP]

SILDENAFIL
causes erection by inhibiting the type V PDEase which degrades cGMP
What is the response to IP3 and DAG release from PIP2?
IP3 releases Ca++ from the SR
-- Ca++ binds to calmodulin which then activates enzymes (E’s)
-- smooth muscle contraction or secretion
Where might we find IP3/DAG-mediated responses?
1. muscarinic receptors
2. alpha1-adrenoceptors
3. Ang II receptors
4. TXA2 receptors
5. V1-AVP receptors
6. H1-histamine receptors
7. 5-HT2-receptors
8. PGE receptors
IP3/DAG and muscarinic receptors: What is affected?
1. sphincter muscle of iris
2. SM of bronchioles
3. bronchial glands
4. SM of GI tract and gall bladder
5. detrusor muscle of urinary bladder
6. pancreatic acini and B-islet cells (glucagon)
7. salivary glands
8. lacrimal glands
9. nasopharyngeal glands
IP3/DAG and alpha1-adrenoceptors: What is affected?
1. radial muscle of eye
2. vascular SM
3. trigone and internal sphincter of GU tract
4. SM of urethra/prostate
5. pilomotor muscles
6. salivary glands
IP3/DAG and AngII/TXA2/V1-AVP/5-HT2 receptors: What is affected?
VSM (vascular smooth muscle)
IP3/DAG and H1-Histamine receptors: What is affected?
1. vascular endothelial cells
2. SM of bronchioles and GI tract
IP3/DAG and PGE receptors: What is affected?
SM of uterus and GI tract
What interrupts the IP3 signaling pathway? How?
Lithium inhibits the recycling of PIP2, thus interrupting the IP3 signaling pathway
Alteration of ion transport by drugs: DIGOXIN and DIGITOXIN
Depolarization allows Ca++ to move into the cell via L-type (voltage-sensitive) Ca++ channels.
-- Some of the Ca++ is pumped into the SR.
-- Additional Ca++ is extruded by a Na/Ca antiporter which uses the high outside/low inside Na+ gradient to move Ca++ out against its concentration gradient.
-- This outside/inside Na gradient is maintained by the membrane Na/K ATPase.

DIGOXIN
-- partially blocks the Na/K ATPase
-- the outside/inside Na gradient is decreased
-- less Ca++ is extruded via Na/Ca exchange
-- this excess Ca++ in the cell is stored in the SR
-- the next depolariaztion results in a greater release of Ca++ from the SR (thus greater contraction)

DIGOXIN and DIGITOXIN are cardiac glycosides
Alteration of ion transport by drugs: Gastric H/K ATPase
This proton pump is INHIBITED by

Omeprazole
Alteration of ion transport by drugs: N/K/2Cl symporter
Symporter is in ascending LofH
-- blocked by FUROSEMIDE and ETHACRYNIC ACID
Alteration of ion transport by drugs: Na channels in principal cells of LDT/CD
blocked by AMILORIDE and TRIAMTERENE
Alteration of ion transport by drugs: Na/Cl symporter in renal DT
inhibited by THIAZIDE diuretics
Alteration of ion transport by drugs: H+ secretion in renal PT and DT
decreased by ACETAZOLAMIDE b/c it inhibits carbonic anhydrase (CA)
Alteration of ion transport by drugs: H+ secretion from LDT/CD
blocked by AMILORIDE and TRIAMTERENE
List the drugs that can change DNA transcription
1. throxine
2. aldosterone
3. glucocorticoids
4. cyclosporine
5. androgens
6. estrogens
7. NSAIDS
Thyroxine and DNA transcription?
INCREASES
-- B-receptors
-- mitochondrial E's for OxPhos (ATP)
Aldosterone and DNA transcription?
INCREASES
-- basolateral ATPase
-- Na+ channels
-- E’s for oxidative phosphorylation (ATP) in the LDT/CD

INCREASED
-- deposition of fibrillar collagen in the extracellular matrix of the heart
Glucocorticoids and DNA transcription?
cortisone, hydrocortisone, prednisone, prednisolone, beclomethasone, triamcinolone

INCREASES
-- transcription of the genes for lipocortin (inhibits PLA2)
-- the inhibitor of NFKB
-- enzymes (E's) for gluconeogenesis

DECREASES
-- transcription of genes for COX-2
-- IL-1 & IL-6 in monocytes & macrophages
-- gene for NFKB
-- E’s for glycogen storage (except glycogen synthetase)
Cyclosporine and DNA transcription?
DECREASED
-- transcription of gene for IL-2 in helper T-cells
Androgens and DNA transcription?
INCREASED
-- erythropoesis
-- hepatic synthesis of C1-esterase inhibitor of complement
Estrogens and DNA transcription?
INCREASED hepatic protein synthesis:
-- transcortin (CBG)
-- thyroxine-binding globulin (TBG)
-- angiotensinogen (renin substrate)
-- transferrin
-- fibrinogen
-- clotting factors 2, 7, 9 and 10.
NSAIDS and DNA transcription?
PREVENT activation of nuclear factor kappa-B
-- prevents the increased expression of the genes which code for many inflammatory mediators