Pharm Test 3

Front 1

EKG

Back 1

p wave = atrial depolarization

QRS interval reflects upstroke of ventricular AP due to opening of Na+ channels

T wave - repolarization of vetricle due to opening of delayed rectifier K+ channels

PR interval measure of the conduction time from atrium to ventricle and represents AV nodal conduction

QT interval = duration of the ventricle AP

Front 2

Cardiac conduction system

Back 2

Sinoatrial node - pacemaker = b/c fires at a more rapid pace

AV node - also act as a pacemaker -but so can purkinje fibers

1. impulse starts at SA node - depolarizes
2. wave of depolarization spreads across the atria
3. wave reaches AV node is and delayed before moving into bundle of his -= allows blood flow from atria to ventricle 200msec delay
4. depolarization travels rapidly in bundle branches spread the depolarization to al lcontractile cells

Front 3

arrythmias

Back 3

consist of cardiac depolarizations that deviate from normal activity due to changes in rate or regularity of impulse formation or its conduction

Front 4

automaticity - slow response fibers

Back 4

SA and AV nodal cells display spontaneous phase 4 depolarization = slow change in membrane pot until threshold is reached
- channels are responsible depolarization = funny channels

no voltage gated Na channels in these tissues. voltage gated Ca2+ channels open once the threshold is reached = phase 0

SA and AV nodal cells are reg by symp and parasymp - stim of Beta adrenergic receptors increases the slope of depolarization of phase 4 depolarization

stimiulation of muscarinic receptors opens K+ channels causing membrane potential to become more negative = decreases slope of phase 4 depolarization

Front 5

QRS

Back 5

opening of Na+ channels and upstroke of vent AP

drug that block voltage gated Na+ channels = widening of QRS interval = Na+ channel blocker

Front 6

PR interval

Back 6

measure of cond time from atrium to ventrical
AV nodal conduction

drug that slows AV nodal conduction widen/lengthen the PR interval

Front 7

QT interval

Back 7

reflects the duration of ventricular AP

drug that cause duration of AP longer -= wider QT interval

Front 8

cardiac action potential in fast response fibers

Back 8

phase O = upstroke rapid depolarization = due to opening of voltage gated Na+ channels = with time depolarization causes channel inactivation that rapidly reduces Na+ conductance

phase 1 - small repolarization

phase 2 - long platue = voltage gated Ca+ channels = conductance repains elevated for most of cycle
- platue
- continued depolarization and maintains the Na_ channels in the inactivated state so a new depolarization cannot be started

phase 3- repolarization = due to opening of voltage gated K+ channels most of systole
- late peak due to delayed rectifyer k+ channels = 2 types rapid delayed Ikr and slow delayed Iks

Ikr is blocked by sotalol, quinidine, amitriptyline, imipramine, cisapride, etc

phase 4 - resting membrane potential

Front 9

prolong QT interval = what kind of arrythmia

Back 9

presauds depounce

ventricular arrythmia

often results in death

Front 10

Na+ channel gating

Back 10

voltage gated Na channels cycle btw 2 conformation states - resting, open and inactivated
movement controlled by activation and inactivation gates

membrane depolarization causes the activation gate (m gate) to open allowing movement of Na int o cell

w/time H gate (inactivation gate) closes causing the channel to be inactivated
in order for the channel to return to the resting state the membrane pot must return to the normal resting membrane potential

Front 11

classes of antiarrythmic

Back 11

class 1 - Na+ channel blockers
class II - beta adrenergic receptor blockers
class III - K+ channel blockers
class IV - Ca 2+ channel blcokers

Vaughan-williams classification

Front 12

funny channels

Back 12

permeable to K+ and Na+ cause depolarization phase 4 of slow resposne fibers SA and AV nodes

Front 13

class IV

Back 13

raise the treshold for firing of slow response fiber and slow phase 0 - decrease slope of phase 0

2 effects
1. reduce automaticity slowing heart rate by raising threshold for opening of ca channels
2. reduce slope of phase 0 depolarization - slows AV nodal conduction = increase PR interval

Front 14

class II agents

Back 14

beta adrenergi blocers
1. decrease AV nodal conduction - prolong PR interval
2. decrease HR

Front 15

muscarinic agents

Back 15

drugs w/vagal activity
1. decrease AV nodal conduction
2. prolong PR interval
3. decrease HR

Front 16

slow AV conduction

Back 16

beta blockers
Ca channel blockers
muscarinic agents

all used for atrial fibrillation - keeps fibrillation from moving to ventricles - can't live very long w/ ventricular fibrilation = slow ventricular response

Front 17

conduction velocity

Back 17

determined by the size of the Na+ current

Front 18

resting potential of dxed cells

Back 18

from ischemia
less than neg = - 50 instead of -90mV

= more Na+ channels are inactivated and the conduction velocity is slowed

- more Na+ inactivated b/c resting state is depolarized = conduction velocity is slowed

Front 19

class I agents mechanism

Back 19

bind preferentially to open and inactivated Na+ channels and thus prevent activation

stabilize inactivated state

during high rates of stimulation - during tachycardia (class I and class IV)

Front 20

binding of anti-arrhthmic agents

Back 20

membrane pot-dependent - dx depolarized tissue
and frequency dependent = tachycardia

Front 21

class III agents mechanism

Back 21

block K+ channels = prolong AP duration

results in prolongation of the QT interval - excessive prolongation of APD lead to torsades de pointes

Front 22

effectory refractory period

Back 22

period when cell is not responsive no mateter how great

Front 23

relative refractory period

Back 23

cells will only respond to a greater than normal stimulus
= cells cant be tetonized

Front 24

refractoriness

Back 24

inability of the cell to be excited
determined by teh time needed for recover of the Na channe;s from inactivation

longer until cell can fire AP = w/ drug that increases refractorieness

class I agents delay the recovery of Na channels from inactivation = increase refractoriness

class III prolong AP =prolong ti mw of depolorization = increased time of inactivated na channels = increase refracteriness

Front 25

major causes of arrhythmias

Back 25

1. abn automaticity
2. triggered activity
3. reentry pathways
4/ conduction block
5. anti arrhthmic drugs

Front 26

abnormalities due to abn automaticity

Back 26

bradycardia - parasymp stim = high stim = tx by pacemaker

tachycardia = sympathethtic stim = over prod of catecholamines - class II - decreases slope of nodal phase 4 depolarization - beta blocker - inhibit binding of catecholamines
class IV agent = decrease slope and amplitude of phase 0 depolarization - frequency dependent binding


ectopic pacemakers - atrial, ventricle etc

= class I agent - decrease firing of fast response fibers

class III prolong APD so less AP generation per unit time- keep in depolarized state

Front 27

abnormalities due to triggered activity

Back 27

early after depolarization - occur when AP is abnormally long= anoter AP firing during repolarization = early after depolarization - Tx w./ class I b/c keeps Na+ in inactivation
w/ class II agents - useful for treating prolonged QT interval (long QT syndrome) inhibit reg of calcium channel = decrease plateua -drug of choice


can occur when the APD is abn prolonged

Front 28

abn due to reentry -local reentry

Back 28

renentry =when impulse reexcites same part during one conduction cycle

1. unidirectional block conduction
- purkinje fiber that branches and terminates on a strip of ventricular mm area of ischemic tissue = area of unidirectional block - can't move in the antigrade - but in the retrograde direction = class I agents block conduction through diseased regions . class III prolong APD and increase refractoriness

2. slow conduction zone allows recovery from ERP

Front 29

class IA

Back 29

quinidine binds to the open state of the Na+ channel
- other drug -procainomide same mechanism = does not have indirect affect no vagolytic or alpha adrenergic actions
- metabolized to N-acetyl procainamide = slow acetylators - lupus like syndrome (drug induced lupus)
- also blocks the delayed rectifier K+ channels

direct actions
1. slows upstroke of AP and slows conduction
2. decrease firing of fast response fibers (inc QRS duration)
3. prolongs APD - K+ channel

increases refractoriness
decreases automaticity of ectopic pacemakers

indirect = pro-arrhytmic
- anti -muscarinic effect - increases AV nodal conduction (dec PR interval)
alpha-adrenergic receptor blocade - reflex tachycardia = vasodilation leads to the reflex

given for A. Fib

Front 30

types of heart block

Back 30

1. block results from adisruption of AV nodal impulse conduction
2. 1st degree - some lengthening of PR
3. 2nd degree - partial block - 2:1. 3:1 and 4:1 conduction block
4. 3rd degree - complete block

Front 31

A fib w/ 3:1 block

Back 31

atria beats 300 beats/min
ventricle - 100 beats.min

quinidine - antimuscarinic effect -speeds AV nodal conduction and tx for afib
removes block = 1:1 conduction
atria = 200 bpm
ventricle = 200 bpm

Front 32

wolf-parkinson-white syndrome

Back 32

bocks conduction through accessory conduction pathway

excitation conducts from atrium to ventricle through accessory conduction pathway (kent bundle), retrograde conduction to AV node and back to the atrium establishing a global reentrant circuit

tx w/ class IA anti arrhythmic agents - quinidine and procanimide b/c blocks accessory pathway

Front 33

class IA drug interactions

Back 33

digoxin - renal P glycoprotein increase plasma levels - inhibits clearance - decrease dose of digoxin

Front 34

class 1A drug side effects

Back 34

1. cinchonism - headache and tinnitus
2. GI - diarrhea - rish of hypokalemia
3. prolonged QT interval - torsades de pointes

Front 35

therapeutic use of class 1A drug interactions

Back 35

1. maintains sinus rhythm in pt w/atrial flutter or atrial fibrillation - not commonly used anymore b/c induce torsades b/c prolonged QT

2. WPW syndrome - blocks conduction through accessory conduction pathway
--- most common use

Front 36

class IB anti arrhythmic agents

Back 36

lidocaine - bind to inactivated state of Na+ channel
- enhanced affinity in depolarized tissue MI

pharm
1. slow upstroke of AP and slows conduction
2. slight decrease in APD but stabilization of Na+ channel inacctivation increases refractoriness
3. least cardiotoxic of antiarrhythmic agents - binds perfrentially to inactivated state

increases refractoriness
decreases automaticity of ectopic pacemakers

other drugs
- mexiletine
- tocainide - not available in US
- congeners of lidocaine that are resistant to first pass metab

Front 37

therapeutic use of class IB anti arrhythmic agents

Back 37

ventricular arrhythmias - lond duration of APs in ventricle - more Na+ channel inactivation

must be given I/V - first pass metabolism - given in hospital settings

Front 38

side effects of class IB anti arrhythmics

Back 38

IV intoxication
initial
1. tinnitus
2. lightheadedness
3. confusion
CNS excitment = seizures
Depression - unconsciousness, hypotension, resp/cardiac arrest

Front 39

class IC anti-arrhythmic agents

Back 39

flecainide - blocks Na+ channels and delayed rectifier K+ channnels

1. slows upsstroke of AP and slows conduction
2. prolongs QRS and QT intervals

Front 40

therapeutic use of class IC antiarrhthmics

Back 40

maintenance of sinus rhythm in supraventricular arrhythmias
aka in atria fibrillation

Front 41

side effects of class 1C

Back 41

increased mortality in pt w/vent arrhythmias and previous MI

used in pt refractory to other class I agents

not in pt w/CHF - contraindicated

Front 42

binding of catecholamines to heart

Back 42

catecholamines -> receptor -> Gs protein -> adenylyl cyclase = ATP => cAMP = open funny channels open Ca2+ channels

- Increase in automaticity slope phase 4
- increase in Ca2+ current phase 0

Front 43

binding of Ach to muscarininc receptors

Back 43

muscarinic -> receptor -> Gi protein -> blocks adenyll cyclase
membrane portinential more neg b/c K+ channel opening

decrease automaticity and regulation of calcium channels

decrease in phase 4 slope in phase 0

Front 44

Class II anti-arrhythmic agents

Back 44

propranolo - non specific Beta adrenergic antagonist

1. decreases slope of phase 4 and phase 0 = slow fiber depolarization
2. decreases AV nodal conduction
3. slow HR
decreases automaticity

other
- Carvedilol - HTN - mixed adrenergic agent = beta blocker and alpha blocker
- sotalol - also class III enantimere - beta blocker and class III anti-arrhythmic activity

Front 45

therapeutic uses of class II agents

Back 45

PSVTs - AV nodal reentry tachy cardia - unidirectional block in one of AV nodal pathways - good tx b/c slows AV conduction

ventricular response to atrial flutter/fibrillation - slows AV conduction

tx of choice in long QT syndrome

Front 46

class III agents mechanism

Back 46

K+ channel blockers - blocks delayed rectifer K+ channels

Amiodarone/Solaterol

1. prolongs APD in atrial and ventricular tissue
2. prolongs QT interval - torsades de pointes risk increased

amiodarone least likely to cause torsades - more problem w/quinidine and solterol

amioderone predom blocks slow component of rectifier K+ channels

increases refractoriness

Front 47

therapeutic use of amiodarone

Back 47

1. atrial flutter and fibrillation - rhythm control - superior to quinidine - directly at atrium

2. ventricular arrhthmias in pt w/ unresponsive to class 1 agents - lidocaine

Front 48

pharmokinetics of amiodarone

Back 48

high volume of distribution=being accumulated in tissue

oral bioavailability - 30%
Vd = 66 L/Kd
elimination half life - weeks = active for weeks-mo after stop taking it

Front 49

side effects of amiodarone

Back 49

1. pulm fibrosis
2. liver toxicity
3. skin accumulation - grey blue skin discoloration
4. corneal microdepositis
5. throid toxicity hypo and hyperthyroidism
6. drug interaction w/digoxin (p-glycoprotein)

Front 50

class IV agents

Back 50

verapamil and diltiazem
block the L-type Ca2+ channel

act predom on heart but some actions on vasculature
niphetapine no effects on heart

1. decrease slope of phase 0 depolarization
2. increase refractoriness of slow fibers
3. indirect - vasodilation - reflex tachycardia overshadowed by direct affect on SA node

decrease AV nodal conduction

increase PR interval
decrease automaticity

delayed after depolarization
1. fast heart lates
2. Ca 2+ overload
3. triggered activity

fast stimulation rates and drugs like digoxin that cause Ca2+ overload

used to treat but now more likely treated by beta blockers or Mg

Front 51

therapeutic use of class IV antiarrhythmic agents

Back 51

1. DADs from digoxin toxicity - beta blockers and Mg2+ first choice = b/c ca channel blockers also inhibit p-glycoprotein involved in digoxin clearance

2. PSVTs - AV nodal re-entry tachycardia

3. Ventricular response to atrial flutter/fibrillation - slow av nodal conductance

4. contraindicated in pt w/heart failure - b/c they decrease contraction

Front 52

adenosine

Back 52

class V anti arhythimc
binds to adenosine receptor in slow response fibers
acts very sim to Ach to muscarinic receptor

Gi prot = ? inhibits the production of cAMP via adenylyl cyclase and opens K+ channels

stimulates GI

decrease automaticity - slow AV nodal conduction
increase PR interval

Front 53

therapeutic use of adenosine

Back 53

1. drug of choice for emergency tx of PSVTs (short half life)

2. advantage - short half life - seconds

3. avoid caffeine and theophylline b/c act as antagonists on adenosine receptor

Front 54

digoxin

Back 54

muscarinic action - slows AV nodal conduction
useful in both atrial fib and fnal heart failure

Front 55

magnesium

Back 55

mechanism undefined

therapeutic use
1. torsades de pointes
2. DADs from digitalis

blocks L type calcium channels

Front 56

etiology of primary or essential hypertension

Back 56

1. low renin levels 20% more common in african american and geriatric pts
2. normal renin levels- most pt
3. high renin levels - rare

Front 57

etiology of secondary hypertension

Back 57

less than 5%

chronic renal or renal vascular dx

endocrime
- pheochromcytoma
- primary aldosteronism

drugs and food
- licorice - imported licorace glycosidic acid - inhibits cortisol conversion to cortisone = more Na+ retained = more H20 retained
- glucocorticoids
- estrogens
- sympathomimetic amines
- "white coat"

Front 58

classification and management of HTN

Back 58

normal -120/80 or less
pre-HTN - 120-139/80-89
= change lifestyle - drugs for compelling indications
- diet exercise, stop smoking
- tx chronic illness

HTN stage 1 = 140-159/90-99
= life style changes
- thiazide type diuretics HCTZ
= drugs for compelling indications + ACCEIS, ARBs, or CCBs

HTN 2 = >= 160 / >-= 100
- life style changes
- 2 drug combinations for most + drugs for compelling indication

Front 59

first line therapy for HTN

Back 59

thiazide type diuretics
ACE inhbitors
AngII receptor blockers
Ca2+ channel blockers

Front 60

second line therapy for HTN

Back 60

beta blockers
adrenergic modifiers alpha 1 blockers, NE depletors, etc
direct acting vasodilators

Front 61

HTN and CHF

Back 61

diuretics
beta blocker
ACEIs/ARBs
spironolactone

Front 62

diabetes and HTN

Back 62

ACEIs/ARBs first line drugs due to benefits in diabetic nephropathy

Front 63

BPH and HTN

Back 63

alpha 1 receptor antagonist

Front 64

Migrane and HTN

Back 64

prophylactic use of beta blocker

Front 65

considerations in HTN tx

Back 65

BP = TPR x CO

CO = HR x SV

decrease BP renin-angiotension feedback loop
- inc Renin
- inc Ang II
- inc aldo
- inc in ECF = expansion /edema

sypathetic feedback loop = inc HR
- reflex tachy

beta adrenergic receptor juxtaglomerular cells

major side effects = orthostatic HTN 0 relaxation of v
1. agents interfering w/ symp tone = prazosin
2. direct acting venodilators = nitrates - nitroglycerin

Front 66

diuretics

Back 66

hydrochlorothiazide

thiazide diuretics - first drugs given to HTN pt

1. kidney diuretic action - acute, Na+/ Cl co-transporter --> dec ECF volume --> dec CO

2, smooth mm vasodilation action - chronic inc PG formation activation of membrane K+ channels inward channels active at rest--> more neg membrane potential

Front 67

therapeutic use of diuretics

Back 67

1st line therapy - african americans and geriatric pts

used in monotherapy or combined w/ ACEIs. ARBs, etc

Front 68

side effects of diuretics

Back 68

hypokalemia
offset w/K+ sparing diuretic or ACEI/ARB

= ventricular arrythmias and suden death
caution when using digoxin and solterol for CHF

2. hperglycemia - inhibits insulin release

3. hyperuricemia - gout uncommon

4. hyperlipidemia - inc triglycerides/LDL ch

5. others - impotence andphotosensitivity

Front 69

diuretic contraindications

Back 69

sulfonamide hypersensitivity

drug interaction
1. lithium - thiazides decrease Li+ clearance
2. NSAIDs - decreases PG formation = decreases vasodilation
3. digoxin - due to hypokalemia

Front 70

ACE inhibitors

Back 70

inhibit angII prod and inc bradykini
= pro inflam and vascular relaxation
= more effective than ARBs
= bradykinin = dry cough, angioedema

dec aldo = hyperkalemia

Front 71

ARBs

Back 71

inhibit AngII release of aldosterone

Front 72

aliskiren

Back 72

direct inhibitor of renin
clinical efficacy

higher incidence of kidney dx

Front 73

captopril and lorsartan

Back 73

ACE and ARB
therapeutic use
- first line use essential HTN used in stage 1 and in combo in stage 2 w/a thiazide - more effective in caucasian and young pts

2. CHF
3. Diabetic nephropathy

side effects
- hyperkalemia
- dry cough and angioedema w/ACE inhibitor = 20%
- lipid neutral

Front 74

contraindications of catopril and lorsatan

Back 74

contraindication
- bilateral renal stenosis
- preg - 2nd/3rd trimester

caution - w/ hypovolemia and hyponatremia

drug interactions -
- K+ supplements
- spironolactone/amiloride - severe hyperkalemia

Front 75

ca+ channel blockers for HTN

Back 75

nifedipine, verapamil, and diltiazem

block l-type Ca2_ channel in smooth and cardiac mm
more effect of verapamil and diltiazem in heart
nifedipine effect primarilly in vascular

Front 76

implications of ca2+ channel blockers

Back 76

only verapamil and diltiazem are used as anti-arrhythmic agents

verapamil and diltiazem will cause AV nodal suppression - don't use w/beta blocker
negative inotropy - contraindicated in CHF

nifedipine will produce reflex tachy used w/ beta blocker

therapeutic use
1. first line for HTN stage 1 and in combo for stage 2 used w/thiazide or ACE inhibitor
2. more effective in african americans and geriatric

verapamil for migrane prophylaxis

Front 77

side effects/contraindications of Ca2+channel blockers

Back 77

specific for arterial smooth mm = low risk of orthostatic HTN

1. cardiac depression - AV nodal suppression, bradycardia, etc - verapamil and diltizem

2. hypotension and reflex tachy - nifedipine

3. constipation w/ verapamil

4. low risk of orthostatic hypotension

Front 78

propranolol and metoprollol

Back 78

inhibits catecholamine induced positive inotropy and chronotropy

reduces renin secretion/ Ang II production

therapeutic use
- second line HTN used in combo w/others
more effective in caucasians and youger pts

good for pt w/heart failure too

Front 79

side effects of propranolo and metoprolol

Back 79

fatigue esp in ppl that exercise a lot - sedentary pt no problem

depression - esp w/propranolol

lipid unfriendly inc triglycerides, dec HDL
other -MI and CHF

Front 80

contraindications of beta blockers

Back 80

asthma and COPD = beta selective B1 selective- but is dose dependent

caution w/
- diabetes masks insulin-induced hypoglycemia
- abrupt withdrawal - tachy, increased tachycardia, increased contractility

drug interaction w/verapamil - AV nodal conduction

Front 81

alpha 1 adrenergic blockers

Back 81

1.inhibits catecholamine induced vascular constriction
2. decrease venous return, decrease CO and dec TRP

Front 82

therapeutic use of a1 adrenergic blockers

Back 82

prazosin - esential HTN - used in combo for stage 1 and 2 no longer first line
BPH - relieves obstructive sx

2. phentolamine
- HTN secondary to pheochromocytoma

Front 83

side effects of alpha 1 blocker

Back 83

1. first dose syncope
2. reflex tachycardia and orthostatic hypotension
3. lipid friendly - dec TG and inc HDL

Front 84

mixed beta 1 and alpha 1 adrenergic blockers

Back 84

carvedilol and labetolol

pharm
- dec CO
- dec TPR

Front 85

therapeutic use of mixed beta1/alpha1 adrenergic blockers

Back 85

essential htn - more efficacious than selective alpha and beta - not used a lot anymore

see CHF

Front 86

side effects of mixedbeta/alpha blockers

Back 86

combination of beta and alpha effects except
1. no reflex tachy or first does syncope
2. no changes in lipids

Front 87

alpha 2 agonists

Back 87

methyldopa (prodrug, active moiety is alpha -methylnorepinephrine
and clonidine
not used in US anymore b/c severe side effects

only used in pts that are refrectary to other drugs

activation of CNS presynaptic A2 receptors resultin reduction of symp outflow = dec TPR

Front 88

therapeutic use of A2 agonists

Back 88

only used in pt that are refractory to other tx in essential HTN
combination for stage 2

Front 89

side effects for A2 agonists

Back 89

sedation
depression
edema = renin angiotensin
bradycardia

methyldopa - + coombs test = hemolytic anemia

Front 90

contraindications for a2 agonists

Back 90

caution - withdrawl HTN - clonidine reduces release of NE

monoamine hypothesis of depression =- results in deficiency of nt such as NE and serotonin

drug interaction w/TCA and mirtazapine - decrease hypertensive efficacy

Front 91

anti adrenergis

Back 91

reserpine and guanethidine

depletes NE

reserpine blocks vesicular uptake and storage of NE and other nt - serotonin and dopamine -


guanethidine - taken into presynaptic nerve terminal by reuptake transporter - peripheral
blocks NE release
depletes NE

therapeutic use - reserpine refractory HTN

Front 92

anti adrenergics side effectes

Back 92

reserpine - depression
inc HCL secretion

guanethidine - orthostatic hypotension and fluid retention

Front 93

direct acting vasodilators - vascular smooth mm cell

Back 93

1. Na+ nitroprusside - directly converted to NO = stimulates guanylyl cyclase = inc cGMP = prot kinase G - dephosphorylation of myosine light chain - relaxation

2. minoxidil binds to sulfonulurea receptor opens ATP -sensitive K+ channel = hyperpolarization (more neg membrane potention = relaxation

3. hydralazine - unknown meck

all cause arterial dilation
but sodium nitroprusside also causes veule dilation too = likely to cause orthostatic htn

Front 94

therapeutic use of direct acting vasodilators

Back 94

hydralazine- severe refractory HTN

Na nitroprusside - HTN emergency, CHF, controlled hypotenssion during surgery

minoxidil - severe HTN >180.110 , and male pattern baldness

Front 95

side effects of direct acting vasodilators

Back 95

reflex tachycardia and fluid retention to some extent
use beta blocker and diuretic

hydralazine - lupus symptoms in slow acetylators

drugs causing lupus like symptoms = hydralazine and procainamide

Na+ nitroprusside - CN- metabolized to cyanided converted by rhodenese to thiocynate - give pt thiosulfate when toxicity

minoxidil - causes hair growth = hypertrichosis of the face back and arms - offensive to women

Front 96

HTN emergencies

Back 96

elevated BP > diastolic 120 end organ damage (brain, heart, kidneys
2. iv Na itroprusside

also nitroglycerin, labetalol mixed alpha1 beta blocker and DHP and CCBs

Front 97

Tx of pulmonary artery HTN sildenafil

Back 97

sildenafil - inhibits PDE 5 - used in tx of erectile dysfn and tx of pulmonary htn - inhibit break down of cGMP = inc cGMP = inc relaxation of pulmonary aa

sildenafil and nitroglyceration - increase cGMP = unsafe drop in BP

sildenafil (Revatio)
- vascular smooth mm relaxation
- decreases pulmonary aa resistence
- therapeutic use primary pulmonary htn
- revatio - white pill
- viagra - blue pill same drug

Front 98

Tx of pulmonary artery HTN proctacyclin - epoprostenol

Back 98

given as an IV pump
primary pulm artery HTN
hooked up to v in chest

constant given to maintain vasodilation

side effects
-flushing
-0 headache
- jaw pain
- related to use of IV pump

Front 99

Angina pectoris

Back 99

chest pain/pressure/tightness caused by an accumulation of metabs resulting from MI
radiate to jaw and shoulder = down L arm

Front 100

types of angina

Back 100

1. clasic (stable) angina
- fixed coronary stenosis
- exertional or exercise induced - requiring increased O2 demand relieved by rest

2. variant (prinzmeta;'s) angina
- vasospasm induced - reduced flow
- occurs during rest or sleep

3. unstable angina
- type of acute coronary syndrome = early stage of MI
- abrupt onset
- prolnged, unassoc w/ identifiable ppt,
- underlying platelet aggregation
- pain more severe and more frequent

Front 101

cause an increase in O2 demand

Back 101

increase HR
increased contractility
increased preload - increased EDV (venous side)_
increased afterload - increase in vascular resistance - arterial side
- dilate venules = dec EDV

ca channel blockers - decrease automatacity and contractility by blocking L-type Ca+ channels - cause arterial dilation - dec afterload -

beta blockers decrease heart rate

Front 102

causes an increase in O2 supply

Back 102

increase in coronary blood flow

regional myocardial blood flow - changes in distribution of blood flow
- nitrates vasodilate increase blood flow to ischemic region

- calcium channel blocker inc blood flow

Front 103

NO mechanism

Back 103

goes into endothelial cells and activates sGuanylyl cyclase that causes GTP =>> cGMP --> prot kinase G activated myosine LC PO4 removed = no longer associates w/actin = vascular smooth mm relaxation

nitrates converted to nitr
by sulfhydrale groups nitric oxide which binds the sGuanylyl cyclase

Front 104

nesiritide

Back 104

binds receptor form of guanylyl cyclase
stimulates results in conversion of GTP to cGMP

Front 105

nitrates

Back 105

nitroglycerin - increase smooth mm cell NO

1. venous dilation at normal doses - decreases preload
2. arterial dilation at higher doses - decreases afterload
3. redistribution of coronaryblood to ischemic areas

decreases cardiac demand
increase O2 supply

Front 106

therapeutic use of nitrates

Back 106

all types of angina stable and variant
2. unstable angina- w/anti-platelet drugs (aspirin ...
3. CHF w/ MI = decrease EDV

Front 107

side effects of nitrates

Back 107

drug interaction w/sildenafil (viagra) -= acts on smooth mm of corpous carvenosus

cGMP broken down by PDE5 converting cGMP -->GMP
PDE5 inhibited by sildenafil
HUGE increase in cGMP - accumulation= unsafe - strong relaxation of vascular smooth mm = unsafe drop in BP

side effects
1. syncope/orthostatic hypotension - low dose
2. headache - most severe headache ever
3. reflex tachycardia - arterial dilation

considerations
1. route of administration - sublingual, transdermal patch
- sublingual - abs very rapidly w/in a few min - acts very qucikly effective for 30 min
patch - active for 3-4 hrs

2. long term therapy - tolerance develops - sulfhydryl hypothesis - sulfhydryl groups in smooth mm invovled in conversion of nitrates to ... get used up and not available for conversion
- break in therapy 8 12 hr every day

Front 108

other nitrates

Back 108

isosorbide dinitrate - metabolite of nitroglycerin - oral bioavailability + hydralazine for CHF - effective in africian americans

2. amyl nitrate - volatile liquie for inhalation - no longer used in US - vial crush - breath vapors - volatile liquid -

Front 109

Ca+ channel blockers and MI

Back 109

Nifedipine, verapamil and diltiazem
block the L type Ca channel in smooth mm and cardiac mm
- nifedipine - no action on heart
diltiazem 50/50 heart and vasculature
verapamil works better on heart

1. neg inotropy and chronotropy - verapamil and diltiazem - exception w/DHP

2. arterial dilation - decreases afterload
3. coronary dilation

dec cardiac demand by dec automaticity and cardiac contraction
increase O2 supply

Front 110

therapeutic use of calcium channel blockers

Back 110

1. stable and variant angina
2. paroxysmal supraventricular tachycardias
3. HTN

Front 111

side effects of Ca2_ channel blockers

Back 111

1. cardiac depression - AV nodal suppression
- bradycardia
2. hypotension and reflex tachycardia - nifedipine
3. see antihtn

considerations
1. use DHPs (nifedipine) w/beta blocker (stable angina)
2. caution use of verapamil and diltiazem w/beta blocker
3. increase serum digoxin concentration (p-glycoprotein inhibition - inhibit clearance of digoxin)

Front 112

CV drugs interacting w/digoxin through inhibition of p-glycoprotein

Back 112

quinidine
amiodarone
verapamil

decrease dose of digoxin

Front 113

beta adrenergic blockers in MI

Back 113

propanolo and metoprolol
1. inhibits catecholamine induced positive inotropy and chronotropy

dec cardiac demand - tx angina

therapeutic use -
1. stable angina - effective during exercise and work
2. tx of acute coronary syndrome w/ MI - dec cardiac work

Front 114

considerations of beta blockers

Back 114

1. increased EDV
2. AV nodal block w/ verapamil, diltiazem and digoxin
3. combination therapy w/nifedipine and nitrate - nitrate reduce beta blocker increases in EDV

Front 115

therapeutic uses of beta adrenergic blockers

Back 115

class II antiarrhythmic agents
- dec AV nodal cond and HR by dec the slope of phase 0 and phase 4 depolarization
= useful for treating PSVTs and in rate control for afib

2. ischemic heart dx - stable angina and ACS (MI) Inhibits catecholamine actions on the heart reducing cardiac work

3. CHF- prevent deleterious effects of catecholamines on the heart

4. HTN dec blood pressure by decreasing CO

Front 116

decrease contractility

Back 116

caused by
coronary a dx
MI
arrhythmias

dec CO

Front 117

dec afterload

Back 117

by HTN
dec CO

Front 118

Dec in LV wall integrity

Back 118

caused by valvular damage and LV wall carring

dec CO

Front 119

dec SV

Back 119

by preload
contractility
and afterload

dec CO = heart failure

Front 120

dec CO

Back 120

heart failure

Front 121

Compensatory systems of heart failure

Back 121

dec CO = sympathetic activation
--> inc contractility and inc HR via release of catecholamines

dec CO => inc in EDV (venous constriction - inc in venous return to heart) --> cardiac dilation = hypertrophy in time

cardiac dilation and inc contractility and inc HR = inc in SV = inc CO
IN SHORT TERM

LONG TERM
- sympathetic activation - vasoconstriction --> inc afterload --> inc resistance that heart needs to pump against
= more stress on heart to expel blood --> further increased EDV == further inc in myocardial wall stress = contractile dysfn

dec CO = dec renal blood flow = inc in renin by juxtuloglomerular cells of kidne y --> inc AngI --> Ang II --> vasoconstrictor very potent --> further vasoconstrictor == further increase in afterload = more resistance for failing heart --> inc EDV

Ang II stimulates production of aldosterone inc --> reabs of Na+ and H2O reabs --> preload --> EDV --> dec CO

aldosterone and catecholamines have direct deleterious effects on heart mm
aldosterone increases fibrosis of the heart - dec in contractile performance

Front 122

heart failure

Back 122

pathophysiologic state in whicch the heart is unable to pump blood at a rate nec to meet the req of metabolizing tis

resulting sx -
1. fatigue
2. SOB
3. pulmonary congestion
4. edema
result from inadequate perfusion of tissue and the retention of fluid

Front 123

catecholamines on heart in CHF

Back 123

remodeling of heart changes of expresion of contractile fibers and ion channels

also induces apoptosis

Front 124

inotropic drug

Back 124

turns off sympathetic system
dec in ventricular filling pressure

frank starling curve moves up and to the left
3. = digoxin, amorinone (phosphodiesterase inhibitor) , dobutamine (beta adrenergic agonists)

Front 125

dobutamine

Back 125

b1 receptor in heart
acts through G stimilatory protein which stimulates adenylyl cyclase causes ATP --> cAMP = activates prot kinase A - phosphorylates Ca+ channel increased opening - increased Ca in cell = cause SR to release more CA
more Ca released = more contraction

Front 126

inamrinone

Back 126

phosphodiesterase 3 inhibitor inc cAMP levels so more Ca+ in cell = more contractility

Front 127

digoxin

Back 127

inhibits 2K+/3Na+ ATPase

binds inhibits mvmt of Na out of myocyte and K+ into myocyte

PM prot - Na/Ca exchanger normally moves Na+ into myocyte and Ca+ out of myocyte

digoxin causes increase in local intracellular levels of Na+ = dec gradient of Na for cell to bring Na in via na/ca enchanger = inc Ca2+ inc inside cell - inc contractility

direct actions
1. inc contraction - positive inotropy = inc CO
2. dec preload, EDV and Heart O2 demand (dec sympathetic activity = less vasoconstriction = dec in afterload) - dec in myocardial wall stress -reduce O2 demand

3. inc K+ conduction - dec APD = by inc intracellular Ca = K+ channels that become activated = shortening of APD

4. shortesn and depresses ST segment - pro=arrhythmic effect by shortening the APD

Indirect effects
1. increases vagal activity - slows AV nodal conduction
2. prolongs PR interval
3. dec symp activity - dec afterload, dec HR

overall EP action
dec refractoriness
dec HR
inc PR interval - useful for afib

Front 128

therapeutic use of digoxin

Back 128

1. low output heart failure -later phases of heart failure w/ accompanying atrial flutter/fibrillation

2. atrial arrhythmias - slow AV conduction/protects ventricles from fibrillation

Front 129

side effects of digoxin

Back 129

very narrow therapeutic window - very easy to be toxic

cardiac side effects
1. arrhythmias - decreases refractoriness = pro-arrhythmic effect - ectopic beats - afib -> v. fib

2. bradycardia - vagal action - dec in automaticity

3. DADs - Ca2+ overload - beta blockers (1st ) Ca2+ channel blockers
inc plasma levels of digoxin w/ ca channel blockers

non cardiac side effects
1.. GI - anorexia, n/v
2. neurological - fatigue, weakness, and confusion
3. visual disturbances - photophobia, and yellow filter effect

Front 130

pharmacokinetics of digoxin

Back 130

oral bioavailability 60-80%
half life = 1 day = steady state requires 4-5 days
Vd= 6.2 sequestered to fat and tis
p-glycoprotein = quinidine, amiodarone and verapmil

clinical steady state acheived in 4-5 half lives
loading dose given to obtain steady state conc immediately

Front 131

cardiac glycosides

Back 131

positive inotropic agents
drug and ionic considerations

K+ and digoxin compete for same binding siteon Na/K+ ATPase = caution w/K+ wasting diuretics(furosemide and insulin hypokalemia enhanced digoxin toxicity

2. quinidine - reduce digoxindosage by half

3. digoxin given prior to quinidine to slow AV nodal conduction

4. life threatening digoxin toxicity - anti -digoxin Ab, atropine and anti-arrhythmic agents

Front 132

plasma K+ interaction w/ drugs

Back 132

hypokalemia - inc toxicity in class III AA agents (soliterol and digoxin) - inc torsades des pointes

hyperkalemia- result from digoxin toxicity

Front 133

other positive inotropicagents

Back 133

dobutamine - Beta adrenergic receptor agonists

inamrinon PDE3 inhibitor

pharm
1. inc contraction postive inotropy inc CO
2. use limited to advanced heart failure
3. may increase mortality in CHF pt
4. paradoxical use of beta blockers

Front 134

vasodilators that vasodilate arterial and venous in CHF

Back 134

shift curve up and to the left

Front 135

vasodilators that vasodilate just arterial

Back 135

shift curve up

Front 136

vasodilator that causes venous

Back 136

moves curve to the left

Front 137

direct acting vasodilators on CHF

Back 137

nitroglycerin, hydralazine and na+ nitroprusside
pharm
1. venous dilation - dec preload - Nitro dec EDV
2. arterial dilation - dec afterload - hydralazine - inc SV

3. arterial and venous dilation - decrease afterload and preload (Na+ nitroprusside

Front 138

drugs that cause lupus like syndromes

Back 138

procainamide - class IA anti-arrhythmic

hydralazine

in pt who are slow acetylators

Front 139

side effects and clinical considerations of nitro, hydralazine, and na+nitroprusside

Back 139

nitroprusside converted to cyanide - problem in pt w/kidnney difficulties
2. hydralazine used w/isosorbide dinitrate - mainly AA pt w/CHF

3.see anti-HTN agents and MI

Front 140

ACE inhibitors and AT-1 blockers

Back 140

Captopril - ace inhibitor
losatrin - AT-1 receptor blocker

1. first line therapyy in CHF pts - reduce mortality
2. both decrease afterload and preload - inc CO - - inhibit ang II vasoconstriction
3. both dec aldo synthesis - inhibit Na+ h2O reabs - dec edema
4. AT -1 blockers - eliminates Ang II "escape" mecanism - ang II enzyme escapes

Front 141

side effects of ACE inhibitors and AT-1 blockers

Back 141

1. hyperkalemia - dec aldo
2. dry cough and angioedema - ACE inhibitors inc bradykinin = dry cough doesnt occur w/ARBs
angioedema - inflammation - most severe side effect - closure of bronchial pathways

prevent diabetic nephropathy
3. contraindicated - pt w/bilateral renal stenosis

Front 142

diuretics and curve

Back 142

shifted to the L

Front 143

diuretics and CHF

Back 143

furosemide - loop diuretic
Hydrochlorothiazide

pharm:
1. reduce ECF volume, dec preload
2. do not reduce CO in most CHF pt (despite dec EDV)
3. decrease pulmonary edema and dyspnea
4. no evidence of reduced mortality

used as needed - used to eliminate edema - improve breathing - relieve peripherial edema
- don't give on a chronic basis

furosemide drug of choice b/c stronger diuretic

Front 144

side effects of diuretics

Back 144

electrolyte loss = K+

hypokalemia

Front 145

beta adrenergic receptor blockers and CHF

Back 145

metoprolol and carvedilol

therapeutic use
1. paradoxical beneficial action
2. mechanism - dec catecholamine -induced apoptosis - dec pathological remodeling, biphasic change in CO
3. use w/ACE inhibitor or AT-1 blocker and diuretics .

Front 146

side effects of beta blockers

Back 146

1. cardiac contraction and excitation - depression
2. CNS sedation and depression
3. Abrupt withdrawl - tachycardia/arrhythmias
4. asthma, COPD
5. masks hypoglycemia in diabetes

Front 147

spironolactone and CHF

Back 147

aldosterone antagonist
1. inhibits aldo-mediated cardiac remodeling
2. randomized aldactone evaluation study - dec mortality in CHF
3. hyperkalemia major side effect
4. use w/ACE inhibitor and beta blocker

Front 148

nesiritide used for CHF

Back 148

human brain natriuretic peptide

therapeutic use/ considerations
1. receptor - guanylyl cyclase - inc cGMP
2. dec preload and pulm capillary wedge pressures = fall in L atrium pressure
3. primary side effect is hypotension

cGMP = prot kinase G dephosphorlates myosine LC = relaxation

benefit over NO = naturetic effect - increases in Na+ and H2O excretion = reduce edema AND decrease blood volume

has to be given IV in hospital

Front 149

Stage A CHF

Back 149

high risk for heart failure w/no structural cdamage or heart failure sx

tx compelling indciations
- HTN
- diabetes

Front 150

stage B CHF

Back 150

structural damage w/ no heart failure sx

MI

tx w/ ACE inhibitors (or ARBs) and beta blockers

Front 151

Stage C CHF

Back 151

structural damage w/current heart failure sx

tx w/ ACE inhibs or ARBs, beta blockers, aldo antagonists and loop diuretics

Front 152

stage D

Back 152

refractory heart failure
tx w/ mechanical assistance
inotropic agents
transplantation

Front 153

characteristics of plasma lipoproteins general structure

Back 153

inner hydrophobic lipid core
- Ch esters
- TGs

outer hydrophilic coat
- phospholipids
- free (unesterified) ch
- apolipoproteins

Front 154

cycle of lipoproteins

Back 154

VLDL from hepatocyte
Lipoprotein lipase on capilarry endothelium releases some FFA + VLDL remnant

which can go to
HDL
LDL
or bind to the LDL receptor and be taken up by hepatocyte

LDL goes to LDL receptor on peripherial cell or hepatocyte to be taken up
once inside -> lysosome --> ch <=> Ch esters

HMG CoA reductase converts acetyl-CoA reductase to mevalonic acid?

Front 155

rationale for treating dyslipidemia

Back 155

inc Ch LDL = inc CHD

dec in LDL = dec CHD

Front 156

chylomicrons

Back 156

large TG rich lipoproteins (largest plasma lipoprotein)

transport TGs from diet or intestines to liver

TGs are removed by action of Lipoprotein lipase (LPL)

provides TGs to mm, adipose and cardiac tissue

Front 157

very low density lipoproteins

Back 157

formed in liver (intestine)

contain 15-20% of plasma ch; rest is TGs derived from liver

metabolized by LPL in cap beds to remove TGs

leads to formation of VLDL remnants (IDL)
- removed by LDL receptors in liver

minor player in formation of atherosclerotic plaques

converted to LDLs

Front 158

Low-density lipoproteins

Back 158

carry 60-70% of plasma ch

arise from metabolism of VLDL/IDL

ApoB-100 is the only apoprotein present - ligand for LDL receptor

removed by LDL receptors in liver or peripherial tis
OR depositied in intimal space of coronary, carotid, or peripheral aa
= oxidatively modified --> atherosclerotic plaque

Front 159

high density lipoproteins

Back 159

transport ch from peripheral cells to liver (reverse ch transport)

HDL receptors in liver

also transfer ch of VLDL

posess anti-atherogenic effects
HDL-2 more ch rich particls
HDL-3 - smaller than HDL-2

Front 160

clinical manifestations

Back 160

elevated LDL, VLDL, TGs

decreased HDL

Front 161

LDL oxidation, plaque formation and progression

Back 161

1. LDL deposited in intimal space
2. LDL is oxidized
3. monocyte recruitment to intact endothelial surface
4. chemoattractants recruit monocytes to intimal space
5. monocytes converted to activated macrophages
6. macrophages digest oxidized LDL
7. macrophage conversion to foam cells
8. dev of fatty streak - precursor to atherogenic plaque
9. weak and unstable plaques are converted to strong and hard
10. arterial remodeling, dysfn and impaired reactivity

Front 162

Plaque formation risk factors

Back 162

HTN
smoking
diabetes
stress
metabolic syndrome

genetic factors

Front 163

plaque pathology

Back 163

early stage = weak and unstable
- thin fibrous cap and large lipid core

increased risk of rupture = thrombosis

older plaques = strong, hard plaques = occlusion

reduced vascular reactivity

Front 164

goal of dyslipidemia tx strategies

Back 164

1. improve lipoprotein profiles
2. reduce plaque formation
3. stabilize existing plaques
4. restore endothelial fn

Front 165

therapeutic lifestyle changes in tx of dyslipidemia

Back 165

A. Dietary intervention
1. limit total calories from fat to less than 20% of daily intake
2. limit saturated fats to ~8% daily intake
3. limit ch intake to less than 200 mg/day
4. complex carbs and fiber = good
5. etoh = bad

B. lifestyle changes
1. exercise
2. wt reduction
3. stop smoking = dec HDL levels, cytoxic effects on endothelial cells, inc oxidation of lipoproteins

Front 166

pharmacology tx strategies to dyslipidemia

Back 166

1. statins
2. niacin
3. fibrates
4. bile acid-binding resins
5. ch abs inhibitors

Front 167

the statins - list

Back 167

Lovastatin
Atorvastatin
Fluvastatin
Pravastatin
Simvastatin
Rosuvastatin

Front 168

mechanism of action of statins

Back 168

HMG-CoA reductase inhibitors

catalyzes an early rate limiting step in ch biosynthesis

Front 169

outcomes of statin use

Back 169

1. reduced ch syn
2. inc expression of LDL receptors
3. dec plasma LDL levels
4. dec hepatic VLDL ( atrovastatin and fluvastatin)
5. dec TG - big or sml depend on baseline levels
6 inc HDL levels?

Front 170

additional cardioprotective effects of statins

Back 170

1. improved endothelial fn
2. inc plaque stability
3. dec inflam
4. antioxidant effects
5. reduced platelet aggregation

Front 171

side effects/ toxicites of statins

Back 171

hepatotoxicity
- inc serum aminotransferase activity
- determine baseline measures, monitor after initiating tx

2. Myopathy - rhabdomyolysis --> acute renal failure
- myalagia
- mm weakness, fatigue
- increased serum creatine kinase levels
more commonly seen in combo tx

Front 172

contraindications of the statins

Back 172

pt w/liver dx (etohism)

preg - pot teratogenic effects

Front 173

Niacin mechanism of action

Back 173

1. reduces transport of free fatty acids to liver
2. reduces liver TG syn
3. decreases VLDL secretion
4. Inc LPL activity

Front 174

outcomes of niacin

Back 174

1. reduced VLDL production
2. reduced TGs (35-40%)
3. reduced plasma LDL levels (20-30%)
4. increased clearance of chylomicrons
5. increased plasma HDL levels (30-40%)

Front 175

niacin formulations

Back 175

crystalline niacine - immediate release formula

sustained release niacin

Niaspan - extended release formula

Front 176

niacin side effects

Back 176

1. cutaneous flushing and itching (crystalline form) = PG mediated : aspirin administration
2. hepatotoxicity (sustained release form)
-> monitor liver fn
3. reduced risk of SEs w/ Niaspan formulation
4. contraindicated w/preg - possible risk of birth defects

Front 177

niacin metabolism

Back 177

nicotinamide pathway (high afifinity/low capacity)
high capacity conjugation pathway

crystallin niacin
- saturates nicotinamide pathway
- shifts metabolism to conjugation pathway
- inc production of intermediate that produces flushing
- PG - mediated vasodilation

Sustained release formulation
- preferentially metabolized by conjugation pathway
- inc formation of toxic metabolites
- dose-related hepatotoxicity

Front 178

Fibrates list

Back 178

clofibrate
gemfibrozil

Front 179

fibrates mechanism of action

Back 179

ligands for PPAR- alpha
- inc gene expression for LDL receptors and LPL among others

Front 180

outcome of fibrates

Back 180

decreased liver secretion fo VLDL
modest decrease in LDL
decreased TG (20-50%)
inc HDL (10-15%)

Front 181

toxicity/side effects of fibrates

Back 181

inc risk of rhabdomyolysis when given in combo w/statins

Front 182

bile acid binding resins - list

Back 182

cholestyramine
colestipol
colesevelam

among the oldest drugs used for tx of dyslipidemias
helped establish that dec LDL = dec CDH

only drugs currently approved for use in children 11-20

Front 183

mechanism of action of bile acid-binding resins

Back 183

- bind to and prevents reabs of bile acids in intestine

- stimulates conversion of ch to bile acids in liver

- inc LDL receptor expression in liver

Front 184

clinical outcomes of bile acid binding resins

Back 184

dec LDL (15-20%)
inc HDL (5%)

potential to inc HMG-CoA reductase expression and stimulate ch syn

co administer a statin

Front 185

side effects of bile acid binding resins

Back 185

GI disturbances - constipation, bloating

- mix w/noncarbonated, pulpy juices

- prepare in advance

- different formulations

Front 186

drug-drug interactions of bile acid-binding resins

Back 186

decreased abs of drugs = many examples

1. thiazides
2. furosemide
3. propranolol
4. warfarin
5. some of the statins

minimized by timing of drug administration

Front 187

ezetimibe mechanism of action

Back 187

inhibits intestinal absorption of ch

Front 188

outcomes of ezetimibe

Back 188

1. reduced LDL levels (15-20%)
2. inc hepatic LDL receptor expression
3. little to no effect upon TGs or HDL levels
4. additive effects when combined w/statins

Front 189

side effects of ezetimibe

Back 189

well tolerated
no increased risk of hepatotoxicity when combined w/statins

Front 190

Vytorin

Back 190

ezetimibe + simvastatin

additive effects

reduces LDL levels an additional 15-20%

rationale - dec ch absorption
ddec ch syntehsis

SEs and Cl assoc w/statins - rhabdomyolysis; pregnancy

Front 191

anemia

Back 191

reduction in RBC which decreases the oxygen carrying capacity of blood

not a dx itself but reflects an abnormality in RBC number, structure, or fn

Front 192

hemopoiesis

Back 192

blood cell production
stimulated by erythropoietin
thrombopoietin and
CSF

Front 193

iron absorption

Back 193

occurs in duodenum and prox jejunum

elemental iron is poorly abs (5%)

heme iron is abs w/ 37% efficiency

elemental iron must be reduced to Fe 2+ then crosses mucosal cell membrane via DMT1 (divalent metal transporter)

Front 194

iron transport/storage

Back 194

Fe2+ transported in blood complexed w./ transport protein transferrin

intracellular Fe2+ is stored as a complex w/ protein ferritin in intestinal mucosal cells, liver, spleen and bone

Front 195

iron utilization

Back 195

in BM iron incorporated into heme for production of RBC

reticuloendothelial cells recover iron from senescent RBCs for reutilization

increased erythropoiesis assoc w/inc number of transferrin receptors on developing erythroid cells

Front 196

iron excretion

Back 196

primarily due to exfoliation of mucosa cells and uterine epithelia

Front 197

hepcidin

Back 197

25 aa peptide syn in liver

controls plasma iron conc and tis distribution of iron by 1. inhibiting intestinal iron abs
2. inhibiting iron recycling by macrophages
3. inhibiting iron mobilization from hepatic stores

- binds ferroportin and induces its internalization and lysosomal degradation

- removal of ferroportin prevents iron efflux from GI enterocyte to plasma - lost from body when cells shed after 1-2 days
- prevent transport of recycled iron to plasma

syn regulated under
- anemia/hypoxia
- inflam
- iron overload

stimulation of it => anemia of chronic dx (cnacer, chronic kidney)

deficiency = ultimate cause of most forms of hemochromatosis

Front 198

most potent suppressor of hepcidin synthesis

Back 198

erythropoietin

Front 199

most potent inducer of hepcidin synthesis during acute inflam

Back 199

IL-6

acute host defense - deprives bacteria of essential iron

Front 200

symptomatic tx of iron overload

Back 200

deferoxamine

Front 201

microcytic hypochromic anemia

Back 201

most commonly due to iron def

iron essential to iron porphyrin heme ring

leads to dec hb content

Front 202

megaloblastic anemia

Back 202

characterized by presence of large immature red cells (megaloblasts)

most common cause of deficiency of vit B12 (cyanocobalamin) or folic acid

Front 203

iron deficiency anemia etiology and prevalence

Back 203

assoc w/either inadequate abs or excessive loss

pregnant women
young kids
elderly
chronic blood loss - GI bleeding and menstruation
common in countries where nut is poor and blood sucking parasites thrive

Front 204

iron def anemia signs and sx

Back 204

pallor
palpitations
dizziness
sensitivity to cold
glossitis
fatigue
stomatitis
tachycardia
angina
nails are rigid longitudinally - flattened or concave

Front 205

management of iron def anemia

Back 205

1. tx underlying dx - etohism, poor nut, malabs
2. replace iron stores using drug therapy
3. complete reconstruction of adequate stores req 6-12 mo of iron therapy

oral iron = ferrous sulfate
- inexpensive and covenient - should take w/vit C for better abs
- ingest w/ meals to reduce gastric irritation
- instruct pt stools will turn black

admin iron dextran IM or IV to pt intolerant to oral iron
- can cause anaphylactic type rxn

Front 206

thalassemia overview

Back 206

group of inherited, chronic blood disorders
def in rate of production of globin prot (of hb)
most prevalent in pt w/mediterranean descent

Front 207

sx and sx of thalassemia

Back 207

chronic anemia
splenomegaly
hepatomegaly
pallor
jaundice
metnal and phys retardation

Front 208

management of thalassemia

Back 208

transfusions

gene therapy to tx beta - thalassemia

Front 209

vit B 12 deficiency

Back 209

lack of intrinsic factor from parietal cells nec for abs

may oocur in pt who have had gastrectomy or sml bowel resection

ppt in AA interconversion and conversion of methyltetrahydrofolate to teterahydrofolate req for purine and deoxythymidylate biosyn = prevents adequate DNA syn in precursor cells so mature RBC don't develop

Front 210

pernicious anemia description

Back 210

autoimmune dx that is fatal in 1-3 years w/o B12 injections due to irreversible damage to nervous system = demyelination and cell death

gastric atrophy and fail to secreted IF and HCL

Front 211

signs and sx of pernicious anemia

Back 211

general macrocytic anemia
tingling of hands and feet
early signs of neurological damage

Front 212

management of pernicious anemia

Back 212

parenteral administration of cyanocobalamin daily for 2 wks then monthly for life

can cause manaphylactic type rxn

intranasal form also available

Front 213

folic acid deficiency cause

Back 213

caused by poor nutrition - lack of leafy greens, liver, citrus fruits, legumes and whole grains
also by malabs syndromes

drugs that impede abs of methotrexate, oral contraceptives, antiseizure drugs

common in etohics
hemodialysis pt

Front 214

folic acid use in the body

Back 214

req for DNA syn leading to RBC formation and maturation

in rapidly proliferating tissues like RBCs - considerable amts of THF are consumed and continued DNA syn req continued regeneration of THF by reduction of dihydrofolate

Front 215

signs and sx of folic acid deficiency

Back 215

sim to vit B12 ( macrocytic anemia) but no neurologic sx

Front 216

management of folic acid def

Back 216

tx w/folic acid replacement therapy
adm in B12 def will NOT prevent neurologic manifestations but will correct the anemia caused by B12 def

Front 217

aplastic anemia causes

Back 217

life threatening stem cell disporder resulting in pancytopenia

may be congenital - caused yb chrom alterations

chem-induced (benzene, insecticides, arsenic, etoh)

drug induced
- alkylating agents
- anti seizure meds
- antimicrobials
- gold

can occur after viral or bacterial infections

Front 218

aplastic anemia sx and sx

Back 218

general manifestations of anemia
fatigue
dyspnea
susceptibility to inf and ableeding = ecchymosis, petechiae, epistaxis

ALL BM elements dec

low retic count

prolonged bleeding time

serum iron and total iron binding capacity are elevated

BM aspiration has increased yellow marrow (fat)

Front 219

management of aplastic anemia

Back 219

identify and remove causative agent

prevent complications from infections and hemmorage

tx choice for adults under 45 = BM transplantation
- immunosuppression for older adults

Front 220

anemia and inflammation

Back 220

inflam stimulus (inf, autoimmunity, cancer) = activates monocytes and T cells

1. inc hepatic syn of hepicidin -> inhibits iron release from RES --> release of recycled iron via ferroportin

2. inhibits erythropoietin release from kidneys by IL-1beta and TNF alpha --> decreased erythropoietin --> dec erythropoietic stimulation

3. inhibits erythroid proliferation esp by THF alpha and INF gamma and IL-1 beta

4. augments hemophagocytosis --> hemophagocytosis by RES macrophages - release of iron via ferroportin --> dec Fe 3+ / transferritin --> back to bone

Front 221

surgery and anemia

Back 221

84-90% due to blood loss
erythropiesis assoc w/high levels of inflam cytokins

Front 222

advanced chronic kidney dx (stages 3-5) and anemia

Back 222

almost always assoc
primarily bc depressed prodution of erythropoietin

oxidative stress and inflammation

Front 223

epoetin alfa

Back 223

recombinant human EPO used w/ iron preparations to correct anemia after surgery or of chronic dx

produced in mammalian cell expression system

Front 224

erythropoietin

Back 224

34-39 k Da glycoprotein
first human hematopoietic growth factor to be isolated

purifed from urine of pt w/severe anemia

erythropoietin receptor is a member of JAK/STAT superfam of cytokine receptors use prot phosphorylation and TF activation to reg cell fns

usually inverse relationship btw hematocrit/hb level and serum erythropoietin level = exception chronic renal failure
in severe anemia increased levels

Front 225

darbepoetin alfa

Back 225

glycosylated form of erythropoietin

differs fnally only in having a 2fold to 3fold longer half life

Front 226

clinical use of erythropoietin

Back 226

anemia of chronic renal failuere - epoetin alfa -improves hematocrit and hb- eliminating need for transfusions

failure to respond = concurrent iron def - corrected by giving oral or parenteral iron - folate supplementation

tx of anemia due to primary bone marrow disorders

secondary anemias

offset anemia produced by zidovudine tx in pt w/ HIV

Front 227

adverse and toxic effects of erythropoietin

Back 227

HTN and thrombotic complciations

FDA warning - to pt w/chronic renal failure or cancer w/hb raised to >12g/dl w/erythropoiesis stimualting agent face greater risk of thrombotic event

pt w/ advanced head and neck cancers - faster tumor growth

myalgias and influenza like sx may occur

overly aggressive tx can inc morbiditiy and mortality in pt w/advanced chronic kidney dx via several mech

Front 228

filgrastim

Back 228

recombinant human granulocyte-CSF produced in bacterial expresion system

nonglycosylated peptide 175 aa

ability to mobilize hematopoietic stem cells 0 inc conc in peripheral blood - major advance in transplantation rather than BM stem cells

tx for chemo-induced neutropenia - accelerates rate of neutrophil recovery after dose intensive myelosuppressive chemo

Front 229

sargramostim

Back 229

recombinant granulocyte-macrophage -CSF produced in a yeast expresion system partially glycosylated peptide 127 aa

multipotential hematopoietic GF stimulates prolif and differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocytic progenitors

Front 230

adverse toxic effects of filgrastim and srgramostim

Back 230

cause bone pain - clears when drug discontinued = filgrastrim

more severe effects w/sargramostrim -esp at higher doses

- diarrhea
- flu-like - fever, malaise, arthralgias, myalgias
-capillary leak syndrome - peripheral edema = pleural or pericardial effusions

Front 231

interleukin 11

Back 231

prot produced by fibroblasts and stromal cells in the BM

Front 232

oprelvekin

Back 232

recombinant form of IL-11 approved for clinical use

tx secondary prevention of thrombocytopenia in pt receiving cytotoxic chemo

Front 233

thrombopoietin

Back 233

glycosylated prot constitutively expressed by variety of organs and cell typoes

hepatocytes major source of human thrombopoietin - pt w/ cirrhosis and thrombocytopenia have low levels

recombinant still investigational agent

Front 234

adverse and toxic effects of oprelvekin

Back 234

fatigue
headache
dixxiness
CV effects = anemia, dyspnea (fluid accum in lungs)
transient atrial arrhythmias
hypokalemia

Front 235

chemo uses

Back 235

most imp for metastatic tumors

poorest progosis - chemo effective

Front 236

dx that chem increases longevity

Back 236

1. burkitt's lymphoma
2. choriocarcinoma
3. acute lymphocytic leukemia of childhood
4. hodgkin's dx
5. lymphosarcoma
6. embryonal testicular carcinoma
7. wilm's tumor
8. Ewing's sarcoma
9. rhabdomyosarcoma
10. retinoblastoma

Front 237

growth fraction

Back 237

each tumor has particular characteristics of prolif
some have hig fraction of dividing cells
solid tumors low fraction

fraction of dividing cells in a tumor (or norm) tis

Front 238

what kind of tumor is the most susceptible to chemo

Back 238

small tumor with higher growth fraction

Front 239

normal cells w/high growth fractions

Back 239

1. BM
2. hair follicles
3. oral
4. intestinal mucoasa

all damaged by chemo drugs

most cause BM depression = leukopenia = infection; thrombocytopenia = bleeding

stomatitis and alopecia

Front 240

Dose limiting toxicity for most chemotherapeutic drugs

Back 240

bone marrow depression

Front 241

dose limiting toxicity

Back 241

undesired adverse effect - useually life threatening on norm cells from minimum toxic concentration of that drug

may be due to cumulative amt of administerd drug

Front 242

marrow sparing drugs

Back 242

Bleomycin

vincristine
asparaginase
hormonal agents
- glucocorticoids
- leuprolide
- tamoxifen
- medroxyprogesterone

streptozocin DLT=renal usually marrow sparing when used alone but ca add to BM toxicity if combined with other BMD agents

Front 243

Log Kill hypothesis

Back 243

cancer chemo agents kill drugs by a first order kinetic process

kill a fixed percentage of cells - not a fixed number

Front 244

mass doubliing time

Back 244

for untreated tumors the time it takes for the tumor to double in mass

Burkitt lymphoma 1d
choriocarcinoma 1.5d
acute lymphocytic leukemia 3-4 d
hodgkins dx 3-4 d
colon80d
lung 90 d (except SCC)

Front 245

S phase specific drugs self limiting

Back 245

toxic to cells syn DNA
Methotrexate
6-mercaptopurine

- kill cells in S phase but protein and/or RNA syn are also inhibited in tumor cells not in S phase
prot req to entere S phase
= S-phase specific but self limiting

Front 246

M phase specific trugs

Back 246

mt based inhibitions and arrests cells in mitosis

Vincristine
vinblastine
paclitaxel

Front 247

S phase specific

Back 247

cytarabine
hydroxyurea

Front 248

G2 phase specific

Back 248

etoposide

Front 249

phase non-specific

Back 249

alylating agents
antitumor abx
procarbazine
cis-platin

Front 250

decreased drug uptake

Back 250

1. alkylating agents
2. vincristine
3. vinblastin
4. dactinomycin
5. daunorubicin
6. doxorubicin
7. methotrexate

Front 251

increased DNA repair

Back 251

alkylating agents

Front 252

increased dihydrofoloate reductase

Back 252

methotrexate

Front 253

altered target enzyme w/dec affinity for drug

Back 253

methotrexate
5-Flurouracil

Front 254

decreased receptor

Back 254

steroids

Front 255

decreased activating kinase

Back 255

cytarabine
5-fluorouracil

Front 256

MDR

Back 256

resistance to
1. vincristine
2. vinblastine
3. etoposide
4. doxorubicin
5. daunorubicin
6. dactinomycin
etc

increased activity of transmembrane prot = P-glycprotein fn as an outwardpump to transport drugs out of cell before they can act

Front 257

group A

Back 257

highly responsive
- very sensitive to drugs
- good evidence for drug induced cures

dx
1. burkitt's
2. embryonal rhabdomyosarcoma
3. gestational choriocarcinoma
4. hodgkins dx
5. wilm's tumor

Front 258

group B

Back 258

responsive
- 50% or greater rate prolonged survival and some normal life expectancy - in combo

dx
1. acute leukemia in kidds
2. Ewing sarcoma
3. histiocytic lymphoma
4. lymphocytic lymphomas
5. osteogenic sarcoma
6. retinoblastoma
7. testicular cancer

Front 259

group C

Back 259

Moderately responsive
- clinical response is often obtained - increased survival

dx
- adult acute leukemias
- breast carcinoma
- carcinoma of the ovary
- carcinoma of the prostate
- endometrial carcinoma
- lung cancer (undiff SCC)
- multiple myeloma
- neuroblastoma

Front 260

class D

Back 260

partially responsive
- tumor regression observed w/ chemo in 20% or more of the casess
- complete remission rare or non existant - min or no prolongation of survival

dx
- adrenocortical carcinoma
- colorectal cancer
- glioblastoma
- head and neck cancer
- pancreatic islet cell carcinoma

Front 261

class E

Back 261

minimally responsive
- objective response observed in less than 20%
- if effect only pallitative
- no prolonged survival

dx
1. esophageal carcinoma
2. hepatocellular carcinoma
3. lung carcinoma (non SCC)
4. melanoma
5. pancreatic adenocarcinoma

Front 262

gestational choriocarcinoma

Back 262

cured by methotrexate

Front 263

common effects of anticancer drugs

Back 263

1. most act byinhibiting DNA syn (except - vinblastin, vincristine, paclitaxel, asparaginase, hormonal agents)

2. most are immunosuppressive (except = bleomycin, sex steroids ,asparaginase, vincristine)

3. virtually all are mutagenic- many are carcinogenic and teratogenic

4. most produce a degree of n/v (ondansetron - relieves these effects)

5. most exhibit severe toxicity to renewal systems

Front 264

undesirable side effect - BM

Back 264

leukopenia
lymphopcytopenia
inc risk of inf or activation of quiescent infection

thrombocytopenia = hemorrhage
immunosuppression
anemia

Front 265

undesirable side effect - digestive tract

Back 265

stomatitis
intestinal ulceration
diarrhea

Front 266

undesirable side effect - hair root

Back 266

alopecia

Front 267

undesirable side effect - tumor mass

Back 267

in case of leukemias and lumphomas - rapid destruction of the tumor cells can result in the release of large amts of nucleic acid breakdown products and the consequent inc in uric acid = renal damage
AKA tumor lysis syndrome

allopuinol - minimize effect

Front 268

undesirable side effect - tissue undergoing repair - surgical wound

Back 268

impaired healing

Front 269

undesirable side effect - gonads

Back 269

menstrual irregularities
amenorrhea
infertility
impaired spermatogenesis
sterility

Front 270

undesirable side effect - fetus

Back 270

teratogenesis

Front 271

principles of combo chemo

Back 271

1. select agents which are active against tumor when used alone

2. select drugs w/diff mech of action to avoid combined resistance

3. select drugs w/minimally overlapping toxicities to reduce adverse effects

Front 272

MOPP regimen

Back 272

used to tx hodgkin's luympphoma

mechlorethamine - alkylator - toxic to BM 20% complete remission

vincristine (oncovin) - mt - CNS toxicity <10% complete remission

procarbazine - not clear - marrow and oral mucosa toxicitiy <10% complete remission

prednisone - lympholytic - marrow sparing <5% complete remission

81% complete remission

Front 273

Alkylating agents

Back 273

1. mechlorethamine
2. cyclophosphamide
3. (mesna)
4. carmustine
5. lomiustine
6. busulfan
7. streptozocin

Front 274

antimetabolites

Back 274

1. methotrexate
2. 6-mercaptopurine
3. thioguanine
4. 5-fluorouracil
5. cytarabine
6. (leucovorin)

Front 275

antitumor antibiotics

Back 275

1. dactinomycin
2. doxorubicin
3. daunorubicin
4. (dexrozoxane)
5. bleomycin

Front 276

hormonal agents

Back 276

1. tamoxifen
2. medroxyprogesterone
3. leuprolide
4. prednisone
5. anastrozole

Front 277

vinca alkaloids

Back 277

vincristine
vinblastine

Front 278

miscellanous chemo agents

Back 278

asparaginase
hydroxyurea
procarvazine
interferon alpha
cisplatin
(amifostine)
etoposide
paclitaxel
131 I
trastuzumab
imantinib

Front 279

alkylating agents mechanism of action

Back 279

cytotoxic by ability to crosslink DNA = inhibits subsequent DNA replication and cell proliferation

Front 280

cyclophosphamide

Back 280

prodrug = req hepatic metab to form active alkylating agent

major therapeutic indications
1. chronic lymphocytic leukemia
2. hodgkins
3. non-hodgkiins lymphomas
4. multiple myeloma
5. some solid tumors
6. also used to treat RA

toxicities
DLT- BM depression

hemorrhagic cystitis - due to acrolein metab of cyclophosphamide
--> mesna is cytoprotective agent which reacts w/acrolein in the urine and detoxifies it = preventing cyclophosphamide-hemorrhagic cystitis

Front 281

carmustine and lomustine

Back 281

alkylating agents

lipophilic drugs able to cross bbb

major therapeutic indications
- primary CNS tumors

principlal toxicity
DLT - BM depression delayed and cumulative
- leukopenia and thrombocytopenia occur 4-6 wk after therapy

Front 282

mechlorethamine

Back 282

major therapeutic indication
Hodgkin dx
principal toxicity
DLT - BM depression

alkylating agent

Front 283

streptozocin

Back 283

alkylating agent

preferentially retained in pancreatic islet cells

major therapeutic indication
- metastatic pancreatic islet cell carcinoma

principal toxicity - renal

Front 284

busulfan

Back 284

alkylating agent

produces a selective depression of granulocytes in low doses

major therapeutic indication
chronic granulocytic leukemia

principal toxicities
- DLT - BM depression
- DLT - pulmonary fibrosis

Front 285

methotrexate

Back 285

folic acid antagonists

MOA
- structural analog of folic acid that binds very tightly but reversibly to the enzyme dihydrofolate reductase

- inhibites syn of thymidine,
purines,
methionine,
glycine

cells killed in S phase but self limiting

transport; high dose MTX and Rescue -
MTX is transported into cells by active transporter shared by folate and leucovorin (folinic acid)

MTX also enters cells by passive diffusion

some tumors have poor active transport and are resistant to normal doses of MTX

these may respond to a protocol = high dose MTX w/leucovin rescue
1. administer of supralethal doses of MTX for 24-36 - all cells will accumulate MTX even tumor cells lacking active transporter
2.rescue normal cells w/leucovorin - normal cells have active transporter which facilitates uptake and bypasses blockade of DHFR allowing normal cells to syn thymidine moophosphate
- tumor cells lacking active transporter will not accumulate leucovorin - killed by MTX

therapeutic indications
- gestational choriocarcinoma-low dose
- ALL (maintenance and CNS prophylaxis
0 osteogenic sarcoma
- head and neck tumors - high dose/ w/leucovorin rescue
- i ncombo protocols for breast and cervical cancers

- psoriasis- very low dose
- RA - very low dose

prinicpal toxicities
DLT - chronic low doses oral = BM depression
DLT high dose oral and IV - BM depression, oral and GI ulceration

Front 286

fluorouracil

Back 286

pyrimidine analogs - antimetab chemo

MOA
- prodruug analog of uracil - converted from FdUMP irreversibly inhibits thymidylate synthase by direct binding to enzyme

syn of dTMP (thymidine) and thus DNA syn blocked

major therapeutic indications
- colorectal cancer
- breast cancer

principal toxicities
DLT - BM depression
DLT - oral and GI ulceration

Front 287

cytarabine

Back 287

pyramidine analog - antimetab angent

MOA
- prodrug converted to triphosphate form ara-CTP which is incorporated into DNA and inhibits subsequent DNA replication

also inhbits DNA pol Beta (repair enzyme)
S phase specific

major therapeutic indication
- acute myelogenous leukemia

principal toxicity
- DLT - BM depression

Front 288

Mercaptopurine

Back 288

purine analog, antimetab agent

MOA

- converted by cellular kinases into active nt form 6-MP ribosyl phosphate act as a feedback inhibitor on initial step in purine biosyn

S phase specific drug

major therapeutic indications
- acute leukemias

principal toxicityy
DLT -BM dep

allopurinol sometimes added to 6-MP regimens to prevent hyperuricemia and uricosuria that result from massive cell killing in therapy of leukemia and lymphomas (tumor lysis syndrome)

blocks 6-MP catabolism by inhibition of xanthine oxidase - toxicity of 6-MP increased
= reduced dose

azathioprine prodrug that converted to 6-MP - used as an immunosuppressant

Front 289

thioguanine

Back 289

antipurine - antimetab chemo agent

MOA
- converted by cellular kinases to active nt form - inhibitor of initial step in purine biosyn

also incorp into DNA and inhibits subsequent DNA replication

therapeutic indications and toxicities - same as mercaptopurine -
BM depression DLT

Front 290

intercalators

Back 290

antitumor antibotics

MOA - intercalating agents bind to ds DNA by insertion btw adjacent base pairs

drugs and metabs initially color urine red

dactinomycin
anthracycline abx - doxorubicin and daunorubicin

Front 291

dactinomycin

Back 291

intercalator - antitumor abx

intercalation of the ring occurs btw adjacent C-G pairs w/polypeptide moiety lying in the minor grove
- decreases template effectiveness for RNA pol = inhibits RNA syn at low drug conc

major therapeutic actions
1. wilms tumor
2. ewing sarcoma
3. embryonal rhabdosarcoma

principal toxicity DLT - BM depression

Front 292

anthracyclin abx

Back 292

doxorubicin and daunorubicin

sim mech to dactinomycin but guanine residues not req

both RNA and DNA syn inhibited

nearly identical structures 0diff spectra of action
1. Daunorubicin - acute lymphocytic and granulocytic leukemia
2. doxorubicin - widest spectrom of action of any cancer drug 0- used for many solid tumors, malignant lymphomas, acute leukemias

principal toxicities
cardiotoxicity DLT - unique to these drugs
- total cumulative dosage abv 550 mg/m2 = greater than 50% mortality due to CHF
- mech of cardiac damage involves iron dependent generation of free radicals cause lipid peroxidation in heart cell membranes

dexrazoxane - cytoprotective agent which chelates iron and reduces cardio toxicity of anthracyclines w/o decreasing their antitumor effects
BM suppression DLT

Front 293

bleomycin

Back 293

non-intecalator - antitumor abx

commercial mixture of preps including bleomycin A2
considered to have min. myelosuppressive activity - imp in combo w/other agents in combo protocols

MOA
- fragmentation of DNA strands by generation of oxygen radical species

major therapeutic indications
- testicular carcinomas (w/vinblastine and cisplatin)
- SCC of head and neck, esophagus, skin, and genitalia

principal toxicities
DLT - pulmonary fibrosis and pneumonitis

- inactivated by deaminase enzyme - low in skin and lungs
- pt on it receiving inhalation anesthesia require red in O2 to reduce risk of pul complications

Front 294

antiestrogens

Back 294

breast cancers freq estrogen dependent

estergen receptors - prerequisite for antiestrogen therapy

Front 295

tamoxifen

Back 295

antiestrogen

MOA
- blocks action of estrogens on breast tis by antagonism of estrogen receptors

in uterus - agonist activity on estrogen receptosrs - increased risk of endometrial cancer

major therapeutic indication
advanced breast cancer

principal toxicities
- hot flashes
- transient mild thrombocytopenia and leucopenia
- vag bleeding
- skin rash
- thrombophlebitis
- retinopathy
- corneal opacity w/high dose long term therapy

Front 296

aromatase inhibitors

Back 296

post menopausal pt main sorce of androgen = adrenal gland

aromatase converts androgens to estrogens in peripheral tissues - fat mm liver

some breast carcinomas have high aromatase activity and syn sufficient estrogen to sustain growth

Front 297

anastrozole

Back 297

competitive inhibitor of aromatase

used in breast cancer in post menopausal pt

prinicpal toxicities
- hot flashes
- bone pain
- dyspnea

Front 298

medroxyprogesterone acetate

Back 298

major indication
-endometrial carcinoma that cannot be tx by surgery and/or radiation
- disseminated breast carcinomas

principle toxicities
- mild fluid retention
- hypercalcemia

Front 299

leuprolide

Back 299

gonadotropin releasing hormone analogs

MOA
- agonist analog of GnRH
- biphasiceffect reduces secretion of LH and FSH
- testosterone syn and estrogen syn = reduced

major therapeutic indications
- prostate and breast cancers

principle toxicities
- transient flare of dx may occur due to initial increased FSH/ LH
- hot flashes
- peripheral edema
- infertility

Front 300

prednisome

Back 300

MOA
- glucocorticoids acting through their specific receptors are cytolytic to lymphocytes
- useful in reducing radiation edema in head areas
- useful for palliative relief in severly ill ppt include fever suppression, restoring appetite, lost wt, strength and sens of well being
NOT MYELOSYPPRESSIVE ( neutrophils, rbc and platelets not reduced

therapeutic inciations
- induction of remission in:
- ALL
- CLL
- myltiple myeloma
- hodgkins dx
- lymphocytic lymphoma
- histiocytic lymphoma
- advanced breast cancer

principal toxicities
- suppression of immune response - oportunistic infections
- osteoporosis
- gi ulceration
- psych disorders
- glaucoma/cateracts
- Na+/H2O retention - edema
-suppresion of hypothalamic-pit-adrenal axis
- impaired wound healing

Front 301

vinca alkaloids

Back 301

act by inhibiting mitosis

bind to mt and cause depolymerization --> leading to reversible metaphase arrest

M phase specific

Vincristine and vinblastin

Vincristine is marrow-sparing for use in combo protocols

Front 302

vincristine

Back 302

indications - ALL in combo w/prednisome
- hodgkins
- AML
- non-hodgkins lymphomas

principal - peripheral neuropathy DLT - manifests as loss of deep tendon reflexes, and foot drop

Front 303

vinblastine

Back 303

hodgkin and non-hodgkin's lymphomas
testicular carcinoma

DLT - BM depression

Front 304

cisplatin

Back 304

MOA
- a platinum complex w/ significant antitumor activity
- kills cells in all stages of cell cycle
- bonds to DNA and can form cross links when it loses both chloride atoms

therapeutic indications
- testicular tumors in combination with etoposide or vinblastine and bleomycin = 80% remission)

advanced ovarian adenocarcinoma

bladder cancer

non SC lung cancer

peripherial toxicities
- Nephrotoxicity - DLT
- BM (myelosuprresion

= Amifostine - cytoprotective agent - reduces cisplatin inducednephrotoxicity

Front 305

paclitaxel

Back 305

MOA
- promotes unreg tubulin polymerization and stabilizes mt by inhibiting depolymerization - arresting mittotic cells
-M phase specific

major therapeutic indications
- metastatic ovarian carcinoma
- activity in breast cancer and non-small lung cancer

principal toxicity
- bone marrow depresion - DLT

Front 306

etoposide

Back 306

MOA
- binds mt - no mitotic arrest
- cells are inhibited from entering mitosis and arrested in G2 phase
- also interacts w/DNA topoiisomerase II stimulating unwinding of DNA and cleavage

major therapeutic indications
- testicular cancer
- lung cancer - SCC
- kaposi sarcoma

principle toxicity
- BM depression - DLT

Front 307

asparaginase

Back 307

MOA
- some neoplastic cells lack the ability to syn asparagine and req it for prot syn
- asparaginase hydrolyzes asparagine depriving tumor cell of a supply of req AA

therapeutic indication
- ALL

principal toxicities
- hepatotoxicity
- anaphylactic rxns

Front 308

hydroxyurea

Back 308

MOA
- inhibits ribonucleotide reductase ultimately blocking DNA syn
- S phase specific

therapeutic indication
- busulfan resistant chronic granulocytic leukemia
- tx of sickle cell dx

prinicple toxicity
- BM depression - DLT

Front 309

procarbazine

Back 309

MOA
- undergoes metabolic activation and reacts w/DNA causing extensive damage

therapeutic indication
- hodgkin lymphoma
- non hodgkin lympoma

prinicple toxicity
- BM depression - DLT

Front 310

interferon alpha-2b

Back 310

MOA
- naturally produced by lymphocytes, macrophagees, leukocytes and fibroblasts
- usually in response to viral infections
- interferons have immunomodulatory activity resulting in antiviral and antitumor actions
- tumoricidal effects due in part to stimulation of natural killer T cells

therapeutic indication
- hairy cell leukemia - pt over 18,
- kaposi sarcoma

prinicple toxicity
- BM depression
- neurotoxicity
- flu-like sx

Front 311

131 I

Back 311

MOA
- Radioactive iodide accumulated in the thyroid gland
- intense local irradiation kills nearby thyroid tumor cells

major therapeutic indication
- thyroid carcinoma

principal toxicity
- hypothyroidism

Front 312

trastuzumab

Back 312

MOA
- humanized monoclonal Abthat binds to the GF receptor Her2/neu (ErbB2)
- results in inhibition of cell prolif and mediates ab-dependent cellular cytotoxicity

therapeutic indication
- metastatic breast cancer overexpresing Her2/neu protein

prinicple toxicity
- cardiotoxicity - ventricular dysfn and CHF
- hyper sensitivity rxn

Front 313

imantinib

Back 313

MOA
- a prot tyrosine kinase inhibitor that inhibits the abn tyrosine kinases (Bcr-Abl) created by philadelphia chrom abn

inhibits prolif and induces apoptosis in Ph+ tumor cells

major therapeutic agents
- philadelphia chrom positive chronic myeloid leukemia
- kit (CD117)- positive gastrointestinal stromal tumors

principal toxicity
- neutropenia and thrombocytopenia
- fluid retention resulting in pleural effusion or pulmonary edema

Front 314

immunostimulants

Back 314

interferon - gamma
interleukin - 2
BCG

Front 315

immunosuppressives

Back 315

cyclosporine
tacrolimus
muromonab -CD3
sirolimus
glucocorticoids
interferon- beta 1
Rho (D) immune globulin

Front 316

interferon gamma

Back 316

MOA
- dec suppressor T cell fn and inc cell-mediated immunity and NK activity
- potent phagocyte activating effects

therapeutic indication
- tx of chronic granulomatous dx - inherited disorder w/ deficient phagocytic oxidative metabolism

principal toxicities
- fever
- headache
- flu
- use w/caution in pt w/seizure disorders
-> cardiac dx
-> exhibiting myelosuppression

Front 317

BCG

Back 317

attenuated mycobacterium bovis - bacillus calmette guerin strain

MOA
- BCG promotes local inflammatory rxn w/histiocytic and leukocytic infiltration in the bladder

- effects assoc w/ reduction of superficial cancerous lesions

therapeutic indicatoin
- intravesical use in tx of primary and relapsed carcinoma in situ of the urinary bladder

principal toxicities
- dysuria, irritative bladder sx - hematuria, cystitis, malaise, fever, anemia

systemic inf w/BCG

Front 318

Interleukin - 2

Back 318

MOA
- cytokine that stimulates T helper cells and T cytotoxic cells to differentiate and to rpoliferate
- inc the toxicity of natural killer cells and LAK

adoptive therapy using LAK cells, peripheral lymphs are isolated from pt tx w/IL 2 in vitro to activate pop of LAK cells and reinfused back into pt

LAK cells then attack the tumor cells
15-30 % complete response

therapeutic indications
- metastatic renal cell carcinoma
- metastaticmelanoma
- investigational for colon and non-hodgkin lymphoma

principal toxicities
- pulmonary edema (congestion dyspnea
- CV - hypotension, tachycardia
- capillary leakage syndrome
- renal toxicity
- hematologic - anemia, leucopenia
- thrombocytopenia
- CNS effects - hallucinaitons, delusions, confusion frequent = due to cerebral edema

Front 319

cyclosporine

Back 319

cyclic peptide isolated from fungus T. inflatum gams - prolongs survival of allogenic transplants in skin, heart, pancreas, BM, sml int, and lungs

suppresses some humoral immunity and greater extent cell mediated rxn = allograft rejection, delayed hypersensitivity and graft vs host dx

MOA
- binds specific intracellular prot receptors = cyclophilins
- cyclophilin--cyclosporine ocmplex potent inhibitor of the prot phosphatase calcineurin
= calcineurin req in T cell receptor pathway in order to induce expression of gene for IL-2 = cyclosporine inhibits prod of IL-2 === activation and prolif of T cells is inhibited

major therapeutic indications
- prophylaxis of organ rejection in kidney, heart, and liver allogenic transplants (glucocorticooids)
- tx chronic rejection in pt previously unresponsive to other immunosuppressive agents

unlabled uses =
- aplastic anemia
-atopic dermatitis
- crohns dx
- ulcerative colitis
- Grave's ophthalmopathy
- insulin-dependent DM
- lupus
-MS
- myasthenia gravis
-RA

principal toxicities
- renal toxicity (25-49%)
- elevated BUN in renal transplants does not nec indicate rejection
- nephrotoxicity often responds to a reduced dose of cyclosporine
- concomitant admin of diltiazem reduces cyclosporine metab = elevating cyclosporine concentrations
- allows lower dose of cyclosporine to be used w/attenuated nephrotoxicity

Front 320

tacrolimus

Back 320

MOA
- macrolide abx
- structually dif from cyclosporine but similar MOA
- binding to immunophiliins the complex inhibits calcineurin
- 100x as potent as cyclosporine A
- alt w/less nephrotoxicity

therapeutic indications
- rejection in liver transplants
- investigational for heart, kidne, BM, and pancreas

principal toxicities
- renal and neurotoxicity

Front 321

prophylaxis of graft vs host dx in BM transplant

Back 321

methotrexate and cyclophosphamide in combo w/cyclosporine

Front 322

muromonab-CD3

Back 322

MOA
- murine monoclonal ab to CD3 ag of T cells
- blocks CD3 fn preventing Ag recognitition in T cell activity
- immunosuppression

therapeutic indications
- acute renal allograft rejection
- steroid-resistant acute cardiac and hepatic allograft rejection

principal toxiciteis
- cytokine release syndrome
-attributed to release of cytokines by activated lymphs and monocytes
- mild = flu-like
- severe - life threatening shock like rxn
- hypersensitivity rxn to mouse proteins - serious sometimes fatal anaphylactic shock

- opportunistic inf w/herpes or fungi most frequent

Front 323

sirolimus (rapamycin)

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MOA
- antiprolif drug binds to an immunophilin and the complex inhibits prot kinase that is central to cell cycle progression = mTOR (molecular target of rapamycin
- inhibition blocks cells at the G1->S phase transition
T cell activation and prolif are inhibited

Therapeutic indications
- prophylaxis of organ transplant rejection in combination w/cyclosporine or tracolimus plus glucocorticoids

principal toxiciteis
- myelosuppression - anemia, leukopenia, thrombocytopenia

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glucocorticoids

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MOA
- suppress the rxns of inflam
- exhibit cytolytic activity toward immature T cells
- general immunosuppressive and anti-inflam agents

therapeutic indication
immunosuppressives - rheumatic disorders
- prophylaxis of organ rejection in allogenic transplants+ cyclosporine
- acute graft rejections
prinicple toxicity
-see endocrine pharm

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Interferon beta 1

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MOA
- immunosuppressant actions on cell mediated immunity

- increase T suppressor activity
- decrease cytokine release

therapeutic indication
- tx of relapsing-remiting MS

toxicities
- myalgia
-injection site rxns
- flu like symptom complex

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Rho (D) immune globulin

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used in Rho (D) neg mother s previously exposed to Rho (D) positive blood ( fetal or during birht

admin ab to Ag eliminates risk of hemolytic dx during subsequent pregnancies

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3 componentsof thrombosis

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1. coagulation cascade
2. platelet pathway
3.vessel wall its self

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coagulation cascade initiation

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Tissue factor binds to circulating factor VII/VIIa

TF/VIIa complexes catalyze conversion of both X and IX into Xa and IXa

IXa key product and Xa in sml quantities

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extrinsic tenase complex

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TF/VIIa/IX/X

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coagulation cascade amplification

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produces large quantities of thrombin IIa

starts w/ IXa generated by VIIa/TF on platelet surface, the IXa/VIIIa/Ca++ = intrinsic tenase and converts large quantities of X--> Xa

amplification occurs as Xa binds Xa/Va/Ca++ = prothrombinase complex

also triggered by conversion of XII --> XIIa converts XI-->XIa activates IX--> IXa

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intrinsic tenase complex

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IXa/VIIIa/Ca++

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propagation of coagulation cascade

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Xa/Va/Ca++ complex = prothrombinase complex

catalytic conversion of fibrinogen to fibrin

requires cross-linking of fibrinby factor XIIIa a transglutaminase - cross-linked fibrin insoluble mesh can trap platelet aggregates = thrombus

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antithrombin

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serine protease found in high concentrations in plasma

inactivates thrombin IIa and factor Xa

preventing coagulation in intrinsic pathway

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tissue factor pathway inhibitor

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protease inhibitor in plasma and syn by endothelil cells


inactivates both TF/VIIa complex and factor Xa

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activated protein C

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includes prot C, prot S and thrombomodulin

system inactivates factor VIIIa
responsible for confiningthrombosis to site of vascular inj

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thrombin

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IIa catalyzes conversion of fibrinogen to fibrin and cleaves factor XIII to XIIIa which cross links fibrin

thrombin is self enhancing procoagulant by converting XI--> XIa = key factor responsible for amplification

IIa activates platelets by binding to protease activated receptor PAR-1 PAR-4

self regulating - activates prot C and PRot S
stimulates endothelium to produce prostacyclin PG12 and NO endothelial derived relaxing factor
= neg feedback to further suppress coagulation

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avg platelet lifespan

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7-10d

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platelet adhesion

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adhesion to collagen via
1. GP Ia/IIa
2. GP IV
3. GP VI
integrins at low shear stress

at site of vascular inj = GP Ib/IX/V integrin <--> vWf

both endothelial cells and megaklaryocytes release vWf
GPIb complex vWf key in platelet adhesion

pasisve doesn't req E

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Platelet activation

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prepackaged GP IIb/IIIa receptors externalized and undergo conformational change
--> enables binding of fibrinogen and vWf and other adhesion factors

secretion of ADP, ATP, serotonin, Ca++. adhesion prot, and coagulation factors from alpha granules

ADP, thrombin, and TXA2 amplify platelet response recruiting additional platelets

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platelet aggregation

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mediated by binding of activated
GP IIb/IIIa receptors to dimeric fibrinogen by recognizing the RGD tripeptide sequence of fibrinogen Arg-Gly-Asp

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vascular endothelium

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monolayer

regulates thrombosis
syn NO -= vasodilates and inhibits platelets

PGI2 endothelial derived vasodilator and inhibitor of platelet aggregation (NOT adhsion) = counterbalanced by endothelial derived vasoconstrictors = endothelin 1 and TXA2

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risk factors for CVD

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hypertension
cigarette smoking
obesity
phys inactivity
dyslipidemia
DM
microalbuminuria est GFR< 60 ml/min
older than 55 men
older than 65 women
fam history of premature CVD

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significant predictor of death from CHD

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elevated systolic BP

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target end organ damage from HTN

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of cardiovascular and renal diseases, including retinopathy,
peripheral vascular disease, stroke
coronary heart disease
heart failure
left ventricular hypertrophy
renal failure.
Signs of target-organ damage herald a poorer prognosis and may present in the heart, blood vessels, kidneys, brain, or eyes. Later consequences include cardiac, cerebrovascular, vascular, and renal morbidities and death

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goals of BP therapy

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reduce CVD and renal morbidity and mortalit y
lower BP to <140/90

if diabetes or chronic kidney dx - less than <130/80

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V hypertension

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salt-volume hypertension

low plasma renin values

salt sensitive
volume excess

old
female
obese
black - race trumps all others

V drugs
- reduce sodium/water
- diuretics (thiazide/loop)
- calcium channel blockers

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R hypertension

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renin-angiotension HTN

high rening
salt resistant
neurohumoral vasoconstrictor excess

young
male
lean
white

R drugs
- reduce renin-angiotensin activity
- ACE inhibitors
- Ca channel blockers
- renin inhibitors
- betablockers

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ALLHAT trial 2000

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dozazosin (alpha 1)
tx arm was discontinued due to higher incidence of stroke compared to chlorthalidone (thiazide) alone

no difference between amlopidine (ca channel blocker), lisinopril (ace inhibitor) and chlorthalidone for primary outcome

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HOT trial 1998

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optimal diastolic BP reduction was to 80-85 mm Hg
= dec MI, stroke , and CV deaths

small reductions in BP clinically imp in terms of outcome

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SHEP trial

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prevention of stroke by antiTHN drug tx in older persons w/ isolated systolic htn

also reduced risk for CHD
CHF
and CVD
dec death

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ACCOMPLISH trial

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benazepril (ACE inhibitor) plus
Amlodipine (Ca+ channel blocker)
assoc w/significantly less CV events than benazepril plus hydrochlorothiazide

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antithrombin

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serine protease
made by liver
inactivates factor Xa and IIa

activated can only inactivate Xa
- ternary complex forms w/heparin antithrombin and thrombin

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antithrombin depenent anticoags

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unfractionated heparin

low molecular wt heparins - enoxaparin

fondaparinux

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heparins

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glycoaminoglycans w/ a unique pentasaccharide structure having affinity for antithrombin

bind antithrombin - conformational change that enhances protease antithrombin activity toward factors Xa and IXa and IIa 300-1000 fold

activated can only inactivate Xa
- ternary complex forms w/heparin antithrombin and thrombin
- heparin must contain at least 18 saccharide units to form complexes

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fondaparinux

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pure inhibitorof Xa

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direct thrombin inhibitors

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argatroban
dabigatran
bivalirudin

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thrombin mediated platelet activation

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cleaving G-prot coupled PAR-1 and PAR-2 receptors

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bivalirudin

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inhibits thrombin mediated platelet activarion via PAR-1 receptor

but platelet activation still occur via PAR-4

bind to an active site and an exosite

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argatroban

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binds active site on thrombin

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dabigatran

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oral direct thrombin inhibitor - reduce stroke and embolic events
in pts w/ nonvalvular atrial fib

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platelet activation inhibitors

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aspirin
clopidogrel
prasugrel