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247 Cards in this Set

  • Front
  • Back
Cholinergic Pharmacology
**Study the yellow chart about receptors/responses.
**Know the Synthesis + Degradation of ACh.
(On back of yellow chart)
What is ACh?
**NT in the:
1) CNS (N and M)
2) Autonomic ganglia (N1)
3) Adrenal medula
=N1-stimulation releases Epi from the adrenal medulla
4) NM junction (N2)
5) Sweat glands (M)
Cholinergic Basis of AD:
**Seems to involve a deficit of ACh in the CNS
=carbamate AChase inhibitors --> like Donepezil
Metabolism of ACh --> i.e. which drugs POTENTIATE the effects of ACh?
"Can't Be Metabolized!"


**Inhibitors of AChase = potentiates effects of ACh
**Used for the diagnosis of asthma

=causes flushing, sweating, salivation, GI cramping, and bronchoconstriction
What is the function of bethanechol?
**Urinary retention in:

1) PD patients being treated w/ benztropine

2) Psychotic patient being treated by typical antipsychotics (=thioridazine)

3) Patient being treated w/ TCAs
What is the effect of choline esters (=i.e. acetylcholine, carbachol) on BP??
=DECREASE BP via NO released from vascular endothelial cells

**Decreased BP blocked by ATROPINE
=Causes miosis + cycloplegia via contraction of ciliary muscle

**Effect DECREASES IOP via increased outflow of aqueous humor
Side Effects of Pilocarpine:

=a tertiary amine

NOT hydrolyzed by plasma Achase --> metabolized by LIVER

=induces CYP450 --> so increases drug metabolism
=Increases sympathetic activity w/ INCREASED HR, BP + cutaneous vasoconstriction
=Increased respiration + GI motility
What about with very LARGE doses?
=muscle fasciculations followed by depolarization blockade

=in the CNS --> convulsions w/ overdose (OD)
ACHase Inhibitors:
=Physostigmine (tertiary)
=Neostigmine (quarternary)
=Edrophonium (quarternary)
Use of Edrophonium:
**Diagnose MG

**Used to differentiate between "myasthenic" and "cholinergic" crisis in patients treated w/ neostigmine

**Used w/ ATROPINE in reversal of a neuromuscular blockade caused by non-depolarizing drugs
=d-tc or pancuronium
**Treatment of MG
=ALWAYS used w/ atropine to prevent indirect muscarinic S/E's

**Used w/ glycopyrrolate in reversal of NMB caused by non-deplarizing drugs
=Isofluophate (DFP)
Symptoms/Signs of Poisoning:
=increased BP (N1)
=skeletal muscle fasciculations (N2)
Where would be the places of risk?
=Biochemistry Laboratory
Treatment of poisoning?
=atropine + pralidoxime (2-PAM)

**2-PAM regenerates phosphorylated AChase
What do humans have that degrade organophosphates and prevent our death?
Poisoning w/ Plants:
**Increased ACh stimulation
=like giving physostigmine
=treat w/ atropine

**Decreased ACh stimuation:
=like giving atropine
=treat w/ physostigmine
**Recall: N-methyl-PIG

=Propantheline (GI spasticity)
=Ipratropium (prevents bronchoconstriction from air pollution/cold air)
Drugs for the Treatment of Glaucoma:
1) Alpha agonists

2) B-blocckers
=timolol, betaxolol, carteolol

3) Diuretics

4) Cholinomimetics

5) Prostaglandin
Increases outflow of AH
Decreases AH secretion
Timolol, Betaxolol, Carteolol
Decreased AH secretion
=Decreased AH humor secretion due to decreased HCO3- (via inhibition of carbonic anhydrase)
Pilocarpine, carbachol, physostigmine, echothiophate
**Increased OUTFLOW of AH
=contract ciliary muscle and open trabecular meshwork
Increase outflow of AH
Ganglionic Blocking Drugs

**Block SNS and PSNS
**Block increase in plasma Epi induced by hypoglycemia
Effects of Blocking Sympathetic Ganglia:
=Arteriodilation lowers TPR
=Venodilation decreases preload
=Decreased cardiac dp/dt
=Decreased CO
=Decreased TPR and CO = hypotension
=Decreased sweating
=Impotence (no ejaculation)
Effects of Blocking Parasympathetic Ganglia:
=Mydriasis and cycloplegia
=Decreased salivation + lacrimation
=Decreased GI secretion, motility and tone
=Decreased gastric acid secretion
=Decreased release of pancreatic enzymes and bile
=constipation and urinary retension
=impotence (no erection)
Neuromuscular Blocking Drugs:
**Can either be:
1) Depolarizing (non-competative)

2) Non-depolarizing (competitive)
1) Succinylcholine
2) Decamethonium

**Phase I = MEP depolarized
**Phase II = repolarized but still refractory

=causes fasciculations prior to flaccid paralysis
=NM blockade
=ECT (shock therapy)
1) d-tubocurarine (curare)
2) pancuronium

=the "-curiums and -roniums"

**MEP never depolarized
**NO fasciculations prior to flaccid paralysis
NM blockade
Changes in Drug Sensitivity w/ Diseases
**In MG, the N2 receptor density is DECREASED

**In burns and denervation injury, the N2 receptor density is INCREASED
What BLOCKS catecholamine release?
=Metyrosine inhibits tyrosine hydroxylase (TH)--> blocks catecholamine release as WELL as the dopamine-B-hydroxylase (DBH) and ATP released w/ NE from nerves

**i.e. tyrosine hydroxylase is the RATE-LIMITING enzyme in the synthesis of catecholamines.

**i.e. used to treat pheochromocytoma
What INCREASES the release of NE?
1) AngII and B2 stimulation
2) alpha2-BLOCK
3) cocaine
4) TCA's
What DECREASES the release of NE?
1) muscarinic (ACh) + alpha2-STIMULATION (=clonidine)
2) PGE's
Selectivity of each agonist for vascular alpha + beta adrenoceptors:
EPI = B2 > B1 > alpha

NE = alpha > B1 > B2
**Think FIGHT or FLIGHT!**

=Decreased TPR and DBP
=Increased SV, CO, pulse pressure, and SBP
=Increased cardiac dp/dt and HR
=Decreased hepatic venous resistance w/ increased venous return
=Increased blood flow to the skeletal muscle, liver, myocardium, and brain
=DECREASED flow to the kidneys, GI tract, and skin
Epinephrine + Halothane
Epi + B-blocker =
ONLY alpha effects = INCREASES BP
Epi + alpha-blocker =
i.e. Epi + phentolamine

**ONLY beta effects:
=increased HR and RBF
=decreased TPR, BP, and ERP in heart
**mostly ALPHA w/ a little BETA

**alpha-2 events predominate:
=Increased TPR and increases DBP
=Increased DBP causes a baroreflexly-mediated DECREASE in HR
=Decreased HR --> more time for ventricles to fill = Increased SV
=CO remains the SAME
=Decreased blood flow in the cutaneous bed, kidneys, GI tract, and skeletal muscle
How would you BLOCK this decrease in HR?
**Adrenoceptor stimulation is DOSE-DEPENDENT

**SMALL DOSE = "renal dose"
=Increases RBF + thus, increases GFR + sodium excretion
=Usually no effect on DBP

**Intermediate Dose:
=Increased dp/dt (B1) w/ little effect on HR
=Increased SV/CO
=Increased DBP (alpha-1)

**Large dose is BAD
=Decreased SV/CO -- can cause tachycardias, worsen ischemia
SO...what would you use post-MI to maintain dp/dt?
=DA increases RBF
What can BLOCK the increase in renal blood flow caused by DA?
Phenyephrine (PE)

**Mydriasis w/o cycloplegia

=decreases uterine contraction in premature labor
**Bronchodilation w/ INCREASED HR:
=i.e. non-selective B1 and B2 agonist

=i.e. SELECTIVE B2-agonists
=pre- and post-synaptic alpha-2 agonist
SO...those were the DIRECT adrenergic agonists (=Epi, NE, DA, PE, etc.)--now, let's talk about the INDIRECT:
**Will have no effects after pre-treatment w/ RESERPINE

=i.e. ONLY directly-acting agonists increase dp/dt and HR in isolated heart from animals pretreated w/ reserpine
What is contraindicated in patients taking phenelzine OR tranylcypromine??
**Eating tyramine-containing foods
=drugs non-selectively inhibit MAO-A and MAO-B
The increase in BP caused by tyramine can be blocked by:
1) Reserpine
2) Guanethidine
3) Cocaine
4) 3 P's
**Used to treat ADHD/ADD

=decreased appetitie
=decreased linear growth rate
Amphetamine Toxicity
**Nervous, excited, agitated
**Increased HR/BP
**Toxic Psychosis
=paranoid schizophrenia
=formication w/ excoriations
=convulsions w/ OD

**Difficult to distinguish from effects of cocaine
Treatment of psychosis?
=direct B1 and B2
=indirect alpha

**No alpha effects after reserpine
**The 3P's:
Which drugs increase HR?

**Prazosin has NO EFFCT on HR
What do you use to treat migranes?
=Ergotamine, dihydroergotamine

**Partial alpha agonists
What are the major S/E's of alpha-blockers?
Blocks alpha IA receptors in the GU tract in patients w/ BPH to enhance voiding
Patient w/ pheochromocytoma tumor:
Treat w/ phentolamine
=decreases BP = EPI reversal
Epinephrine Reversal
**Epi reversal by alpha-blockers such as the 3P's:

=vasopressor effect of a large (SUPRAphysiological dose) of Epi is REVERSED to a VASODEPRESSOR effect by an alpha-blocker
A HUGE dose of Epi increases BP via alpha receptor stimulation.

=treatment w/ an alpha-blocker LOWERS BP
=another injection of a LARGE dose of EPI now causes a large DECREASE in BP because only vascular B2 receptors can be stimulated by Epi
=After treatment w/ the non-selective B-blocker propranolol (=BLOCKS both B1 and B2) --> another injection of a large dose of Epi has NO EFFECT on BP
Example: BP during surgery for a pheochromocytoma
=Pretreatment w/ an alpha blocker PLUS a non-selective B-blocker would prevent any changes in BP caused by the release of EPI from hte pheochromocytoma during surgery
Example: Infusion of a physiological dose of EPI
The infusion of a physiological dose of Epi LOWERS DBP and INCREASES SBP.
=this dose vasoconstricts some vascular beds via alpha stimulation and dilates other beds via B2 stimulation

**the NET effect is arteriolar vasodilation w/ a fall in TPR and thus DBP
**SBP is going to INCREASE bc EPI increases CO via increased venous return, cardiac contractility, + decreased afterload.
**Epi after blockade of vascular alpha-receptors can only stimulate B2 receptors to cause VASODILATION
=large fall in TPR and DBP

**Epi after blockade of vascular B2-receptor can ONLY stimulate vascular alpha-receptors to cause VASOCONSTRICTION and thus a large RISE in TPR and DBP
Beta Blockers
Atenolol + Metoprolol
=Block B1

Propranolol + Timolol
=Block B1 and B2
=decreased HR, AV conduction, and dp/dt
=decreased O2 requirement via decreased dp/dt and HR

=BUT LV-EDV increases
SO, a B-blocker decreases O2 demand by decreasing HR, dp/dt/ and afterload--how does nitroglycerin decreases O2 demand by:
B-blockers can BLOCk increases in HR caused by:
1) Hemorrhage
2) Minoxidil
3) Hydralazine
4) Diazoxide
5) Nitroprusside
6) Nitroglycerin
Side Effects of B-Blockers:
=AV block
=Delayed recovery of glucose in patients w/ Type I DM after s.c. injection of too much insulin
=Decreased IOP w/o cycloplegia

**You would NOT use propranolol because it causes LOCAL ANESTHESIA of cornea
A patient is treated w/ a beta-blocker for angina. They abruptly discontinue the drug. What happens?
**Beta-Blocker Withdrawl Syndrome:
=palpitations + tremor
=chest pain

**Increased cardiac B-receptor stimulation --> increased O2 demand --> precipitates angina + MI
Patient w/ Hyperthyroidism:
**Being treated w/ propranolol
=decrease tachycardia + tremor
=prevent the peripehral conversion of T4 --> T3
A type I diabetic patient is being treated w/ a glaucoma drug that causes HYPOGLYCEMIA. Which drug?
=DECREASES NE release via depletion of neuronal NE stores --> poisons NE storage vesicles

=NO EFFECT of TAP drugs (=tyramine, amphetamine, phenylpropanolamine) after pretreatment w/ reserpine
=NO alpha effects of ephedrine after reserpine
1) Decreased nerve-stimulated NE release
2) Competitive inhibitor of NE uptake
3) anti-HT effect BLOCKED by TCA's
=i.e. TCA's block entry of guanethidine into neuron
=Blocks uptake of NE, Epi, DA, 5-HT in CNS
=Blocks uptake in peripheral sympathetic neurons --> potentiates effects of NE and Epi but NOT isoproterenol
How does it cause euphoria?
Via release of DA in the nucleus accumbens
How does it cause a local anesthetic effect?
=via blockade of Na channels in sensory neurons
Toxic Doses/OD Symptoms:
=Dilated pupils
=Halo vision
=Itchy skin
=Increased BP/HR

**Difficult to distinguish from amphetamine toxicity
Withdrawl Syndrome:
1) Sleepiness
2) Depression
3) Anhedonia
MAO Inhibitors:
**Used to treat depression


**inhibit BOTH MAO-A + MAO-B
Selectively inhibits MAO-B to prevent breakdown of DA in the CNS
"Cheese" Reaction
Inhibition of MAO-A in the gut wall allows dietary tyramine to enter the circulation
=tyramine releases NE to cause HT and tachycardia
Clonidine + Alpha-Methyldopa
=DECREASE SNS activity via stimulation of alpha-2 receptors in the CNS

=DECREASE plasma NE and renin activity
Sedation, dry mouth, edema
S/E's of alpha-methyldopa:
="Flu" syndrome
=(+) Coomb's Test
Clonidine Withdrawl Syndrome
=increased HR
=abrupt return of BP to HT value
=abdominal pain
How does this differ from B-blocker withdrawl syndrome??
recall: in B-blocker withdrawl -->
=increased HR w/ palpitations but NO tremor, sweating, abdominal pain, or increased BP
Recall: Drugs that DECREASE plasma NE?
=ganglionic blockers
Recall: Drugs that INCREASE plasma NE?
=sodium nitroprusside
Arterial Vasodilators
**Hydralazine, Minoxidil, Diazoxide**

**Dilate resistance vessels
=decreased TPR + BP
=increased HR, dp/dt, CO, PRA, and plasma NE
1) Edema
2) SLE-like Symptoms
=malar rash

**Discharge hydralazine + treat w/ steroid
1) Hirsutism
2) Edema

**Effect additive w/ finasteride
**Inhibition of insulin release

Sodium Nitroprusside (SNP)
**Dilates arteries + veins via release of NO from sodium nitroprusside molecule

=in a NT patient --> decreases TPR + venous return = NO CHANGE in CO
=in a patient w/ CHF --> decreases preload + afterload --> leads to an INCREASE in CO
What happens when you infuse SNP into someone w/ poor renal function?
=muscle weakness

**treat w/ THIOSULFATE
=combines w/ CN to form thiosulfate which can be eliminated renally

**Block Ca channels at SA/AB nodes, cardiac myocytes, and arterial VSM
1) Decrease BP
=nifedipine > diltiazen > verapamil

2) Decrease AV conduction via increase in ERP
=Verapamil > diltiazem

3) Nifedipine causes a SLIGHT increase in HR
=decrease oxygen demand
=i.e. decreases dp/dt, HR, and afterload w/ increased oxygen delivery via dilation of coronary arteries + arterioles

AV nodal re-entry tachycardia
=V + D
Drugs which DECREASE dp/dt:
Effects of Angiotension II
1) Increased BP
2) Increased SNS activity via CNS
=enhances release of NE
=blocks NE uptake
3) Release of ADH
4) Release of Aldosterone
5) Decreases mesenteric blood flow
OTHER DRUGS that decrease mesenteric blood flow
**Use these drugs to treat GI bleeding:
=NE + AngII
ACE Inhibitors:
**Captopril, Enalapril

=prevent conversion of AngI --> AngII
1) Decrease TPR and BP w/ NO CHANGE in HR and CO

2) Block formation of AngII

3) Block enzymatic destruction of bradykinin
=increase plasma [ ] of bradykinin
=i.e. potentiate the decrease in BP caused by IV bradykinin
Side Effects:
1) Fetal Toxicity
=category X

2) K+ retention

=caused by BK and PG
=BLOCKED by aspirin
**Angiotensin II receptor antagonist --> NO COUGH
Why would you use in the treatment of CHF?
=Increae CO by decreasing preload and afterload

=reverses cardiac remodeling caused by angiotension II
Why would you treat a hypertensive patient w/ DM with an ACE-inhibitor?
=decrease BP and decrease proteinuria (i.e. protects kidneys)
1) Acetazolamide
2) Furosemide, ethacrynic acid
3) Thiazides
4) Amiloride and triamterene
5) Spironolactone
**Inhibits carbonic anhydrase in PT and DT to prevent reabsorption of bicarbonate
=increased excretion of Na, K, + bicarbonate
=urinary pH increases to 8-8.5
=THEREFORE, can be used to increase urinary pH to enhance renal clearance of acids (=salicylates)
1) Inhibits formation of AH and CSF
=some effect to decrease gastric acid secretion

2) Used to treat glaucoma + altitude sickness
=i.e. acidosis via renal loss of bicarbonate STIMULATES respiration
Side Effects
HYPERchloremic metabolic acidosis
SO, quick review:

What STIMULATES Respiration?
=Theophylline, caffeine
What INHIBITS respiration?
SO, how would you make urine ALKALINE?
CAI or Na bicarbonate

=increase renal Cl of acidic drugs
How would you make urine ACIDIC?
=ammonium chloride

=increase renal clearance of BASIC drugs
=ethacrynic acid

**Inhibit Na/K/2Cl symporter in the ascecnding limb of hte loop of Henle
=also blocks Na transport in the macula densa of the DT
1) Increased urinary excretion of Na, K, Ca, Mg, Cl, and water
2) Increased delivery of Na to LDT/CD causes K LOSS
3) Cl loss causes hypokalemic, hypochloremic metabolic alkalosis
4) Urine isotonic in presence and absence of ADH
5) Prostaglandin-dependent inccrease in RBF and GFR
6) Increased Hct via decreased plasma volume
What does the block of the Na transporter in the macula densa do?
**Blocks Na transporter in the macula densa cells of the DT --> no sodium sensed --> INCREASED PRA and AngII --> secondary hyperaldosteronism --> exacerbates K loss
1) Acute pulmonary edema
2) CHF
3) Peripheral edema
4) Hypercalcecmia
1) Hypokalemia w/ alkalosis
2) Hypomagnesemia
3) Hyperglycemia
4) Dilutional hyponatremia
=i.e. cannot make a dilute urine in order to excrete free water
5) Hyperuricemia
=bad for gout
6) Li toxicity caused by increased reabsorption in PT
Drug/Drug Interactions:
1) Can cause bilateral hearing loss via toxicity to CNVIII --> potentiated by aminoglycosides (i.e. gentamicin)

2) ENHANCES digoxin toxicity via hypokalemia
=less K+ to compete w/ digoxin for Na-K-ATPase binding sites
=acts in DT and decreases GFR in all patients
=BLOCKS NaCl symporter in principal cells of the DT
1) Increases excretion of Na, K, Mg, Cl, and water
=decreased free water clearance--> urine always hypertonic = dilutional hyponatremia
2) DECREASED secretion of Ca in hypercalcinuria
=used to decrease formation of kidney stones!
3) Increased delivery of Na to LDT/CD causes K+ loss
4) Blocks Na transporter in macula densa --> again, exacerbates K+ loss
1) HT
2) Edema
3) Kidney stones
4) DI
=distal loss of Na and water ENHANCES the reabsorption of filtrate in the PT --> LESS volume sent distally
=decreases urine volume by 50%
=Hypokalemia w/ alkalosis
=Uniformly decreased GFR
=Lithium toxicity
Drug-Drug Interactions
**Also enchances digoxin toxitcity

**Diuretic effect contracts the blood volume = POTENTIATES the fall in BP caused by anti-HT drugs--esp. clonidine and alpha blockers!
K+ SPARING Diuretics

1) Triamterene
2) Amiloride
3) Spironolactone
=aldosterone receptor antagonist

**ALL are contraindicated in renal insufficiency because they can cause fatal hyperkalemia
Amiloride and Triamterene
1) Block Na channels in principal cells of LDT/CD
=Increased Na excretion w/ decreased K excretion

**Make urine alkaline by inhibiting H+ ion secretion from intercalated cells of the DT
**Aldosterone Antagonist**
=also a partial agonist at androgen/progesterone receptors
1) Blocks aldosterone receptors in the principal cells of the LDT/CD
2) Increases urinary loss of Na and water w/ decreased K excretion
Who does this drug have NO EFFECT on?
=the adrenalectomized patient
1) Secondary hyperaldosteronism associated w/ cirrhosis or nephrotic syndrome

2) Reverses cardiac remodeling caused by aldosterone in patients w/ HF
=Gynecomastia (males)
=Menstrual irregularities
=Deepend voice (females)
A patient treated w/ an OCP containing estrogen and norethindrone develops hirsutism--why?
**Hirsutism results from androgenic effects of the progestin norethindrone which is a derivative of 19-nortestosterone
How would you treat this?
A postmenopausal female develops hirsutism--how would you treat it?
A patient w/ an adrenal tumor has increased BP and plasma HCO3, and DECREASED plasma K+ and PRA. Plasma Na is normal. What is the diagnosis?
**Conn's Syndrome
=aldosterone-secreting adrenal tumor

**Treat w/ spironolactone
How would you PREVENT the hypokalemia caused by furosemide and HCTZ?
1) K+ sparing diuretics
2) ACE inhibitors
3) Beta-blockers

**AND to a certain extent, p.o. K supplements
The Effects of Diuretics on Urinary Flow, pH, and Elecrolyte Composition.
**FIRST, look at urine flow rate.

=IF urine flow rate is 8-10 ml/min --> the drug is either furosemide OR mannitol.

=IF the urine flow rate is 2-3 ml/min, the drug is acetazolamide, a thiazide, or a K+ sparing agent
NEXT, what should you look at?
**Next, look at the QUANTITIATIVE changes in electrolyte excretion.

1) Furosemide can be distinguished from mannitol by the fact that furosemide causes the GREATEST INCREASE in electrolyte excretion.

2)THEN, you have to distinuish between acetazolamide, a thiazide, and a K+ sparing agent.
How do you distinguish between these?
1) Acetazolamide causes a MASSIVE increase in bicarbonate excretion.

2) The K+ sparing agent decreases K+ excretion.

3) The drug that remains is a thiazide.
Cardiac Glycosides
=t1/2 = 1-1.5 days
=RENAL clearance
=Decreased GFR decreases Cl and increases t1/2

=t1/2 = 7 days
=HEPATIC clearance
=Decreased clearance and increased t1/2 in patients w/ cirrhosis and CHF
What if you combine them w/ cholestyramine or antacids?
=DECREASED GI absorption

=i.e. decreased plasma digoxin and decreased cardiac effect
Dosing in OLDER patients:
**Older patients have a decreased Vd, so DECREASE the loading dose

**Also have a decreased GFR, so DECREASE the maintenance dose
=realize that older patients can have decreased GFR even w/ normal serum creatinine
Effect of quinidine on digoxin:
Quinidine will INCREASE plasma digoxin by displacing digoxin from skeletal muscle and DECREASING renal clearance
What is the MOA of digoxin?
**Inhibits Na-K-ATPase
=increases dp/dt but decreases resting membrane potential (Vm)
=lack of pumping Na OUT causes cautomaticity in fast fibers
Potentiates inhibition of ATPase
=causes automaticity and a DECREASED ERP in ventricles
Low Mg
=Same as a calcium overload inside cells --> causes automaticity
HIGH Calcium
Ca overload inside cells = causes automatcity
How does it work in the CNS?
**Acts to INCREASE vagal tone
=decrease HR
=decrease atrial contraction
=decrease AV conduction
=Control (DECREASE) ventricular rate in patients w/ atrial flutter or fibrillation

**Increased vagal tone DECREASES AV conduction --> so fewer atrial signals pass the AV node
Side Effects:
=AV block
=n/v (i.e. CTZ)

**CNS Side effects:
=abnormal color vision + halo vision esp. in elderly
Antidysrhythmic Drugs
Quinidine MOA
**Blocks Na channels in fast fibers
=Na channel block DECREASES phase 4 automaticity and phase 0 slope --> DECREASED CONDUCTION VELOCITY

**Delays ventricular repolarization via K channel block
=Increased APD, ERP, and QT interval

**SA Node:
=NO direct effect
=anticholinergic effect causes tachycardia

**AV Node
=Atropine-like effect INCREASES conduction, but DIRECT effect decreases conduction
**Treat atrial and ventricular dysrhythmias
Treatment of Atrial Flutter and Atrial Fibrillation
**Give digoxin BEFORE quinidine in tx. of a-fib/flutter SO digoxin can PREVENT the increase in AV conduction from the atropine-like action of quinidine
=Hypotension (alpha block)
=Decreased dp/dt
=Diarrhea **limits use**
=Tinnitus w/ OD
Patient w/ atrial fibrillation is given quinidine to slow ventricular rate but the ventricular rate INCREASES soon after quinidine. WHY?
**An immediate atropine-like effect of quinidine INCREASED AV conduction
=treat w/ VERAPAMIL or DILTIAZEM to decrease AV conduction + slow ventricular rate
**Can cause SLE and arthritis in slow acetylators
=i.e. these people have a genetic defect --> an inactive form of the acetylase enzyme --> SO they cannot clear the drug by hepatic biotransformation
**Causes a MARKED decrease in dp/dt
=marked antimuscarinic effects --> dry mouth, constipation
When would it be contraindicated?
Lidocaine, MOA
**Blocks Na channels in fast fibers

**Given IV due to low F
1) Decreases phase 4 automaticity to prevent PVC's

2) NO EFFECT at the SA or AB nodes, on BP or dp/dt
Local anesthetic effect via Na channel block in sensory fibers

**treat w/ benzo's
Amiodarone, MOA:
**Increase APD, ERP in fast fibers by INHIBITING K+ channels
=POWERFUL suppression of phase 4 automaticity (=blocks Na channels)

=Non-competitive alpha AND beta-blockade (-->can cause hypotension and bradycardia)

=Slows sinus rate and AV conduction
Treatment of recurrent ventricular tachycardia/fibrillation
=Pulmonary fibrosis
=Hypo- OR hyperthyroidism
=Blue, purple, OR slate gray skin
=Corneal microdeposits
Verapamil MOA
**Blocks L-type calcium channels at hte SA and AV nodes AND cardiac myocytes
1) SA Node
=decrease HR

2) AV Node
=decrease conduction velocity and ERP
=i.e. FEWER atrial signals pass through the AV node to the ventricles

3) Myocardium
=decreased dp/dt = DECREASED CO
**used to treat AV nodal re-entry tachycardia
Decreased dp/dt and CO in HF

AV block
Patient w/ atrial fibrillation and NO HF has palpitations and dizziness
Treat w/ Verapamil

=will increase ERP of AV node --> slows ventricular rate --> improved AV filling --> Increased CO
1) Antiplatelet drugs
2) Heparin
3) LMW Heparins
4) Warfarin
**Irreversibly inhibits COX-1 of platelets to prevent the synthesis of TXA2
Abciximab, Eptifibatide, Tirofiban
**Antagonists of the platelet IIb/IIIa which uses fibrinogen to bind platelets together

**Given IV in ER and OR
Ticlopidine and Clopidrogrel
**Antagonists of platelet purinergic (ADP) receptors
A patient requires an antiplatelet drug after MI or stroke, but the patient has aspirin hypersensitivity. How to treat?
**Use ticlopidine or clopidrogrel
Heparin MOA
**Accelerates binding of antithrombin III (ATIII) to activated clotting facts 2, 9-12
=increases aPTT
1) A glucosaminoglycan
2) NOT effective p.o.
3) NOT metabolized by the liver
=removed from circulation by the reticuloendothelial system
4) INCREASES lipoprotein lipase
=hydrolyzes TG's --> glycerol + FFA to DECREASE postprandial lipemia
Treat MI and DVT's
Protamine Sulfate
=Antiplatelet effect additive w/ aspirin
What causes heparin resistance?
Heparin resistance results from DECREASED ATIII in blood
LMW Heparins

**Acts primarily on Xa --> so little effect to increase the aPTT
Anticoagulant effect only PARTIALLY reversed by protamine sulfate
Cleared by the KIDNEYS instead of the RE system

=longer t1/2 than heparin
Warfarin, Dicumarol MOA
**Inhibits post-translational vitamin K-dependent gamma-carboxylation of glutamate residues on factors 2, 7, 9, and 10 via inhibtion of enzyme vitamin K epoxide reductase
1) ONLY works in vivo
2) Slow onset of action
=2-3 days --> full effect at 5 days
=INCREASES PT (INR)--> greatest effect on factor 7
=Prevent emboli in patients w/ prosthetic heart values
=Prevent thrombotic strokes in patients w/ A-fib
Drug-Drug Interactions
**Highly bound to plasma proteins --> MANY drug-drug interactions

**displacement of warfarin from plasma proteins has 2 effects:
=INCREAED Cl of warfarin
How is Warfarin metabolized?
SO, inhibition of CYP450 is going to:
**INCREASES plasma warfarin and PT

=Grapefruit juice
**DECRASES plasma warfarin + PT

=Chronic EtOH
=Benzopyrene (cig. smoke)
=vitamin K1

=Factor IX concentrate --> contains factors 2, 7, 9, 10
Patient overdoses w/ warfarin OR attempts suicide w/ rat poison. Which clotting factors and lab tests are affected?
=Decreased activity of factors 2, 7, 9, and 10


**NO EFFECT on factors 8, 13, or bleeding time
What type of cardiac dysrhythmia requires treatment w/ warfarin?
Thrombolytic (=Fibrinolytic) Drugs
**ALL ultimately convert plasminogen --> plasmin
=plasmin destroys fibrin to lyse clots

1) Urokinase
2) tPA
3) Streptokinas
**Direct activation of plasminogen
**When tPA and plasminogen bind to fibrin in close proximity, plasminogen is converted to plasmin by tPA
=normal, intrinsic activation of plasmin
**Changes conformation of plasminogen to expose an active protease site that hydrolyzes another plasminogen --> plasmin
Side Effects of Fibrinolytic Drugs
=Systemic destruction of clotting factors 5 and 8 --> causes bleeding ESP. in CNS (=hemorrhagic stroke)
A patient w/ an MI is treated w/ several drugs. He develops intracranial bleeding. Which drug caused it?
INHIBITORS of Fibrinolysis
=aminocaproic acid

**A lysine analog that binds to hte lysine-binding sites on plasmin which BLOCKS the binding of plasmin to fibrin
Antilipemic Drugs
1) Statins
2) Ezetimibe
3) Gemfibrozil and Fenofibrate
4) Niacin
=i.e. Lovastatin

=inhibits HMG CoA reductase --> reduces intracellular hepatic sterol pool --> suppresses teh promotor region of the genes which code for HMG CoA reductase and LDL receptors
=Lack of sterol results in the INCREASED synthesis of HMB CoA reductase and LDL receptors
=THUS, increased hepatic LDL receptors to take up LDL and lower Tc
NET Effects:
=Decrease Tc
=Decrease LDL and TG's
=Slight increase in HDL
=myositis/myopathy --> muscle pain and weakness associated w/ an increased CPK

**muscle damage can progress to rhabdomyolysis
=inhibition of cholesterol absorption from the GI tract DECREASES intracellular hepatic sterol pool
=leads to INCREASED gene expression of hepatic LDL recectprs --> increased receptors take up LDL to lower Tc
NET Effect:
**Selective for LDL cholesterol
=only Tc and LDL decrease
Used in patients who develop muscle weakness on a statin
Gemfibrozil and Fenofibrate
=activates lipoprotein lipase (esp. in skeletal muscle) to incrase hydrolysis of VLDL
Net Effect
=Decrease Tc
=Decrease LDL, VLDL, TG's
=Slight increase in HDL
Used to treat hypertriglyceridemia
=myositis/myopathy --> muscle pain and weakness associated w/ increased CPK

**muscle damage can progress to rhabdomyolysis
MOA = unknown

**Used to increase HDL cholesterol
Flushing and itching in face and upper body
Antianginal Drugs
**All DECREASE oxygen demand and/or INCREASE oxygen supply
=ALL increase endocardial blood flow

1) B-blockers
2) Nitrates
3) Calcium channel blockers
**Atenolol, metoprolol, propranolol, timolol
**Decreases the rate-pressure product (HR x SBP)

**Also decreases cardiac afterload = decreases DBP

**Net Effect = decreased cardiac O2 demand

i.e. glyceryl trinitrate, isosorbide mono and dinitrate
**NO donors which selectively VENODILATE
=venodilation decreases venous return to decrease LV wall tension during diastole and systole

**SO, decreases cardiac oxygen demand!
Biggest problem w/ nitroglycerin:
Calcium Channel Blockers
MOA of Verapamil + Diltiazem
**Negative chronotropic and inotropic effects DECREASES rate x pressure product (HR x SBP)

**Also decreases cardiac afterload = decreased DBP

**ALSO dilates large epicardial vessels + small endocardial resistance vessels
MOA of Amlodipine and Felodipine
**Decreased cardiac afterload (DBP) and INCREASED blood flow through large epicardial vessels and small endocardial resistance vessels
**Decreased oxygen demand and increased oxygen supply
Treatment of Congestive Heart Failure

=Systolic Dysfunction
1) Decrease preload w/ diuretic drugs
2) Decrease both preload + afterload (balanced vasodilation) w/ an ACEI or ARB
3) Enhance cardiac contractility w/ digoxin
4) Reverse cardiac remodeling caused by:
=Ang II --> ACEI or ARB
=Aldosterone --> spironolact.
=SNS --> carvedilol