Term
| Actions of Angiotensin II |
|
Definition
powerful vasoconstrictor, acts directly on vascular smooth muscle. Prominent in arterioles and less in veins.
Causes vasoconstriction indirectly by acting on sympathetic neurons, adrenal medulala, and CNS.
promotes synthesis and secretion of aldosterone. Happens even when agiotensin II levels are too low to elicit vasoconstriction.
Pathogenic alterations to heart and vasculature:
cardiac hypertrophy/remodeling
in hypertension, may be responsible for increasing blood vessel wall thickness |
|
|
Term
|
Definition
Acts on collecting duct to increase Na reabsorption/potassium excretion.
Pathological CV effects:
can promote cardiac remodeling/fibrosis
can activate sympathetic NS and suppress uptake of norepi in the heart = dysrhythmias |
|
|
Term
|
Definition
catalyzes formation of angiotensin I from angiotensinogen.
produced by juxtaglomerular cells of kidney and is released into bloodstream.
Release increases in response to decline in blood pressure, blood volume, blood pressure, plasma Na+, or renal perfusion pressure.
Release can also be stimulated by B1 adrenergic agonists. |
|
|
Term
| Causes of reduced renal perfusion |
|
Definition
| Stenosis (abnormal narrowing) of renal arteries, reduced systemic blood pressure, reduced plasma volume. |
|
|
Term
|
Definition
catalyzes conversion of angiotensin I to angiotensin II.
located in the luminal surface of all blood vessels.
sometimes called kinase II (when acting on bradykinin) |
|
|
Term
| Instances when RAAS is most active |
|
Definition
|
|
Term
| Some possible methods ACE inhibitors are interfered with. |
|
Definition
Tissue production of angiotensin II
pathways for production of angiotensin II that do not involve ACE. |
|
|
Term
| Uses for ACE inhibitors, most prominent adverse effects |
|
Definition
hypertension, heart failure, diabetic neuropathy, MI.
prophylactic use in at-risk individuals.
Adverse effects:
cough (5-10%, because of increase in bradykinin production)
angioedema (allergic reaction, causing swelling of the lips & tongue)
first-dose hypotension (because ANGII causes hypertension)
hyperkalemia (preventing Aldosterone from causing Na+ reabsorption and K+ excretion, so K+ accumulating).
Fetal injury-pregnancy category X
Increase in serum creatine.
**Is contraindicated in patients with bilateral renal artery stenosis (narrowing of the renal artery) because this would cause vasodilation of the artery and decrease renal perfusion. |
|
|
Term
| Advantages of ACE inhibitors of sympatholytics/diuretics |
|
Definition
No interference with CV reflexes. (exercise capacity not effected, orthostatic hypotension in minimal)
used safely in pts with bronchial asthma.
Do not promote hypokalemia, hyperuricemia, or hypoglycemia |
|
|
Term
| Angiotensen II Receptor Blockers: common ending, method of action, side effects |
|
Definition
"sartans" or "ARBs"
Blocks receptors for angiotensin II and
therefore the actions of angiotensin II
E.g. valsartan, candesartan, losartan, etc….
Similar pharmacologic effects as ACEInhibitors
(see ACE –I)
Similar side effects
Potentially less cough as does not lead to increased production of bradykinin |
|
|
Term
| Digoxin: Uses, controversy |
|
Definition
Used for “inotropic” properties in CHF (increase force of contraction)
Clinical trials have not demostrated
survival benefit
May decrease hospitalizations and improve
exercise tolerance
Problems with toxicity (has a narrow therapeutic range)
Controversy regarding use in certain
populations
E.g. does it do more harm in females |
|
|
Term
| Digoxin: Method of action |
|
Definition
Inotropic agent
Inhibits Na
+
-K+
-ATPase
This causes increase in intracellular Ca
2+
Increase myocardial contractility
“Parasympathomimetic” –
Increases vagal impulses and increases
response of SA node to acetylcholine
Result = decrease automaticity of SA node and
conduction through AV node |
|
|
Term
|
Definition
Dysrrhythmia
Hypokalemia (caution with non K+sparing
diuretics!)
Potassium competes with digoxin for binding
to Na+/K+ ATPase – decreased K+ increases
dig induced inhibition of the pump
Digoxin levels
Narrow therapeutic index
Toxicity can occur within the therapeutic range |
|
|
Term
| Digoxin toxicity signs in GI, CNS, and CVS |
|
Definition
GI
Nausea, vomiting, diarrhea, anorexia
CNS
Confusion, drowsiness, dizziness, blurred
vision, hallucinations
CVS
Arrhythmias, AV conduction blocks, ventricular
extrasystole, SVT, junctional rhythms, VT |
|
|
Term
| Digoxin - Length of half life, when and how to monitor and a special note about toxicity. |
|
Definition
Serum drug monitoring
Long half life!!
Monitor if
suspected toxicity
changes to drug regimen
changes in renal function
Consider other clinical factors
Some patients can have toxicity in the “therapeutic
range” |
|
|
Term
| Three ways Dysrhythmias can develop |
|
Definition
Disturbances of impulse formation
automaticity – cells that spontaneously generate APs
Automaticity – SA, AV nodes, His-Purkinje system
Disturbances of conduction
AV block (e.g. 1st degree, 2nd degree, 3rd degree)
Reentry
Problems with both 1 and 2 |
|
|
Term
| parts of cardiac action potential that drugs can affect |
|
Definition
Depolarization (Na influx)
Contraction (Ca++ influx)
Repolarization (K+ eflux) |
|
|
Term
| Parts of cardiac slow potentials that drugs affect |
|
Definition
Depolarization (Ca influx)
Phase 4 (spontaneous depolorization through funny currents...) |
|
|
Term
| Vaughan Williams Classification of Drugs of arrhythmia |
|
Definition
Class I – Blocks sodium channels (phase 0)
Class II – Beta blockers
Class III – Potassium channel blockers (phase 3)
Class IV – Calcium channel blockers (phase 2)
Others – digoxin, adenosine |
|
|
Term
| All medications that are used to treat disrhtymnias are also ____ |
|
Definition
| Pro-arrhythmic (new or more frequent occurrence of pre-existing arrhythmias.. tendency of anti-arrhythmic drugs to facilitate the emergence of new arrhythmia's. |
|
|
Term
| Drugs for Chronic, Stable, Angina |
|
Definition
Nitrates
Acute relief with spray and SL tabs
What about patches?
Symptom control (chronically):
Calcium channel blockers (CCBs)
Beta blockers (already talked about)
Long acting nitrates
Others (more for “CV protection”)
Aspirin |
|
|
Term
| General method of action of drugs for chronic, stable, angina. |
|
Definition
Based on the theory of decreased O2 supply in light of increased metabolic demand
Increase delivery
drugs to increase coronary blood flow
Decrease demand
Drugs to decrease cardiac work
Decrease:
HR
Ventricular volume
Blood pressure
Contractility |
|
|
Term
| Nitrates - Method of action |
|
Definition
Decreases O2 demand
Increased venous capacitance
pooling of the blood in the peripheral veins - reduces venous return and ventricular volume and decreases myocardial wall tension (preload)
Orthostatic hypotension
Reducing systemic and pulmonary arterial pressure (afterload)
Coronary vasodilation
Redistributes blood flow along collateral arteries and from epicardial to endocardial regions
Dilates coronary artery stenosis and narrowed coronary arteries
Relieves coronary spasm |
|
|
Term
| Nitrates - Nitroglycerin MOA and adverse effects |
|
Definition
therapeutic doses, acts more on veins
less arteriole dilation
Adverse effects
Headache, orthostatic hypotension, reflex tachycardia, facial flushing |
|
|
Term
|
Definition
Tolerance
Tachyphylaxis
Mechanism ? - depletion of sulfhydryl groups or oxidative injury to mitochondrial aldehyde dehyrogenase (enzyme needed to convert nitroglycerin into nitric oxide) |
|
|
Term
| Nitrates - Routes of Administration |
|
Definition
Sublingual
Translingual spray
Buccal
Oral sustained-release
Transdermal delivery systems
Topical
Intravenous
Know how to counsel someone on nitro spray or tablet administration |
|
|
Term
| Nitrates - Drug Interactions |
|
Definition
Consider kinetic and dynamic interactions
E.g. other drugs that reduce BP – dynamic interaction but likely a common combination with nitrates
Drugs that inhibit reflex tachycardia
E.g. Beta blockers
E.g. CCBs (some) |
|
|
Term
| What would be a concern with using nitrates and sildenafil |
|
Definition
Sildenafil acts to increase cGMP
phosphodiesterase 5 (PDE-5) inhibitor (this enzyme normally acts to breakdown cGMP)
These used together will cause massive vasodilation, resulting in severe hypotension. |
|
|
Term
| Drugs for Angina Pectoris - CCBs MOA |
|
Definition
They block the entry of Ca2+ into the cell, and therefore reduce the contraction of the heart muscle and constriction of BV. This will reduce the amount of O2 needed by the heart, allowing it to function longer without developing ischemia.
VSM (vascular smooth muscle) – Ca+2 regulates contraction
Arterioles and arteries
Coupled with beta1 receptors (therefore blocking these causes decrease velocity, rate, and contraction of the heart muscle).
SA, AV node, myocardium |
|
|
Term
| CCBs - Classification and physiological effects of both classes. |
|
Definition
Dihydropyridines:
nifedipine
amlodipine
felodipine
nicardipine
Non-dihydropyridine:
verapamil
diltiazem
Dihydropyridines
Affect VSM: do not slow heart rate at therapeutic levels.
Non-dihydropyridines
verapamil and diltiazem
Affect VSM, heart |
|
|
Term
|
Definition
Adverse effects
Hypotension
Reflex tachycardia
> with nifedipine but consider other dihydropyridines
Bradycardia
More with verapamil and diltiazem
Peripheral edema – due to vasodilation – has been shown to happen with both but ? dihydropyridines have more peripheral vasodilation |
|
|
Term
| Cholesterol - how and where do we get it? |
|
Definition
Made intracellulary
Numerous enzymatic process
E.g. hydroxymethylglutaryl CoA reductase (HMG CoA)
Uptake from systemic circulation
Synthesized in liver & secreted into circulation
Lipoproteins are the carriers
inner lipid core and an outer membrane protein
membrane protein allows interaction with other receptors on cells |
|
|
Term
| Ways to mange Cholesterol (6) |
|
Definition
Non-drug therapy
HMG CoA reductase inhibitors
hydroxymethylglutaryl CoA reductase
Bile acid-binding resins
Nicotinic acid
Fibric acid derivatives (fibrates)
Cholesterol absorption inhibitor |
|
|
Term
|
Definition
Mechanism
Inhibiting HMG CoA leads to:
increased # of high affinity LDL receptors in hepatocytes
Causes decrease in circulating LDL pool & increase LDL’s catabolic rate
takes 4 – 6 weeks for FULL effect (b/c of synthesis of receptors) |
|
|
Term
| Beneficial effects of Statins |
|
Definition
Decreases LDL (range 20 – 60 % reduction)
Dose dependent effect
Increases HDL
Nonlipid reduction beneficial effects
Promote cholesterol plaque stability
Reduce inflammation at the plaque site
Slow progression of of calcification
Reducing platelet deposition and aggregation
Many large clinical trials have shown cardiovascular and mortality benefits for those with existing CV disease. |
|
|
Term
| Statins - Metabolism, interactions |
|
Definition
Many drug-”other” interactions
Substrates &/or inhibitors of CYP450 system
3A4
e.g. do not combine simvastatin with grapefruit juice
Always check for interactions! |
|
|
Term
| Statins - Adverse effects |
|
Definition
Hepatoxicity (1-2%) – monitoring LFTs
Myopathy – myositis – rhabdomyolysis
Rhabdomyolysis (skeletal muscle gets broken down rapidly, is hard for kidneys to filtrate and leads to renal failure) – rare but severe consequence
Also leads to acute renal failure
risk for this side effect when combined with …
fibrates, drugs inhibiting statin metabolism
Counseling patients
notify if symptoms muscle pain or tenderness
If symptoms – evaluate/assess
Check - CK (creatine kinase) (d/c when CK higher to e.g. >10 X ULN (upper limit then normal))
Assess renal function & urine for myoglobin (will be released due to muscle injury) |
|
|
Term
| Antiplatelets - Groups and Examples |
|
Definition
1)Cyclooxygenase inhibitors
ASA
2)Adenosine Diphosphate
(ADP)Receptor Antagonists
Clopidogrel
3)Glycoprotein IIb/IIIa receptor antagonists
Abciximab
Ep1fiba1de
Tirofiban
Others:
Dipyridamole |
|
|
Term
| Anticoagulants - Groups and Examples |
|
Definition
1)VitaminK antagonists
Warfarin!(a.k.a.!Coumadin
2)Factor Xa and thrombin (IIa)inhibitors
Heparin
LMWH
Selec1ve Factor Xa inhibitors
Fondaparinux
Rivaroxaban
3)Direct thrombin (IIa) inhibitors
Argatroban
Lepirudin
Dabigatran |
|
|
Term
|
Definition
Alteplase
1)Streptokinase
2)Reteplase
3)Tenecteplase
Act to via plasminogen to enhance the activity of plasmin (natural occurring anti coagulate)
Side effects– bleeding, Others.
Use in acute care, special circumstances
E.g. stroke,MI |
|
|
Term
| Hemostasis - Definition and two stages |
|
Definition
Process to stop bleeding
Stage 1 - Formation of platelet plug
Stage 2 - Plug/coagulation reinforcement (production of fibrin)
Fibrin produced by 2 convervent pathways - Instrinsic and Extrinsic (aka tissue factor pathway), both needed for optimal production of fibrin. |
|
|
Term
| The body's three defences against coagulation |
|
Definition
Antithrombin III (antithrombin) - protein that complexes with clotting factors. Inactivates several clotting enzymes.
Plasmin - Enzyme that digests fibrin meshwork of clot (plasminogen is its precursor)
Protein C - proteolytically inactivates Factor Va (5) and Factor VIIIa (8). Is vitamin K dependent.
Protein S - Cofactor for protein C |
|
|
Term
| Three ways to Inhibit platelet aggregation |
|
Definition
All inhibit platelet receptor:
COX inhibitors (ASA)
ADP receptor Blocker (blocked by a ADP blocker in the antiplatelets)
Direct GP IIb/IIIa receptor blocker (GP IIb/IIIa blocker in antiplatelets). |
|
|
Term
| Difference between Cox-1 and Cox-2 & how they are released |
|
Definition
Damage to phospholipid bilayer results in release of arched acid and results in COX 1 & 2 release.
Cox 1 are constitutive, found in most normal cells and tissues.
Cox 2 - induced at inflammation sites. Cytokines and inflammatory mediators that accompany inflammation induce COX 2 production. (also constitutively expressed in certain areas of kidney and brain and is induced by endothelial cells by laminar shear forces) |
|
|
Term
|
Definition
At sites of injury COX catalyzes the synthesis of
PGE2 (prostaglandin E2) and PGI2 (prostacyclin)
→ → → → promotes inflammation and sensitizes receptors
to painful stimuli
• In the gastric epithelial cells of the stomach :
→ → → → PGE2
and PGI2
helps protect
gastric mucosa
• Reduced secretion of gastric acid,
increased secretion of HCO3
, and
cytoprotective mucous
and maintenance of submucosal blood flow.
• In platelets → → → → promotes
synthesis of TXA2 (thromboxane) → → → → stimulates
platelet aggregation
• In the kidney catalyzes the synthesis of
PGE2
and PGI2 → → → → promotes
vasodilation and therefore helps to
maintain renal blood flow
• PGs also normally act to inhibit reabsorption of
Cl- and ADH – inihibiting leads to Na+ and
water retention
In the brain → → → → COX-derived
prostaglandins mediate fever and
contribute to perception of PAIN
• In the uterus → → → → COX-derived
prostaglandins help promote
contractions at term |
|
|
Term
| Receptor/Counterreceptor pairs involved in platelet-neutrophil interactions |
|
Definition
P-Selectin/PSGL-1 - initial attachement
GPIb/Mac-1 - Stabilization
TREM-1 ligand/TREM-1 amplifcation of neutrophil activation |
|
|
Term
| Glucocorticoids role as antiplatelet |
|
Definition
• suppress the induced expression of
COX-2, and thus COX-2–mediated
prostaglandin production.
• They also inhibit the action of
phospholipase A2, which releases AA from the cell membrane & then release of COX 1 & 2. |
|
|
Term
| ASA - Dose as antiplatlet, method of action, adverse effects |
|
Definition
Dose is low - 81-325mg/day (post MI, stroke prophylaxis in those with TIAs, acute treatment of MI)
Irreversible COX (1 & 2) inhibitor
Used for post MI, or stroke, or suffering with arthritis.
Adverse Effects:
- Bleeding, GI Ulceration (as it blocks COX 1)...
- Enteric coatings do not guarentee protection from bleeding |
|
|
Term
|
Definition
Combines with antithrombin III and inhibits IIa and and Xa
binds Anti IIa > anti-Xa
** Inhibits factors IIa (thrombin), Xa (10), IXa (9), XIa (11), XIIa (12).
Thrombin = IIa |
|
|
Term
| Heparin: How are effects measured and what is the antidote |
|
Definition
Measured via aPTT
Protemine Sulfate |
|
|
Term
| Heparin - How is it absorbed, does it cross the placenta, how is it excreted, and what are the adverse effects |
|
Definition
Not absorbed across GI - given IV or SV. Does not cross placenta.
Undergoes metabolism and renal excretion.
T 1//2 - 1.5 hours
Adverse Effects:
Hemorrhage, Hypersensitivity, heparin induced thrombocytopenia (HIT - pradoxical decrease in plates and increased coagulation, caused by antiplatelet antibodies), Osteoporosis
HIT is thrombocytopenia (low platelet count) occurs in heparin users. This predisposes them to thrombosis formation in BV (HITT) due to formation of antibodies that activate platelets. |
|
|
Term
| Low molecular Weight Heparins (the Parins) - how does it differ in structure, dosing, monitoring, activity and side effects |
|
Definition
Shorter molecule
Fixed dosing schedule and weight based dosing - longer half-life (once daily or BID). SC only.
No monitoring of aPTT - Xa levels instead but these are not routinely measured (more anti Xa over Anti-IIa)
Anti-Xa > anti-IIa
Side effects - Bleeding, but lower chance of thrombocytopenia |
|
|
Term
| Anticoagulatants - Warfarin - route of admin, method of action, what is the antidote? |
|
Definition
Oral
Vitamin K antagonist - affects synthesis of vitamin K dependent clotting factors (VII (7), IX (9), X (10), prothrombin (II)
Protein C and S are vitamin K dependent as well
The antidote is vit. K. |
|
|
Term
| Warfarin - Time to onset, half life, monitoring |
|
Definition
Delayed effect on coagulation - No effect on clotting factors already formed, takes 6 hours-2.5 days to start working.
Need to consider drug and clotting factor half life.
Prolonged effect after stopping
- Long half life of drug - 1.5-2 days
Monitoring - INR (PT ratio multipled by correction factor)
INR= prothrombin time, normal range (without anti coagulate is around 1), and goes up when on anti coagulate).
Outpatient monitoring of INR |
|
|
Term
| Warfarin - Adverse effects, Interactions, Warnings/Counter indication, Antidote |
|
Definition
Hemorrhage, bleeding
Interactions - Drug-Drug, Drug-food, etc...
Pharmacokinetic drug-drug - enzyme inhibition or induction (E.g. Amidarone, analgesics, antibiotics, antidepressants)
Pharmacodynamic interactions - e.g. vitamin K
Drugs Can:
Increasse effects of Warfarin
- promote bleeding
Decrease effects of Warfarin
- potentially lead to thromboembolytic events
Warnings/CI similar to heperain and...
Vit K def
Liver Disease
Alcoholism
CI - Pregnancy-Lactation
Antidote
Vitamin K
Given po when possible. SC avoided because of errarit absorption, IV can have serious consequences (anaphylaxis) if not administered appropriately. |
|
|
Term
| What is the main purpose of anti coagulates and antiplatelets, and what don't they do? |
|
Definition
To prevent the formation of growing thrombi or help the body while it works to dissolve the formed thrombi.
They do not lyse the clots. |
|
|
Term
| How does both intrinsic and Extrinsic pathways get activated? |
|
Definition
Intrinsic= trauma to the blood or exposure of collagen to the the blood.
Extrinsic= trauma to the vascular walls. |
|
|
