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281 Cards in this Set
- Front
- Back
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Na channels are targets for
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local anesthetics
antiepileptics antidysrhythmics |
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Ca channels are targets for
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antihypertensives
antianginals antidysrhythmics |
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3 L-type Ca channel blockers
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nifedipine
verapamil diltiazem |
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L-type Ca channel blockers are so named because
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they inactivate very slowly once in A-state relative to NA channels
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Actions of L-type channel blockers
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1. Slows recovery from I to R state
2. Prevents Ca entry during A-state |
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Mechanism of L-type Ca channels
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Resting state = no Ca entry.
Activated state = Ca enters and binds calmodulin Inactivation = I-II linker blocks channel Facilitation = phosphorylation of subunit III by CaMKII increases probability of channel returning to R state |
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Mechanism for L-type channel phosphorylation
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1. NE binds to beta-1 receptor
2. Beta-1 receptor linked G protein activates its adenyl cyclase 3. Adenyl cyclase uses ATP to make cAMP 4. cAMP activates A-kinase 5. A-kinase phosphorylates Ca channel using ATP |
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Direct activation mechanism for SR Ca release
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Ca enters via Ca channel and activates ryanodine receptor (RyR) on SR
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Indirect activation mechanism for SR Ca release
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1. Alpha-1 adrenoreceptor activation activates G protein alpha subunit
2. G protein alpha subunit activates PLC 3. PLC cleaves PIP2 into DAG and IP3 4. IP3 actiavtes IP3 receptor on SR |
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K channel are targets for
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oral hypoglycemics (sulfonyl ureas)
class III antidysrhythmics vasodilator K channel openers |
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Voltage gated K channels mediate 2 things
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1. phase 3 of cardiac action potential
2. repolarization of neurons after AP |
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Ca-gated K channels function to
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Terminate excitatory processes caused by increased intracellular Ca
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2 examples of ligand-gated K channel functions
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1. Acetylcholine causes atrial hyperpolarization
2. ATP dependent K channels in the pancreas cause insulin release from beta-cells |
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Acteylcholine-mediated atrial hyperpolarization mechanism
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1. ACh interacts with M2 receptor in atria, activating Gk G-protein
2. Gk's beta-gamma subunit activates GIRK, a K channel 3. GIRK opens causing K efflux |
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Insulin release mechanism
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1. ATP dependent K channels close when internal ATP increases due to high plasma glucose
2. K buildup in the cell causes depolarization 3. Ca channels open upon depolarization 4. Ca influx causes insulin secretion as granules fuse to membrane |
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Na/K ATPase swaps __ Na for every ___ K.
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3 Na ions out; 2 K ions in
* Na leaves against concentration gradient and requires ATP |
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Ca/Mg-ATPases, 2 types
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1. Plasma membrane pump (PMCA)
2. SR pump (SERCA) |
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PMCA
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- mediate Ca extrusion from the cell
- activated by Ca binding to calmodulin |
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Calmodulin decreases intracellular Ca entry in 2 ways
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1. Shuts down Ca entry via I-II linker blocking channel
2. Pumps Ca out of the cell via PMCA activation |
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SERCA
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mediates Ca sequestration into SR
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SERCA activation mechanism
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1. Phosphorylation of phospholamban in cardiac SR by A-kinase
2. Phospholamban phosphorylation increases SERCA activity 3. Increase Ca sequestration means stronger contractions |
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Phospholamban
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Associated with SERCA
- normally inhibits SERCA activity - phosphorylation by A-kinase removes inhibition |
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Beta-1 receptor stimulation has positive inotropic effect via 2 mechanisms (both involving A-kinase)
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1. Increased Ca entry via L-type Ca channel phosphorylation
2. Increase Ca storage via SERCA for increase contraction strength |
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H/K ATPase mediates
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Parietal cell acid secretion
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Omeprazole
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- blocks H/K ATPase pump to inhibit gastric acid secretion
- selective for stomach by only being active at acidic pHs |
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Na/Ca Exchanger mediates
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Ca removal from myocytes after cardiac contraction
***driving force is Na gradient Exchanges 3 Na in for every 1 Ca out |
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Na/K/2Cl Cotransporters located in
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Ascending loop of Henle
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Na/K/2Cl Cotransporters targeted by
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Loop diuretics (eg. furosemide)
Na gradient is driving force |
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Typical angina
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Increased O2 demand and decreased O2 supply (usually due to atherosclerosis, etc)
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Variant Angina
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Vaused by vasospasm of the coronay artery
- chest pain while at rest |
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Therapeutic arims for typical and variant angina
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Typical: increase coronary bloodflow and decrease myocardial workload
Variant: reduce or prevent coronary vasospasm |
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Typical angina is often associated with what EKG result?
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ST segment depression
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Organic nitrate activates cGKI using what mechanism?
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- GTN undergoes intracellular activation to NO
- NO activates the soluble isoform of guanylyl cyclase, resulting in increasing cGMP - cGMP activates its kinase, cGKI |
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cGKI activates 2 molecules to inhibit Ca-dependent pathway of muscle contraction
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1. RGS2 (acts on G-alpha subunit_
2. IRAG (acts on SR) |
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2 ways NO has an anti-anginal action
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1. Vascular Dilation:
- venodilation*** (unique) reducing preload - arteriolar dilation reducing afterload and peripheral resistance 2. Improved perfusion of ischemic myocardium by increasing collateral flow (***NO uniquely selective for ischemic myocardia) |
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Sublingual GTN lasts ____ and has peak effects at _____.
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1. 20-30 minutes only
2. 2-3 min |
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GTN is usually given
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sublingually (more intense, predictable)
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ISDN (isosorbide dinitrate) is usually given
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orally
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ISDN undergoes 1st pass metabolism in which organ?
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Liver
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Glutathione transferase metabolizes
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ISDN
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GTN ointment uses ___ GTN, which lasts for at least _____.
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2% GTN, lasting for at least 4 hours
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Transdermal GTN patches
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-slow onset
- used for chronic angina - rapid tolerance develops (must take off for a few hours each day) |
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Amyl, butyl nitrite
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Used as recreational sexual aids
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IV GTN is used in
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heart failure
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Adverse GTN effects
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Due to vasodilation
- headaches - flushing - cerebral ischemia, postural hypotension Methemoglobinemia |
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GTN causes methemoglobinemia because
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It mediates Fe2 -> Fe3
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NaNO2 (sodium nitrite) is used as an antidote for
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cyanide poisoning
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Nitrate tolerance with chronic oral ISDN administration
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1. decreased antianginal effect
2. decreased hemodynamin effect |
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4 Mechanisms of GTN Tolerance
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1. Decreased vascular biostransformation of GTN to NO (Most important!)
2. Altered guanylyl cyclase 3. Increased phosphodiesterase activity 4. Increased oxidative stress |
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Isosorbide mononitrate is sometimes used instead of ISDN because it has
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a smaller 1st pass effect in the liver
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Ca influx through voltage-dependent Ca channels in cardiac cells is required for
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1. contraction of cardiac myocytes (phase 2)
2. conduction in SA and AV nodes (phase 0) |
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Ca entry blockers affect cardiac function in 3 ways
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1. negative inotropic effect
2. decreased pacemaker rate at SA node (so HR drops) 3. decreased conduction through AV node |
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Nifedipine differs from verapamil and diltiazem in 3 ways
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1. Nifedipine has distinct BS
2. Nifedipine has no cardiac effects at clinical doses, only dilating VSM 3. Nifedipine causes reflex tachycardia since it does not block anything in the heart |
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Ca entry blockers are the drug of choice for
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Variant angina since it prevents coronary vasospasm.
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Cardiac glycoside chemistry
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sugar attached to a steroid with an unsaturated lactone ring via a glycosidic bond
1 unsaturated lactone ring essential 2. angle of C and D rings in steroid is unique 3. pharmacological activity resides wholly in the aglycone (ie. non-sugar part) 4. sugar determines water, lipid solubility |
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Source of digitalis
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Foxglove plant
- purple = digitoxin only - white = digitoxin, digoxin, deslanoside |
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CHF is caused by
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CAD, myocardial infacts, hypertension.
Results in decreased contractility, resulting in insufficient CO and subsequent compensatory mechanisms by the heart. |
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Hypertension is the ___ leading cause of global disability.
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3rd
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HTN is caused by
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the force of blood pushing perpendicularly against the vessel wall
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WHO estimates HTN is the ___ risk for death in women and the ___ risk for death in men.
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Leading for women; 2nd for men.
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___ of CVD is attributable to HTN
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50%
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People have a high risk for developing HTN later in life even if they're normotensive at middle age. ___ of people who have normal BP at middle age will develop hypertension prior to death.
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90%
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Target organ damage in HTN (6)
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1. Cerebrovascular disease
2. Hypertensive retinopathy 3. LVH 4. CAD 5. Chronic kidney disease 6. Peripheral artery disease |
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Intermittent claudication is associated with ____. Define it as well.
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Associated with peripheral artery disease due to HTN.
It's a cramping of the leg muscles. |
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Chronic kidney disease is one of the results of chronic HTN. Name 2 results.
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1. Hypertensive nephropathy; results in low GFR.
2. Albuminuria. Blood proteins in urine; they also get taken back up into nephrons, which slowly kills them. |
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Hypertrophic cardiomyopathy
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Genetic disease.
Unlike LVH, it has nothing to do with HTN. |
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Pulse pressure
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Difference between systolic and diastolic pressure.
High pulse pressure increases damage in vessels since waves of blood are higher. |
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High pulse pressure risks for women vs men.
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Women less at risk before 50 but more at risk after.
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Prevention of high pulse pressure
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Exercise, which decreases gradual rigidity of aortic wall.
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Classes of HTN
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optimal
normal high-normal grade 1 (mild) grade 2 (moderate) grade 3 (severe) isolated systolic HTN after grade 1 intervention is necessary |
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Systolic blood pressure changes and age
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Very high systolic BP when young results in high pulse pressure, which is deadly in those 55 and under.
For older people, increased systolic pressure is not associated with greatly increased risk of mortality. ***Decreases in systolic pressure is what decreases mortality. Diastolic drops are limited in their effectiveness. |
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% Canadians with HTN
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- less than 10% of those under 30
- more than 50% of those 65-74 - almost everyone by 85 |
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Primary vs secondary HTN
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1. Primary = idiopathic
2. Secondary = due to known pathology |
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3 Causes of Secondary HTN
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1. Pheochromocytoma
2. Renal Stenosis 3 Aldosteronism |
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Pheochromocytoma
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adrenal tumour resulting in creased catechoamine secretion from medulla
NE acting on alpha 1 receptors results in vasoconstriction and huge BP increase |
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Renal STenosis
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partial occlusion of renal artery, increasing renal vascular resistance
body adapts by increasing RAS system activity ang II increase causes Na resabsorption and kidney vasoconstriction |
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Aldosteronism
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excess aldosterone leads to excess Na reabsorption
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BP Threshold Values for Treatment
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- normally over 140/90
- patients with target organ damage start at 140/90 even if no HTN - patients with known atherosclerosis should be treated even if BP is normal - patients with diabetes or chronic kidney disease should be treated if over 130/80 |
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___% of Canadians with HTN have other cardiovascular risk factors.
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90%
NB. Canada also has the best rate of treated and controlled HTN in the world! |
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Normal long term regulation of arterial pressure is controlled by the kidney and has 3 components.
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1. Vasoconstrictor tone
2. Blood volume 3. Vascular structure ***Cardiac output is NOT involved since only acts on short term basis and neither is the baroreceptor reflex. |
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Only time cardiac output has long term effect on BP.
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In severe congestive heart failure, CO insufficient so BP pathologically drops to reduce work for the heart. Treat by decreasing BV.
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3 factors involved in regulating vasoconstrictor tone.
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1. Local regulatory mechanisms
2. Neural sympathetic NS stimulation via alpha receptors 3. Humoral has insignificant role. |
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Kidney tubular reabsorption functions to
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establishes the set point for long term levels of arterial pressure with respect to sodium balance
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Vascular structure
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some hypertensive patients have genetically altered vasculature
vascular hypertrophy increases vascular resistance |
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Average vascular hypertrophy and increased resistance
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8% narrower vessels but 40% more resistance!
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2 Classes of Drugs Targeting Blood Volume
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1. Diuretics
2. RAS Inhibitors Drugs cause initial drop in BV, body adapts and BV returns to normal but BP drops. |
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3 types of RAS inhibitors
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1. ACE inhibitors
2. AT1 receptor antagonists (ARBs) 3. Renin Inhibitors *Beta-blockers indirectly do so by decreasing SNS-mediated renin release. |
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RAS pathway
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Angiotensinogen
Angiotensin I (inactive!) Angiotensin II Increased BP set point for blood volume. |
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3 Key Effects of Ang II
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1. Na retention
2. Renal vasoconstriction 3. Cardiovascular tissue effects BUT concentrations of And II in blood are insufficient for generalized vasoconstriction unless massive bleeding occurs. Only localized vasoconstriction. |
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Angiotensin I and SNS positive feedback look
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Ang I increases SNS activity, which in turn increases renin release.
Renin activates angiotensinogen to ang I. |
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Only 2 classes of drugs decrease both vasoconstrictor tone AND mortality.
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1. Ca channel blockers
2. Indirect acting agents - B blockers, RAS antagonists, diuretics These all decrease SNS activity and thus renin release. |
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Amlodpine
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Ca channel blocker
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Alpha-adrenergic blocker in treating vasoconstrictor tone
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Too broad an effect to give alone but can give incombination with other drug.
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Hydralazine
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Vasodilator ineffective in treating vasoconstrictor tone
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Drugs used to treat LVH and vascular structural changes
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RAS inhibitors > Ca channel blockers > Beta-blockers and other diuretics
Some activate trophic systems to don't decrease LVH as well even if they decrease BP similarly. |
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Diuretics alter rate of urine production by
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1. Affecting glomerulat filtration rate in the short term.
2. Affecting renal tubular mechanisms in the long term. |
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Sites of Na Reabsorption
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65% in proximal convoluted tubule
20% in ascending loop of Henle 10% in early distal convoluted tubule Manipulation of 1 site causes compensation at all other sites! |
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Drugs affecting GFR
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***Short term use only
1. Cardiac inotropic drugs 2. Drugs that alter renal vessel bloodflow 3. Drugs that affect systemic BP, indirectly affecting bloodflow. |
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7 Classes of drugs affecting renal tubules
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1. thiazides
2. loop diuretics 3. K sparing 4. aldosterone antagonists 5. osmotic diuretics 6. carbonic anhydrase inhibitors 7. RAS inhibitors |
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Thiazides
- site of action - mechanism - uses |
- Site: distal convoluted tubule
- Mech: inhibits NaCl reabsorption - Used for HTN and CHF |
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Loop Diuretics
- site of action - mechanism - uses |
- Site: ascending loop of Henle
- Mech: inhibits Na-K-2Cl co-transporter - Used for short term edema, hypercalcemia, CHF * long term = K wasting! (leads to arrhythmias |
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K wasting
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Thiazides and loop diuretics prevent Na reabsorption from urine.
Urine has lots of Na and Na/K exchangers exchange Na for K. Can lead to arrhythmias. |
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Hydrochrolothiazide
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Thiazide
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Furosemide
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Loop diuretic
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K-Sparing
- site of action - mechanism - uses |
- Site: distal nephron (5% site)
- Mech: inhibits electrogenic Na reabsorption - Used to prevent hypokalema |
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Aldoesterone Antagonists
- site of action - mechanism - uses |
-Site: distal nephron's collecting tubules
- MechL competitive antagonism of aldosterone - Used for HTN, CHF |
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Amiloride
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K-sparing diuretic
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Triamterene
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K-sparing diuretic
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Spironolactone
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Aldoesterone antagonist
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Osmotic Diuretics
- site of action - mechanism - uses |
-Site: throughout nephron
- Mech: sits in tubule and draws water out, protecting Na - Used to prevent renal failure and decrease intracranial/intraocular pressure * work for 24hrs before body adapts |
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Mannitol
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Osmotic diuretic
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Carbonic Anhydrase Inhibitors
- site of action - mechanism - uses |
- Site: proximal tubule; also in the eye
- Mech: increases bicarbonate excretion - Used for bicarbonate elimination, urinary alkalinization, glaucoma ***thiazides are carbonic anhydrase inhibitors * not long term |
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Acetazolamide
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Cabonic anhydrase inhibitor
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RAS Blockers
- site of action - mechanism - uses |
-Site: proximal tubule and renal post-glomerular resistance vessels
- Mech: decreases Ang II-mediated proximal tubule sodium reabsorption (decreases Na/H pump and Na/K ATPase activity); alters intrarenal hemodynamics - Used for HTN, edema, CHF, diabetes, renal failure, post MI |
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Who introduced cocaine to Western medicine?
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Freud
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3 methods of local anesthesia
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1. physical (trauma, hypothermia, anoxia)
2. chemical (alcohol, phenol) 3. drugs |
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2 ways of classifying local anesthetics
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1. Duration
2. Structure |
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3 Durations of local anesthetics
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1. Short (procaine)
2. Medium (lidocaine, mepivacaine) 3. Long (bupivacaine, tetracaine, ropivacaine) |
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Ester Local Anesthetics
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Procaine
Tetracaine Cocaine |
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Amide Local Anesthetics
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Lidocaine
Bupavicaine Ropavicaine Mepivacaine |
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All local anesthetics are salts of ___.
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A weak base
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The ionized form of a local anesthetic functions to _____ while the unionized form functions to ____.
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1. Bind to receptor
2. Cross the membrane More alkaline environment means a higher % of chemical in non-ionized form that's able to cross membrane. Why? pKas (50% ionization) of most local anesthetics are higher than physiological pH |
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Local anesthetic onset time is determined by
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pKa and tissue pH
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Potency of local anesthetic is determined by
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lipid solubility
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Duration of local anesthetic is determined by
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protein binding
- depends on bloodflow to area - can increase duration using vasoconstrictors |
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Local anesthetic metabolism
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1. Esters are hydrolyzed in plasma except cocaine, which is metabolized in the liver.
2. Amides are enzymatically metabolized in the liver. |
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3 Types of Local Anesthetic Toxicity
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1. High plasma level due to overdose or IV injection
2. Allergies (rare with amides but more common with esters) 3. Injection site (inadvertant spinal injections) |
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Minimizing Local Anesthetic Toxicity (3 ways)
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1. Limit dose
2. Minimize absorption (aspirate on syringe, vasoconstrictors) 3. Prophylactic benzodiazepine |
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Toxicity Symptoms for Local Anesthetics
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1. Early excitatory symptoms:
- numbness - visual disturbances - lighthdeadedness, tinnitus - twitching 2. Serious: - loss of consciouness - convulsions - coma -respiratory arrest - cardiovascular depression and death |
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Treatment for Local Anesthetic Toxicity
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A - airway
B - breathing C - circulation (fluids, vasopressors) D - drugs to control seizures |
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Clinical uses for local anesthetics
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- topical (skin, airway)
- infiltration - peripheral nerve block (regional anesthesia) - plexus block - IV (Bier ) block to anesthetize a limb - central neural blocks (epidural for pregnancy, spinal) |
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First coined term anesthesia
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Dioscorides
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Conducted 1st public demonstration of general anesthesia
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Morton
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Anesthesia
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State of loss of sensation used to protect patient from the pain and physiologic trespass associated with surgery.
Secondary purpose is to provide a still surgical field. |
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4 Key Components of Anesthesia
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1. Unconsciousness
2. Muscle relaxation 3. Blockade of autonomic reflexes 4. Analgesia |
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2 Classes of Inhaled Anesthetics
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1. Gases: N2O, cyclopropane, xenon
2. Volatile liquids: halothane, isoflurane, sevoflurance, desflurane, ether, methoxyflurane, chloroform |
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Intravenous Anesthetics (5)
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- barbiturates
- propofol -benzodiazepines - ketamine -methohexital |
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Phases of a General Anesthetic
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1. Induction (renders patient unciousness)
- IV or inhaled - use blunt intubation to secure airway 2. Maintenance - inhaled generally 3. Emergence - pharmatokinetics (elimination) OR use drug antagonists |
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Inhaled anesthetic chemistry
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Generally carbon-fluoral chains
Delivered from lungs -> blood -> brain Can determine concentration from partial pressure |
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Minimum Alveolar Concentration
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The concentration of inhaled anesthetic required to prevent 50% of subject from responding to a painful surgical stimulus with gross purposeful movements.
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Mechanism for Inhaled Anesthesia
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Unknown but must involve
1. Reticular activating system 2. Depresses cell membranes |
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4 Theories of How Inhaled Anesthetics Depress Cell Membranes
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1. Lipid Solubility: Meyer-Overton theory that potency is related to their solubility in olive oil
2. Critical volume: alteration inc ell membrane composition 3. Fluidization: change in conformation of membrane fluids 4. Pressure Reversal: high pressure reverses effects of anesthesia |
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N2O Good and Bad Effects
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Good:
- quick onset/offset - strong analgesic effects - minimal cardiovascular and respiratory effects - low potency Bad: - low potency - increases volume of air-filled spaces |
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Halothane
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- Smooth to inhale
- Changes depth easily - Depresses cardiovascular function and respiration - Relaxes muscles - LIVER TOXICITY (halothane hepatitis) |
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Isoflurane
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- halogenated ether
- low organ toxicity - CV STABILITY so great for cardiac surgeries - suppresses EEG bursts |
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Sevoflurane
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- least irritating to airways
- good for inhalational induction, asthmatics, smokers, kids |
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Desflurane
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- fast onset/offset
- LEAST SOLUBLE IN BLOOD - great for high turnover |
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Malignant Hyperthermia
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- Inherited disease of skeletal muscle
- Hypercalcemia leads to hypermetabolic state - Triggered by exposure to volatile anesthetics and succinylcholine ( a neuromusclar blocking agent) |
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Symptoms of Malignant hyperthermia
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- muscle rigidity
- tachycardia - acidosis - hypercarbia - hypoxemia - hyperthermia |
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Treatment for malignant hyperthermia
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- stop triggering agent
- 100 oxygen - Dantrolene (inhibits Ca release) - Treat acidosis with bicarbonate or ventilate - Actively cool - Support other vital signs |
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Dantrolene
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Ca release inhibitor used for malignant hyperthermia
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IV General Anesthetics
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- Barbituates
- Benzodiazepines - Etomidate - Propofol - Ketamine |
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Ideal IV induction Agent
|
- rapid onset
- rapid recovery - short duration of effect - no huge side effects - low cost |
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IV General Anesthetic Drug Redistribution
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Drug enters blood and some goes to vital organs; rest goes to muscle and fat.
Muscle and fat acts as a deposit site. |
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Awakening after general anesthetic drug bolus is by ____.
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Redistribution
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Barbiturate BP, HR, respiratory, and other general effects.
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- decreases BP
- increases HR - decreases resp - suppresses EEG |
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Propofol BP, HR, respiratory, and other general effects.
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- decreases BP
- no HR change - decreases resp - antinausea |
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Ketamine BP, HR, respiratory, and other general effects.
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- increases BP
- icnreases HR - no resp effect - psychomimetic effects - catechcholamine release - bronchodilator |
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Etomidate BP, HR, respiratory, and other general effects.
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- no BP effect
- no HR effect - decreases resp - adrenal suppression - stable hemodynamics! |
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Monitoring depth with general anesthetics
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- Movement
- Brain activity - HR, BP |
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CHF Symptons
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Left-sided CHF: difficulty breathing
Right-sided CHF: swelling in extremities (Blood return depends on diastolic and venous pressure gradient. As end-diastolic pressure decreases, the gradient decreases too so blood in veins increases and pressure builds up. Pressure buildup results in fluid leaking out of vascalature.) |
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Frank-Starling Compensation for CHF
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Heart decreases blood pumped since more blood left in ventricle at the end of diastole results in increased fibre stretching. Increased stretch increases the force of contraction.
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Extrinsic Compensation for CHF
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Increased sympathetic NS activity
- cardiovascular: increased heart rate, increased contracility (beta-1) - renal: increased RAS system increases blood volume and thus BP (increase BV makes things worse coupled with edema) |
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Digitalis Mechanism of CHF relief
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Binds and inhibits Na/K-ATPase in cardiac tissue, decreasing the Na GRADIENT ACROSS THE MEMBRANE. Since Na gradient is driving force for Na/Ca exchanger that pumps Ca out, this leads to an increase in intracellular calcium. This allows increased SERCA Ca uptake, increasing force of contraction.
***Digitalis increases CO without increasing HR |
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3 Ways Digitalis Relieves CHF Symptoms
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1. Decreases hypertrophy
2. Decreases sympathetic activity (so drop in HR, vasoconstriction) 3. Decreases edema (increased renal perfusion, decreased venous congestion) |
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Direct Electrical Effects of Digitalis
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Direct Effects:
1. Decreased RMP due to Na pump inhibition. This decreases slope of phase 0 and slows conduction velocity. 2. Decreased duration of phase 2 since intracellular Ca is increased. Decreased APD and ERP. 3. Increased slope of phase 4 so increased automaticity. |
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Indirect Electrical Effects of Digitalis
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Increased vagal activity in CNS***
- decreased HR - decreased AV node conduction Decreased response to NE at SA and AV nodes Increased baroreceptor sensitivity |
|
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Digitalis' effect at the SA node
|
Indirect effects predominate, resulting in decreased HR
|
|
|
Digitalis' effect at the AV node
|
Combined direct and indirect effects:
- decreased RMP - increased vagal acivity and decreased NE sensitivity |
|
|
Net result of digitalis in the heart
|
1. Decreased conduction velocity
2. Increased ERP ***Decreased impulse transmission to ventricles*** |
|
|
Adverse Effects of Digitalis
|
- GI: anorexia, nausea
- Neurological: headache, fatigue - Vision: blurred - CV: electrical effects |
|
|
Cardiovascular adverse effects of digitalis
|
- sinus bradycardia (HR less than 60/min)
- AV block - AV junctional rhythm (Purkinje becomes pacemaker) - Ventricular dysrhythmias due to ectopic impulses |
|
|
Treatment for Extra Beat due to Digitalis
|
oral K which competes with drug
|
|
|
Treatment for Digitalis Overdose
|
Digitalis antibodies
|
|
|
Treatment for more serious dysrhythmias
|
IV K and antidysrhythmics such as lidocaine
|
|
|
Digitalis interaction with K
|
Competitive for same enzyme. Hypokalemic patients more sensitive to digitalis so must use K-sparing diuretic.
|
|
|
Digitalis interaction with quinidine
|
Quinidine displaces digoxin from tissues to bloodstream and decreases its renal clearance.
|
|
|
Digitalis interaction with antibiotics
|
Antibiotics inhibit gut flora that inactivate 15-20% of digoxin
|
|
|
Digitalis elimination
|
Exclusively by kidneys
|
|
|
Digitalis half life and peak effect time
|
- lasts 1.6 days
- effects peak in 3-6 hours (40-70% absorbed; 25% plasma protein binding) |
|
|
Rapid vs Slow Digitalization of Patient
|
Rapid: loading dose then maintenance dose
Slow: maintenance dose over a week; slower but safer |
|
|
Therapeutic and toxic plasma concentrations of digoxin
|
Therapeutic: 0.5-2 ng/mL
Toxic: over 2.5 ng/mL |
|
|
ECG Components
|
P = atrial depolarization
QRS = ventricular depolarization T = ventricular repolarization PR segment: AP getting through the AV node QT segment: duration of ventricular action poentation |
|
|
What has the fastest rate of phase 4 depolarization?
|
The SA node
|
|
|
Membrane potential is determined by
|
1. Concentration of Na, Ca, K
2. Its permeability to ions |
|
|
RMP is
|
Potential during diastole in non-pacemaker cells
It equals the equilibrium potential for K, which is -61log[Ki]/[Ko] Adding extracellular K results in partial/complete depolarization. |
|
|
Fast action potential phases and tissues.
|
- occur in atria, ventricles, Purkinje fibres
- Phase 0 = Na entry - Phase 1 - Phase 2 = Ca entry - Phase 3 = K exit - Phase 4 = rest |
|
|
Slow action potential phases and tissues
|
- occurs in SA node, AV node
- Phase 0 = Ca entry - Phase 3 = K exit - Phase 4 = changes in membrane permeability to Na and K (starts from less engative membrane potential and slower phase 0) |
|
|
Pacemaker cell firing rate depends on 3 things
|
1. Maximum diastolic voltage
2. Slope of phase 4 3. Threshold voltage *Slope of phase 4 depends on If (funny current) Na channels and the membrane's changing permeability to Na and K ions |
|
|
Ach and adenergic stimulator effects on phase 4 slopes in pacemaker cells
|
- Ach: decreases phase 4 slope
Adenergic stimulators: increase phase 4 slope |
|
|
Funny currents can be up/down regulated by
|
cAMP
|
|
|
Na channel refractory period (ERP) depends on
|
Membrane voltage
K efflux eventually returns cell to resting state |
|
|
Ca channel ERP depends on
|
Time
|
|
|
Relative duration of ERP and APD in SA and AV nodes
|
ERP much longer than APD
(many antidysrhythmics prolong the ERP) |
|
|
Responsiveness
|
maximum rate of depolarization in phase 0 (Vmax)
|
|
|
Responsiveness depends on
|
RMP at moment of depolarization
Reflects the number of Na channels that have returned to resting state. |
|
|
If RMP is more negative than ___, slope of phase 0 is maximal.
If RMP is more positive than ___, no conduction since all channels inactivated. |
1. -90mV
2. -60mV |
|
|
Conduction velocity
|
how fast the wave travels through the heart
|
|
|
Conduction velocity depends on 2 things
|
1. AP amplitude
2. Slope of phase 0 Partial depolarization slows conduction velocity since it decreases the slope of phase 0. |
|
|
Causes of dysrhythmias
|
- ischemia
- altered elctrolytes - increased catecholamines - drugs - diseased/scarred tissue |
|
|
2 kinds of dysrhythmias
|
Disturbed impulse generation
Disturbed impulse conduction |
|
|
2 Kinds of generation problems
|
1 Altered normal automaticity
- change sin phase 4 depolarization from increased vagal or sympathetic acitvity 2.Abnormal automaticity - delayed afterdepolarizations (eg from digitalis toxicity) - second depolarization early in diastole; if hits threshold premature depolarization can occur, called a COUPLED EXTRASYSTOLE. - if a coupled extrasystole happens every time, it's called a bigeminal rhythm |
|
|
3 Criteria for Disturbed Impulse Conduction
|
1. Obstacle to conduction
2. Unidirectional block of impulse 3. Conduction time through damaged area must be longer than the ERP of surrounding tissue |
|
|
Mechanisms of antidysrhythmics
|
1. reduce HR by decreasing slope of phase 4
2. Prolongs ERP relative to APD 3. Decreases membrane responsiveness by decreasing conductionv elocity and changing a 1 way block to a 2 way block 4. Blocks Na and Ca channels in A and I state |
|
|
Class I Antidysrhythmics
|
Na channel blockers
- high affinity for A or I state channels - low affinity for R state channels Therefore have an increased effect on depolarized tissue. -Bin and come off with each cardiac cycle. - Little affinity for normal cells unless toxic levels in the blood. Effects: 1. Decreases number of available Na channels to decrease conduction velocity. 2. Increases ERP to increase recovery time |
|
|
Class IA Dysrhythmics
|
1. Unidirectional block becomes bidirectional block.
- A-state: decreases conduction velocity - I-state: increased ERP - K channel block increases APD * ERP increased more than APD 2. Decreased Automaticity due to less Na influx |
|
|
Class IB Dysrhythmics
|
1. Decreases automaticity
2. No change in conductionv elocity in normal tissue but decreases conduction velocity in depolarized tissue. Lidocaine blocks I state channels preferentially over A state channels. Greater effect in ventricular and Purkinje cells since phase 2 is longer. |
|
|
Class IC Dysrhythmics
|
Huge decrease in conduction velocity.
Used to maintain sinus rhythm in supraventricular dysrhythmias. |
|
|
Class II Antidysrhythmics
|
Beta blockers decreasing SNS activity, especially at AV node. Increases ERP at AV node to control ventricular rate.
|
|
|
Class III Antidysrhythmics
|
K channel blockers that block Na an dK channels.
Increases both ERP and APD, but more ERP than APD. |
|
|
Class IV Antidysrhythmics
|
Ca entry blockers which decrease AV conduction
|
|
|
Class V Antidysrhythmics
|
Other
Eg. Adenosine opens special K channel and hyperpolarizes membrane |
|
|
5 Readons for overprescribing antibiotics
|
1. Patients often expect them
2. Substitute for diagnostic judgement 3. Used prophylactically when there is no evidence for efficacy 4. Post-graduate education by the pharmaceutical industry 5. Non-availability of facilities to aid in diagnosis |
|
|
6 Mechanisms of Antibiotic Actions
|
1. Inhibit or damage cell wall synthesis (penicillins, cephalosporins, bacitracin, vancomycin)
2. Inhibits cell membrane synthesis or damage cell membrane (polymixins) 3. Alters synthesis of proteins (Aminoglycosides, tetracyclines) 4. Alters syntehsis or metabolism of nucleic acids (rifampin, ciprofloxacin) 5. Alters metabolsim (sulfonamides, trimethoprim) 6. Nucleic acid analogs (acyclovir, AZT) |
|
|
Basis of antimicrobial chemotherapy is
|
Selective toxicity
|
|
|
3 bacterial structures that make good antibiotic targets
|
1. Peptidoglycan cell wall (humans don't have)
2. Plasma membrane (bacteria lack sterols in their cell walls) 3. Cytoplasm (enzymes, ribosomes, metabolic pathways) |
|
|
Gram Positive vs Gram Negative Cell Walls
|
Gram Positive: thick peptidoglycan layers
Gram Negative: Outer membrane, periplasmic space, then thin layer of peptidoglycan. Less peptidoglycan and harder to penetrate = harder to kill. |
|
|
Combining antibiotics results in
|
1. Antagonism
2. Synergy 3. Indifference |
|
|
Examples of antagonistic combination of antibiotics
|
Any bacteriostatic drug will inhibit cell wall-active agents.
eg. Tetracyclines and penicillins. |
|
|
Examples of synergistic combination of antibiotics
|
1. Cell wall synthesis inhibitors make it easier for aminoglycoside entry into cell. (eg, ampicillin and gentamicin)
2. Drugs acting at sequential steps in a metabolic pathway (eg. sulfonamides and trimethoprim) 3. One drug prevents inactivation of the other (eg. clavulanate is a beta-lactamase inhibitor) |
|
|
Disadvantages of combinations
|
- increased cost
- selecting for resistance to antibiotics - increased risk of toxicity - superinfections (eradicating 1 type of bug creates ideal environment for secondary infections) |
|
|
Indications for combining antibiotics
|
- severe infections with unknown etiology
- treatmetn of mixed bacterial infection - preventing emergence of resistant microorganisms - 2 drugs may achieve effect not achievable by 1 alone |
|
|
Bacterial resistance mechanisms
|
- altered receptors and enzymes
- altered rates of entry or removal - enhanced inactivation - synthesis of resistant pathways - failure to metabolize drug |
|
|
Penicillin Structure
|
6-aminopenicillanic acid ring with different R groups
R groups affect acid stability, beta-lactamase resistance (larger R groups protecting ring), and spectrum of organisms |
|
|
Beta lactamase cleaves the 6-aminopenicillanic ring at which site?
|
B ring amide bond
|
|
|
Allergy to 1 penicillin means assuming that the person has
|
allergy to ALL penicillins
|
|
|
Penicillin mechanism
|
- Inhibits cell wall cross linking via transpeptidase enzyme
- Bactericidal since weakened cell wall likely to burst |
|
|
3 mechanisms for penicillin resistance
|
1. destruction by beta-lactamase (enzyme can be inhibited by clavulanic acid)
2. failure to reach taget (down regulating porins in gram negative bacteria) 3. failure to bind target (transpeptidase mutations) |
|
|
Clavulanic acid
|
Beta-lactamase inhibitor
|
|
|
Penicillins are excreted by the
|
Kidney -> 90% tubular secretion
(30-60 minute half life) |
|
|
Probenecid
|
Inhibits kidney penicillin excretion
|
|
|
Pen G benzathine
|
Long acting penicillin
- given intramuscularly - maintains serum levels for 10 days |
|
|
Chronic use and misuse of penicillins can result in
|
Hypersensitivity
Drug Resistance Superinfection |
|
|
Cephalosporins
|
A cell wall damanging agent.
- Can only be given parenterally - Used to treat UTIs - Eliminated renally |
|
|
Aminoglycoside Mechanism
|
Bactericidal drugs that bind irreversibly to the 30S ribosomal subunit, inhibiting protein synthesis.
|
|
|
3 effects of binding the 30S subunit
|
Blocks initiation
Blocks further translation and elicits premature termination Faulty protein synthesis by causing incorporation of the incorrect amino acid |
|
|
Advertse reactions to aminoglycosides
|
Ototoxicity is a MAJOR problem
- vestibular and auditory dysfunction - progressive destruction of vestibular or cochlear sensory cells - early changes are reversible, but after sensory cells are lost cellular regeneration is no longer possible - damage may be potentiated by LOOP DIURETICS Nephrotoxicity is likely in patients with existing kidney disease - reversible damage to kidney tubule cells - decreased excretion can aggravate ototoxicity |
|
|
Aminoglycosides are usually administered
|
Intravenously or intramuscularly (not absorbed after oral administration since highly polar)
Used often in combination with penicillin for gram negative enteric bacteria |
|
|
Aminoglycosides are excreted
|
Almost entirely by glomerular filtration
|
|
|
Aminoglycoside resistance (3 ways)
|
1. enzymes inactivate drug
2. altered transport into cells 3. ribosome binding site altered |
|
|
Tetracyclines
|
Bacteriostatic blockage of tRNA binding site on ribosome 30S subunit (ie. inhibits TRANSLATION)
|
|
|
Tetracyline enters the cell via
|
Passive diffusion AND energy-dependent mechanisms, concentrating the drug inside the cell
|
|
|
Tetracycline resistance (3 ways)
|
1. decreased accumulation as efflux pump proteins get transduced
2. production of proteins that interfere with tetracycline binding to ribosome 3. enzymatic inactivation |
|
|
Tetracycline toxicity
|
It readily binds to calcium in newly formed bones and teeth, so in children results in reduced bone growth and teeth discolouration.
|
|
|
Tetracyclien forms an insoluble complex with
|
Divalent cations such as calcium and magnesium
|
|
|
Sulfonamide chemical structure
|
1. A S directly linked to the benzene ring
2. A free para-NH2 or a group that can be converted in vivo to a free NH2 group |
|
|
Neomycin, streptamycin, gentamycin
|
Aminoglycosides
|
|
|
Sulfonamides are related to
|
PABA (paraaminobenzoic acid)
|
|
|
Sulfonamide mechanism
|
Structural analog of PABA means it is a competitive inhibitor of DIHYDROPTEROATE SYNTHASE. This is an enzyme needed for folic acid, which allows thymidine synthesis from uracil.
Mammals don't have this enzyme so selective for bacteria. Bacteriostatic and reversible. |
|
|
Short-acting sulfonamides are used for
|
UTIs
|
|
|
Long-acting sulfonamides are used for
|
Ulcerative colitis and IBS
|
|
|
Sulfonamide ressitance (3 ways)
|
- mutations causing overproduction of PABA
- decreased membrane permeability - dihydropteroate synthase mutation results in low sulfonamide affinity |
|
|
Sulfonamide toxicity
|
- allergies
- urinary tract obstruction! drug precipitates in renal tubules - HEMOLYTIC ANEMIA in patients without GLUCOSE-6-PHOSPHATE DEHYDROGENASE to generate NADPH. These patients are more sensitive to oxidative stress. |
|
|
Patients without glucose-6-phosphate dehydrogenase are more susceptible to
|
Sulfonamide toxicity since they have low NADPH levels.
|
|
|
Trimethoprim mechanism
|
Inhibits bacterial DIHYDROFOLATE REDUCTASE in the folic acid pathway. About 50000X more selective for bacterial enzyme than human enzymes.
|
|
|
Trimethoprims are used in combination with
|
sulfonamides
|
|
|
Quinolones
|
Inhibits bacterial topoisomerase II
- effective for many beta-lactamase resistant strains |
|
|
Ciprofloxacin
|
A quinolone!
|
|
|
DNA viruses are treated with
|
DNA polymerase inhibits
|
|
|
Acyclovir & its mechanism
|
A DNA pol inhibitor. Acyclic guanine derivative with high specificity for herpes simplex.
- acyclovir requres 3 phosphorylations by THYMIDINE KINASE for activation - completes with deoxy GTP for viral DNA pol (30X more selective for bacterial than human DNA pol) - incorporation into viral DNA causes chain termination |
|
|
Acyclovir resistance
|
1. Thymidine kinase mutations
2. Viral DNA pol mutations |
|
|
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
|
Used for retroviruses such as HIV
- converted to triphosphates by cellular kinases - competitive inhbition of HIV reverse transcriptase and chain termination - resistance due to mutation of reverse transcriptase |
|
|
Zidovudine
|
a NRTI deoxythymidine analog
|
|
|
Retrovirus mechanism
|
- Binds to cell membrane and fuses
- Reverse transcriptase makes cDNA and then dsDNA - dsDNA gets interated into the host genome |
|
|
Which HIV glycoproteins bind CD4 receptors on host T cells?
|
gp 41 and gp120
|
|
|
Lamivudine
|
a NRTI cytosine analog
|
|
|
Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
|
- noncompetitive inhibitors of reverse transcriptase
- conformational change reduces enzyme activity - don't require intracellular phosphorylation - must be combined with at least 2 other active agents to avoid resistance |
|
|
Protease inhibitors
|
Prevents maturation of virion
- viral structural proteins and enzymes are synthesized as polyproteins - require cleavage by viral potease to form individual proteins |
|
|
Protease inhibitor drug interactions
|
Metabolized by P450 3A4 but ALSO INHIBITORS IT, thus increasing levels of other drugs.
|
|
|
Fusion inibitors
|
bind to gp41 subunit of viral envelope protein and prevents conformational change needed for fusion of viral and host cell membranes
|
|
|
Saquinavir
|
Protease inhibitor
|
|
|
Envfuvirtide
|
Fusion inhibitor (binds to gp41 subunit)
|
|
|
4 Classes of Drugs for Retroviruses
|
1. NRTIs
2. NNRTIs 3. Protease inhibitors 4. Fusion inhibitors |
|
|
Amantadine
|
Inhibits viral membrane protein M2
M2 fuctions as ion channel allowing acidification of virus interior. This is important for fusion of the viral membrane with the endosome membrane. |
|
|
Amantadine is active against
|
Influenza A only
- used prophylactically in high risk patients |
|
|
Neuraminidase inhibitors
|
Bind to active site of neuraminidase, preventing release of viral progeny from host
|
|
|
Neuraminidase inhibitors are effective against
|
Influenza A AND influenza B
|
|
|
Oseltamivir
|
Neuraminidase inhibitor
|
|
|
Interferons
|
Family of inducible proteins used to treat hepatitis.
3 classes: alpha, beta, gamma |
|
|
Interferon mechanism
|
IFNs use the JAK-sTAT pathway to induce host enzymes that inhibit TRANSLATION of viral mRNA into viral protein.
|
|
|
Monoclonal antibodies, antisense oligonucleotides, siRNA, interase inhibitors, glycosylation inhibitors, maturation inhibitors are all
|
Ne developments in antiviral therapy
|
