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58 Cards in this Set

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Ion channels
To inhibit depolarization
- block sodium channels = decreased sodium conductance
- block calcium channels = decreased calcium conductance
- open potassium cannels = increased potassium conductance
- open chloride channels = increased chloride conductance
Drugs acting through sodium channels
nicotinic type I receptors = autonomic ganglia
agonists = ACh and nicotine (enhance Na conductance)
antagonists (ganglionic blocking drugs) = trimethaphan, hexamethonium
Drugs acting through sodium channels
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
Drugs acting through sodium channels
sodium channels of cardiac fast fibers = atria, ventricles
class IA drugs = procainamide, disopyramide, quinidine
class IB drugs = lidocaine - only affects ventricles
Drugs acting through sodium channels
sodium channels in CNS
the antiepileptic drugs phenytoin, carbamazepine, &
valproate inhibit the spread of electrical signals by prolonging the state of
inactivation of the sodium channel
Drugs acting through sodium channels
Na+ channels in sensory nerve fibers
= 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)
Drugs acting through sodium channels
Sodium channels coupled to 5-HT3 receptors in CTZ
induce nausea/emesis,
blocked by ondansetron
Ca++ channel blockers
= nifedipine, diltiazem & verapamil = block L-type channels
in heart and vascular smooth muscle (VSM)
Ca++ channels in SM of GI
SM of GI tract blocked by Al, Fe, diltiazem and verapamil
Ca++ channels in SM of uterus
SM of uterus blocked by Mg++
T-type Ca++ channels in CNS
Ca++ channels in CNS blocked by ethosuximide
Glutamate stimulation of NMDA receptors coupled to Ca++ channels
Ketamine and phencyclidine (“angel dust”) block NMDA receptors and prevent the
excitatory effects of glutamate to cause “dissociative” anesthesia and
hallucinations. Felbamate prevents seizures by blocking NMDA receptors.
Internal Ca++ channels of SR
Ca++ channels of SR blocked by dantrolene which prevents the release of
“trigger” Ca++ = DOC for tx of neuroleptic malignant syndrome and anesthesia-
induced malignant hyperthermia (hyperpyrexia); dantrolene also used to prevent
spasticity caused by neuro diseases, but causes generalized muscle weakness bx
it relaxes all skeletal muscle, not just the spastic muscle.
Drugs acting through potassium channels = hyperpolarization = inhibition
Muscarinic receptors at the SA node - coupled to a K-channel via a G-protein
agonists
ACh, pilocarpine, AChase inhibitors (indirect through increased ACh)
antagonists = atropine et al., pancuronium, quinidine, TCA’s, older antihistamines
like diphenhydramine
Drugs acting through potassium channels = hyperpolarization = inhibition
5-HT1A-receptors in the CNS
buspirone is a partial agonist = antianxiety
Drugs acting through potassium channels = hyperpolarization = inhibition
Vascular smooth muscle
arterial vasodilators (hydralazine, minoxidil, diazoxide)
activate ATP-modulated K-channels = hyperpolarization = relaxation = vasodilation
Drugs acting through potassium channels = hyperpolarization = inhibition
Fast cardiac fibers - antiarrhythmic drugs
Class IA = procainamide, disopyramide & quinidine prolong repolarization (APD &
ERP increased); only quinidine actually widens the QRS and ↑ the Q-T interval

Class IB = lidocaine accelerates repolarization (APD decreased)

Amiodarone and sotalol – delay ventricular repolarization via block of K+ channels;
APD, ERP and Q-T interval increase

Terfenadine blocks K+-channels and delays repolarization in the ventricles, but
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
Cisapride also causes torsades by partially inhibiting the K-repolarization current.
Drugs acting through potassium channels = hyperpolarization = inhibition
pancreatic β-islet cells - the orally active hypoglycemic
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

Diazoxide opens ATP-regulated K+-channels to prevent depolarization and thus
inhibit insulin secretion

Thiazide diuretic drugs and furosemide also inhibit insulin secretion, but the MOA
is unknown
Drugs acting through potassium channels = hyperpolarization = inhibition
GABAB-receptors coupled to K+-channels in the CNS; agonist
baclofen
Baclofen enhances GABA-mediated K+ conductance to hyperpolarize presynaptic
terminals and thus reduce the release of an excitatory NT glutamate in the spinal
cord. Baclofen used to tx spasticity ass w cerebral palsy, multiple sclerosis and
stroke. Baclofen is as effective as BZ’s, but causes less sedation. Baclofen also
causes less of a decrease in muscle strength than does dantrolene
Drugs acting through potassium channels = hyperpolarization = inhibition
Opiates
Opiates (morphine) hyperpolarize neurons via mu receptors
Drugs acting through potassium channels = hyperpolarization = inhibition
D2-receptors in the anterior pituitary
dopamine, bromocriptine and pergolide
hyperpolarize cells to prevent prolactin release (NB: in other parts of the brain
DA inhibits adenyl cyclase or calcium conductance)
Drugs acting through potassium channels = hyperpolarization = inhibition
α2-adrenoceptors in the medulla
clonidine hyperpolarizes to inhibit peripheral
sympathetic outflow
Chloride channels
GABAa-receptors = hyperpolarization = inhibition
Effect of GABA enhanced by: ethanol, propofol, volatile anesthetic agents, BZ’s
(increased frequency of channel opening) and barbiturates (increased duration of
channel opening)
Valproate increases [GABA] by increasing glutamic acid dehydrogenase and
inhibiting GABA transaminase
Gabapentin releases GABA from its neurons.
Chloride channels
Glycine receptors on Renshaw cells (spinal interneurons)
Glycine released from Renshaw cells inhibits α-motor neurons; strychnine blocks
glycine receptors in the spinal cord = no α-motor neuron inhibition = convulsions
Cyclic AMP (CAMP) - receptors coupled to adenyl cyclase via a G-protein
β1-adrenoceptors
β1-adrenoceptors
heart =↑ heart rate, contractility & impulse conduction;↓ APD and ERP
adipocyte = lipolysis = increased plasma free fatty acids
renal JG cells = increased renin release
Cyclic AMP (CAMP) β2-adrenoceptors
β2-adrenoceptors
lungs = (bronchial SM) = relaxation = bronchodilation = increased FEV1
vascular smooth muscle = 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
Cyclic AMP (CAMP) D1-dopamine receptors
D1-dopamine receptors
vasodilation in the kidney, blocked by D1- D2-receptor blockers like haloperidol
Cyclic AMP (CAMP) H2-histamine receptors
H2-histamine receptors
relaxation of VSM (direct and through NO) causes vasodilation
increased gastric acid secretion from oxynitic cells
Cyclic AMP (CAMP)
PGI2 (prostacyclin) and PGE receptors
PGI2 (prostacyclin) and PGE receptors
relaxation of vascular smooth muscle = vasodilation
decreased platelet aggregation
Cyclic AMP (CAMP) - V2-AVP receptors (renal collecting duct)
V2-AVP receptors (renal collecting duct) = AVP (ADH) increases water reabsorption
This cyclase inhibited by PGE’s, atrial natriuretic factor, lithium and demeclocycline
Antidiuretic effect of AVP potentiated by chlopropramide and carbamazepine.
Cyclic AMP (CAMP) - 5-HT1-receptors
5-HT1-receptors
relaxation of vascular smooth muscle causes sustained vasodilation
Cyclic AMP (CAMP) - hormones
hormones = ACTH, FSH, LH, glucagon, PTH activate adenyl cyclases
Cyclic AMP (CAMP) -phosphodiesterase inhibitors
phosphodiesterase inhibitors
theophylline, aminophylline = bronchodilation = tx of neonatal apnea
papaverine = relaxation of s.m. in the corpus cavernosa = penile erection
dipyridamole = decreased platelet aggregation when used with aspirin
amrinone and milrinone = increased cardiac dp/dt (tx of terminal CHF)
Signal transduction via cyclic GMP (CGMP) - THINK antianginal drugs!
Nitric oxide (NO) is produced tonically by the vascular endothelial cells.
nitrate vasodilators (nitroglycerin) and Na nitroprusside are converted to NO which
activates guanyl cyclase: CGMP relaxes arterial/venous VSM (a kinase
dephosphorylates the MLC’s) and inhibits platelet aggregation.
Atrial natriuretic factor (ANF) also ↓ BP by activation of guanyl cyclase and ↑ [CGMP]
sildenafil causes erection by inhibiting the type V PDEase which degrades CGMP
IP3 and DAG
IP3 releases Ca++ from the SR; Ca++ binds to calmodulin which then
activates enzymes (E’s) = smooth muscle contraction or secretion
Receptors of VSM or SM
1. muscarinic receptors = sphincter muscle of iris, SM of bronchioles, bronchial
glands, SM of GI tract and gall bladder, detrusor muscle of urinary bladder,
pancreatic acini and α-islet cells (glucagon); salivary glands, lacrimal glands,
nasopharyngeal glands

2. α1-adrenoceptors = radial muscle of eye, vascular SM, trigone and internal
sphincter of GU tract, SM of urethra/prostate, pilomotor muscles, salivary glands

3. Ang II receptors -=VSM

4. TXA2 receptors = VSM

5. V1-AVP receptors = VSM

6. H1-histamine receptors = vascular endothelial cells, SM of bronchioles and GI tract

7. 5-HT2-receptors = VSM

8. PGE receptors = SM of uterus and GI tract

9. Li+ inhibits the recycling of PIP2 and thus interrupts the IP3 signaling pathway
Alteration of ion transport by drugs
Cardiac glycosides= digoxin & 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
Alteration of ion transport by drugs - Gastric H+-K+ ATPase (proton pump)
(proton pump) - inhibited by omeprazole
Alteration of ion transport by drugs- Na+: K+:2Cl- symporter in ascending limb of Henle’s loop
ascending limb of Henle’s loop is blocked by furosemide
and ethacrynic acid.
Alteration of ion transport by drugs - Na+: Cl- symporter in renal DT
renal DT - inhibited by thiazide diuretic drugs
Alteration of ion transport by drugs - Na+ channels in principal cells of LDT/CD
principal cells of LDT/CD - blocked by amiloride and triamterene
Alteration of ion transport by drugs- H+ ion secretion in renal PT and DT
renal PT and DT -↓ by acetazolamide bx it inhibits CA
Alteration of ion transport by drugs - H+ ion secretion from LDT/CD
LDT/CD - blocked by amiloride and triamterene
Changes in DNA transcription thyroxine
↑ β-receptors & mitochondrial E’s for oxidative phosphorylation (ATP)
Changes in DNA transcription aldosterone
↑ basolateral ATPase, Na+ channels and E’s for oxidative
phosphorylation (ATP) in the LDT/CD; increased deposition of fibrillar collagen in
the extracellular matrix of the heart
Changes in DNA transcription glucocorticoids
cortisone, hydrocortisone, prednisone, prednisolone,
beclomethasone, triamcinolone
- increased transcription of the genes for lipocortin (inhibits PLA2), the inhibitor of
NFΚB and enzymes (E's) for gluconeogenesis
- ↓ transcription of genes for COX-2; IL-1 & IL-6 in monocytes & macrophages;
gene for NFΚB, and E’s for glycogen storage (except glycogen synthetase)
Changes in DNA transcription cyclosporine
decreased transcription of gene for IL-2 in helper T-cells
Changes in DNA transcription androgens
increased erythropoesis and hepatic synthesis of C1-esterase inhibitor
of complement
Changes in DNA transcription estrogens
- increased hepatic protein synthesis = transcortin (CBG), thyroxine-
binding globulin (TBG), angiotensinogen (renin substrate), transferrin, fibrinogen
and clotting factors 2, 7, 9 and 10.
Changes in DNA transcription NSAID’s
NSAID’s prevent the activation of nuclear factor kappa-B: this action prevents the
increased expression of the genes which code for many inflammatory mediators.
Idiosyncratic drug reactions Plasma pseudocholinesterase deficiency
the NMB caused by succinylcholine last
hours instead of minutes.
Idiosyncratic drug reactions Barbiturates
produce excitation and anxiety instead of sedation in older patients.
Idiosyncratic drug reactions The older antihistamines
(e.g. diphenhydramine) cause excitation instead of sedation
in very young children and older patients.
Idiosyncratic drug reactions Aspirin and other NSAID's
precipitate an anaphylactic-like reactions (a.k.a. aspirin
hypersensitivity) in patients with nasal polyps. Blockade of PG synthesis by the
NSAID shunts all the arachidonic acid to leukotriene synthesis → LT's cause
rhinoconjunctivitis, angioedema and urticaria.
Idiosyncratic drug reactions Glucose-6-phosphate dehydrogenase deficiency
hemolytic anemia is produced by
primaquine, isoniazid, sulfonamides, nitrofurantoin or eating fava beans
Idiosyncratic drug reactions . SHIP drugs exhibit toxicity in slow acetylators
a. sulfapyridine (contained in the drug sulfasalazine) =hemolytic and aplastic
anemia, hepatic damage.
b. hydralazine = SLE-like syndrome
c. isoniazid = hepatic damage, peripheral neuropathy - tx neuropathy w pyridoxal
phosphate (vitamin B6)
d. procainamide = SLE-like syndrome
Idiosyncratic drug reactions Malignant hyperthermia (hyperpyrexia)
a gene defect prevents Ca++ from being
sequestered correctly in the sarcoplasmic reticulum (SR) of skeletal muscle.
- anesthesia with a volatile anesthetic agent (e.g., halothane) plus the administration
of succinylcholine causes the massive release of Ca++ = masseter muscle spasm
- S/S = ↑ B, HR, & muscle contraction w hyperthermia, lactic acidosis and cardiac
dysrhythmias
- tx w dantrolene sodium which prevents the release of Ca++ from the SR
Idiosyncratic drug reactions Neuroleptic malignant syndrome
etiology NOT related to malignant hyperthermia
= produced by rapid blockade of central DA receptors with the typical antipsychotic
drugs like haloperidol
- S/S = resembles severe Parkinson's dx w catatonia = EPS, stupor, hyperthermia,
↑ CPK, myoglobinuria, ARF
- Tx w dantrolene sodium + bromocriptine (a D2-receptor agonist)