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129 Cards in this Set

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Ion Channels
=To INHIBIT depolarization, what could you do?
1) Block Na Channels
=decreased Na conductance

2) Block Ca Channels
=decreased Ca conductance

3) Open K Channels
=Increased K conductance

4) Open Cl Channels
=Increased Cl conductance
Drugs Acting Through SODIUM Channels
1) Nicotinic Type I Receptors
2) Nicotinic Type II Receptors
3) Na Channels of Cardiac Fast Fibers
4) Na Channels in the CNS
5) Na channels in sensory nerve fibers
6) Na channels coupled to 5HT3 receptors in the CTZ
Nicotinic Type I Receptors
=Autonomic Ganglia

Agonists:
=ACh + nicotine
=ENHANCE Na conductancce

Antagonists:
=Trimethaphan + hexamethonium
="Ganglionic Blocking Drugs"
Nicotinic Type II Receptors
**Skeletal muscle motor endplate

Agonists:
=ACh, nicotine, + succinylcholine
=Enhance Na conductance

Antagonists:
=d-tubocurarine (d-tc), pancuronium, Mg++
=i.e. the -curiums and -roniums
Sodium Channels of Cardiac Fast Fibers
**Atria + ventricles

Class IA Drugs:
=procainamide
=disopyramide
=quinidine

Class IB Drugs:
=Lidocaine --> ONLY affects VENTRICLES!
Sodium Channels in the CNS
**The antiepileptic drugs:
=phenytoin
=carbamazepine
=valproate

=inhibit the spread of electrical signals by prolonging the state of inactivation of the Na channel
Sodium channels in sensory nerve fibers
**The cationic form of LOCAL anesthetic drugs (=cocaine, procaine, lidocaine) will BLOCK Na conductance by binding to a site in the channel on the AXOPLASMIC side (=i.e. inside cell)
Sodium Channels Coupled to 5-HT3 Receptors in the CTZ
=induce n/v

**Blocked by ondansetron!
Calcium Channel Blockers
1) Nifedipine
2) Diltiazem
3) Verapamil

**Block L-TYPE Ca channels in the HEART + vascular smooth muscle
Ca channels in the SM of GI tract are blocked by:
1) Al
2) Fe
3) Diltiazem
4) Verapamil
Ca channels in the SM of the uterus are blocked by:
Mg
T-type Ca channels in the CNS are blocked by:
ethosuximide
What blocks glutamate stimulation of NMDA type Ca receptors?
**Ketamine + phencyclidine (="angel dust") BLOCK NMDA receptors and PREVENT the excitatory effects of glutamate -->

Causes "dissociative" anesthesia + hallucinations

**FELBAMATE prevents seizures by blocking NMDA receptors
What blocks internal Ca channels of the SR?
**DANTROLENE
=prevents the release of "trigger" Ca

**i.e. Dantrolene is the DOC for treatment of:
=neuroleptic malignant syndrome
=anesthesia-induced malignant hyperthermia
What else can Dantrolene be used for?
**Prevent spasticity caused by neuro. diseases

**Causes GENERALIZED muscle weakness however--i.e. it relaxes ALL skeletal muscle NOT just the spastic muscle
Drugs acting through POTASSIUM Channels:
Hyperpolarization = Inhibition
Muscarinic receptors at the SA node are coupled to a K-channel via a G-protin
Agonists:
=ACh
=Pilocarpine
=AChase inhibitors --> i.e. indirectly through increased ACh

Antagonists:
=atropine
=pancuronium
=quinidine
=TCAs
=older antihistamines--like diphenhydramine
5-HT1A recectprs in the CNS
BUSPIRONE is a partial agonist = ANTI-ANXIETY
Vascular SM
1) Arterial Vasodilators
=hydralazine
=minoxidil
=diazoxide

**All will activate ATP-modulated K-channels --> hyperpolarization = relaxation = vasodilation
Class IA
Class IA:
=procainamide
=disopyramide
=quinidine

**ALL will prolong repolarization (=APD + ERP increased)
**ONLY quinidine actually widens the QRS and increases the QT interval
Class IB
=Lidocaine

**Accelerates REPOLARIZATION
=APD decreased
Effects of Amiodarone + Sotalol
**Delay ventricular repolarization via block of K+ channels

=Increased APD, ERP, and Q-T interval
What does Terfenadine do?
**Blocks K+ channels AND delays repolarization in the VENTRICLES

=BUT, under normal conditions, terfenadine is completely metabolized by CYP450 to its active metabolite = FEXOFENADINE
What can happen if you give the macrolide ERYTHROMYCIN w/ terfenadine?
**Erythromycin will INHIBIT the CYP450
=SO, terfenadine inhibits repolarization + can increase the QT interval enough to cause TORSADES DE POINTES (i.e. ventricular tachycardia)
What else can cause torsades de pointes by partially inhibiting the K-repolarization current?
Cisapride
K+ Channels and the Pancreatic B-islet Cells:
**Orally active drugs:
=tolbutamide
=chlorpropamide
=glypizide

are going to CLOSE K+ channels --> causing cell to DEPOLARIZE

=depolarization will OPEN voltage-sensitive Ca channgels --> Ca flows in to activate PLC which INCREASES IP3 which then release MORE Ca from the SR

=all this increased free intracellular Ca causes INSULIN SECRETION!
What drug can open ATP-regulated K+ channels to PREVENT depolarization and thus insulin secretion??
Diazoxide
What other drugs inhibit insulin secretion by an unknown mechanism?
Thiazide diuretics

Furosemide
GABA (B) Receptors are coupled to K+ Channels in the CNS:
Agonist:
=Baclofen
How does Baclofen work?
=Baclofen enhances GABA-mediated K+ conductance --> HYPERPOLARIZES presynaptic terminals + thus REDUCES the release of the excitatory NT glutamate in teh spinal cord
What is Baclofen used for?
**Used to treat spasticity associated with:
=cerebral palsy
=MS
=stroke

**Is as effective as BZ's BUT causes less sedation

**ALSO causes less of a decrease in muscle strength than does dantrolene!
What do opiates do?
HYPERPOLARIZE neurons via mu receptors
D2-receptors in the Anterior Pituitary
**Dopamine, bromocriptine, and pergolide can HYPERPOLARIZE cells to PREVENT prolactin release

note: in other parts of the brain, DA inhibits adenyl cyclase OR Ca conductance!
alpha-2 adrenoceptors in the MEDULLA
**Clonidine HYPERPOLARIZES to inhibit peripheral sympathetic outflow
CHLORIDE CHANNELS:
1) GABA (A) Receptors

2) Glycine Receptors on Renshaw Cells
GABA (A) Receptors
**Hyperpolarization = INHIBITION
What ENHANCES the effect of GABA (A)??
1) Ethanol
2) Propofol
3) Volatile anesthetic agents
4) Benzos
=increased FREQUENCY of channel opening
5) Barbiturates
=increased DURATION of channel opening
How does VALPROATE increase GABA?
**Valproate increases GABA concentration by increasing glutamic acid dehydrogenase + INHIBITING GABA transaminase
What can release GABA from its neurons?
Gabapentin
Glycine Receptors on Renshaw Cells (=spinal interneurons)
**Glycine released from Renshaw cells INHIBITS alpha-motor neurons

**Strychnine blocks glycine receptors in the spinal cord
=NO alpha-motor neuron inhibition --> CONVULSIONS
cAMP Receptors
=receptors coupled to adenyl cyclase via a G-protein

Includes:
=B1 adrenoceptors
=B2 adrenoceptors
=D1 dopamine receptors
=H2 histamine receptors
=PGI2 (prostacyclin) + PGE receptors
=V2-AVP receptors
=5-HT1 receptors
B1-Adrenoceptors = in the HEART
**Heart:

=increase HR
=increase contractility + impulse conduction
=decrease APD + ERP
B1-Adrenoceptors = in the ADIPOCYTE
=lipolysis --> INCREASED plasma free fatty acids
B1-Adrenoceptor = in the RENAL JG CELLS
=increased renin release
B2-Adrenoceptors = LUNGS
**i.e. BRONCHIAL SM

=relaxation = bronchodilation = increased FEV1
B2-Adrenoceptors = VSM
=relaxation
=vasodilation of arteries + veins
B2-Adrenoceptors = UTERUS
=Relaxation

=inhibition of parturition
B2-Adrenoceptors = LIVER
=glycogenolysis via protein kinase activation of phosphorylase A
B2-Adrenoceptors = MAST CELL
=decreased free intracellular Ca INHIBITS degranulation
D1-dopamine receptors
=vasodilation in the kidney
What bloccks D1-dopamine receptors?
=D1-D2 receptor blockers like HALOPERIDOL
H2-Histamine Receptors
**relaxation of VSM
=DIRECT + through NO
=causes VASODILATION

**increased GASTRIC ACID secretion from oxynitic cells
PGI2 + PGE Receptors
=relaxation of VSM --> vasodilation

=decreased platelet aggregation
V2-AVP Receptors
**Located in the RENAL COLLECTING DUCT

=AVP (ADH) increases water reabsorption
What can INHIBIT this process?
1) PGE's
2) atrial natriuretic factor
3) lithium
4) demeclocycline
What can POTENTIATE the antidiurectic effect?
=chlopropramide
=carbamazepine
5-HT1 Receptors
Relaxation of VSM causes SUSTAINED VASODILATION
What HORMONES can activate adenyl cyclases?
1) ACTH
2) FSH
3) LH
4) Glucagon
5) PTH
What are the phosphodiesterase inhibitors?
1) Theophylline, aminophylline

2) Papaverine

3) Dipyridamole

4) Amrinone and milrinone
Theophylline, Aminophylline
**Bronchodilation

=treatment of neonatal apnea
Papaverine
=Relaxation of smooth muscle in the corpus cavernosa

=Penile ERECTION
Dipyridamole
=decreased platelet aggregation when used w/ aspirin
Amrinone and Milrinone
=increased cardiac dp/dt

=i.e. treatment of terminal CHF
Signal Transduction via cGMP:
**THINK antianginal drugs!!

=NO is produced tonically by the vascular endothelial cells
=NO activates guanyl cyclase
=cGMP relaxes arterial/venous VSM --> i.e. a kinase dephosphorylates the myosin light chains + THUS INHIBITS PLATELET AGGREGATION
What drugs are converted to NO?
=Nitrate vasodilators (i.e. nitroglycerin)

=Na nitroprusside
ANF
=also decreases BP by activation of guanyl cyclase and thus increases cGMP
Sildenafil
=causes erection by INHIBITING the Type V PDEase which degrades cGMP
IP3 and DAG
=IP3 releases Ca from the SR

=Ca then bings to calmodulin whicch then activates enzymes --> SM contraction or secretion
Which receptors does this include?
1) Muscarinic Receptors
2) alpha-1 adrenoceptors
3) Ang II receptors on VSM
4) TXA2 receptors on VSM
5) V1-AVP receptors = VSM
6) H1 histamine receptors
=Vascular endothelial cells
=SM of bronchioles + GI tract
7) 5-HT2 receptors on VSM
8) PGE receptors
=SM of uterus
=GI tract
Where are the muscarinic receptors located that use this IP3/DAG method?
=sphincter muscle of iris
=SM of bronchioles
=bronchial glands
=SM of GI tract + GB
=detrusor muscle of urinary bladder
=pancreatic acini and alpha-islet cells (glucagon)
=salivary glands
=lacrimal glands
=nasopharyngeal glands
What can INHIBIT the recycling of PIP2 and THUS interrupt the IP3 signaling pathway?
Lithium
Normal process of Ca entry into cardiac cells:
=Depolarization allows Ca to move into the cardiac cell via L-type (=voltage-sensitive) Ca channels

=SOME of this Ca is pumped into the SR--additional Ca is extruded by a Na-Ca antiporter which uses the HIGH outside/LOW inside Na to move Ca out against its concentration gradient

**This outside/inside Na gradient is maintained by the membrane Na-K-ATPase
SO, what would a drug like digoxin do?
=Digoxin partially blocks the Na-K-ATPase --> SO, the outside/inside Na gradient is DECREASED

=THUS, less Ca is extruded by the Na-Ca exchange
=this excess Ca in the cell is stored in the SR

=AND, the next depolarization results in an even GREATER release of Ca from the SR
What drug can inhibit the gastric H+-K+ ATPase (=proton pump)??
Omeprazole
What drug can block the Na/K/2Cl symporter in the ascending limb of Henle's Loop??
=Furosemide

=Ethacrynic acid
What can block the Na/Cl symporter in the renal DT?
=thiazide diuretic drugs
What can block Na channels in the principal cells of the LDT/CD??
=Amiloride

=Triamterene
What can block H+ ion secretion in renal PT and DT?
=decreased by ACETAZOLAMIDE bc it inhibits CA
What blocks H+ ion secretion from the LDT/CD??
**Bloccked by:

=Amiloride
=Triamterene
Changes in DNA Transcription:
=i.e. what causes INCREASED vs. DECREASED gene transcription?
Thyroxine
=INCREASED B-receptors + mitochondrial enzymes for oxidative phosphorylation (=ATP)
Aldosterone
=INCREASES basolateral ATPase, Na channels, + enzymes for oxidative phosphorylation in the LDT/CD

=INCREASED deposition of fibrillar collagen in the extracellular matrix of the heart
Glucocorticoids

=1st--what are the glucocorticoids?
=Cortisone
=Hydrocortisone
=Prednisone
=Prednisolone
=Beclomethasone
=Triamcinolone
What do they do??
1) Increased transcription of the genes for:
=lipocortin via inhibiting phospholipase A2
=the inhibitor of NFKB =enzymes for gluconeogenesis

2) Decreased transcription of genes for:
=COX-2
=IL-1 and IL-6 in monocytes + macrophages
=Gene for NFKB
=Enzymes for glycogen storage (EXCEPT for glycogen synthetase)
Cyclosporine
=DECREASED transcription of the gene for IL-2 in helper T-cells
Androgens
=INCREASED erythropoesis and hepatic synthesis of C1-esterase inhibitor of complement
Estrogens
**Increased hepatic protein synthesis:
=increased transcortin (CBG)
=increased thyroxine-binding globulin (TBG)
=increased angiotensinogen (=renin substrate)
=increased transferrin
=increased fibrinogen and clotting factors 2, 7, 9, + 10
NSAIDs
=Prevent the activation of nuclear factor kappa-B

=this action PREVENTS the increased expression of the genes that code for many inflammatory mediators
What is a Scatchard Plot?
=Measures the affinity of a ligand for a receptor

**Slope:
= -1/KD = AFFINITY

**Number of receptors per mg of protein:
= Bmax = X-intercept
Idiosyncratic Drug Reactions
=They usually have a GENETIC BASIS
What if you have a Plasma Pseudocholinesterase Deficiency?
=the NMB caused by succinylcholine lasts HOURS instead of minutes!
Barbituates in OLDER patients:
=cause EXCITATION + ANXIETY instead of sedation
OLDER ANTIHISTAMINES (=i.e. diphenhydramine) in young children OR older patients:
=Cause excitation instead of sedation
Patients w/ Nasal Polyps
=Aspirin + other NSAIDs precipitate an anaphylactic-like reaction (=i.e. aspirin hypersensitiviy) in patients w/ nasal polypos

**i.e. blocckade of PG synthesis by the NSAID shunts all the arachidonic acid to leukotriene synthesis --> LTs cause:
=rhinoconjunctivitis
=angioedema
=uticaria
G6PD-Deficiency
**Can cause HEMOLYTIC ANEMIA when taking:

=primaquine
=isoniazid
=sulfonamides
=nitrofurantoin
=eating fava beans
SLOW ACETYLATORS
**i.e. SHIP Drugs will exhibit toxicity in slow acetylators:

1) Sulfapyridine (=contained in the drug Sulfasalazine)
=hemolytic + aplastic anemia
=hepatic damage

2) Hydralazine
=SLE-like syndrome

3) Isoniazid
=hepatic damage
=peripheral neuropathhy

4) Procainamide
=SLE-like syndrome
What can we treat the peripheral neuropathy found in slow acetylators taking ISONIAZID with?
Pyridoxal phosphate = VITAMIN B6
What is the basis of Malignant Hyperthermia (Hyperpyrexia?)
=Gene defect prevents Ca from being sequestered correctly in the SR of skeletal muscle
What can cause it?
=Anesthesia w/ a volatile anesthetic agent (=i.e. Halothane) PLUS the administration of SUCCINYLCHOINE causes the massive release of Ca

=masseter muscle spasm
Symptoms and Signs:
=Increased BP
=Increased HR
=Muscle contractions
=Hyperthermia

Also see:
=lactic acidosis
=cardiac dysrhythmias
Treatment?
DANTROLENE SODIUM

=prevents the release of Ca from the SR
What is the etiology of Neuroleptic Malignant Syndrome?
=NOT RELATED TO malignant hyperthermia!

=Produced by a rapid blockade of central DA receptors w/ the typical antipsychotic drugs like HALOPERIDOL
Symptoms/Signs:
**Resembles severe Parkinson's Disease w/ Catatonia

=EPS
=Stupor
=Hyperthermia
=Increased CPK --> ARF
=Myoglobinuria
Treatment?
Dantrolene Sodium + Bromocriptine (=a D2-receptor agonist)
Abbreviations:
Vd = Volume of Distribution
Vd
Cl = Clearance
Cp
Cp = Plasma concentration
Cpss
Cpss = Plasma [ ] at steady state
Cpo
Cpo = estimated plasma concentration at zero time
Xo
Dose (mg)
XL
Loading dose

**Depends ONLY on the Vd
XM
Maintenance Dose

**Depends ONLY on the Cl
F
Bioavailability

=ONLY used w/ p.o. treatment

**When given IV, F = 1.0
t1/2
Elimination half-life
k
fractional rate of elimination
rate in
=dosing rate
rate out
=elimination rate
Cpo =
Cpo = (Xo x F) / Vd
XL =
XL = (Cp x Vd) / F
k =
k = 0.7 / t1/2
t1/2 =
Vd/Cl
Cl =
Cl = rate out/Cp
AT Cpss =
rate in = rate out
What drugs INDUCE CYP450??
1) Phenobarbital
2) Phenytoin
3) Carbamazepine
4) Nicotine
5) Chronic EtOH consumption
What drugs INHIBIT CYP450?
1) Erythromycin
2) Ketoconazole

**Note:
=the time is right for them to ask about grapefruit juice as an inhibitor of CYP450
=the question will probably involve decreased clearance of a calcium channel blocker
How can the renal clearance of ACIDIC drugs (=aspirin) be INCREASED?
=by making the urine ALKALINE

i.e. via administration of:

1) Sodium bicarbonate
2) Carbonic anhydrase inhibitor (=i.e. acetazolamide)

**The LOWER pKa of the acidic drug = the GREATER the increase in renal clearance when the urine is made alkaline!
How can the renal clearance of BASIC drugs (=i.e. amphetamines) be incrased?
**By making the urine ACIDIC via administration of ammonium chloride

**The higher the pKa of the basic drug, the GREATER the increase in renal clearance when the urine is made acidic
Which drug exerts a pharmacologic effect--free or bound?
ONLY FREE
What is the effect of decreased plasma protein concentration?
=Decreased plasma protein concentration (=albumin) INCREASES the fraction of free drug in plasma