Selective PDE III Inhibitors Flashcards
PDE III inhibitors decreases the degradation of cellular cAMP which results in (ACTION IN CARDIAC MUSCLE)
Increase levels of cAMP leads to an increase in intracellular calcium concentration in cardiac muscles and produces POSITIVE inotropic effects and increased speed of relaxation
Agents PDE III also called
cyclic AMP-PDE III inhibitors.
Effects of catecholamines are ________ why?
increased; because they also increased concentration of cAMP through beta-adrenergic receptors
Milrinone: Useful in the management of acute
acute left ventricular dysfunction as may follow cardiac surgery or an acute MI
What is milrinone?
A_________ derivative that is a _______ ________, PDEIII inhibitor that produces dose-dependent positive ________
and _________properties with minimal effect on ________ and ______ _______
A bipyridine derivative that is a selective, competitive, PDEIII inhibitor that produces dose-dependent positive inotropic
and vasodilating properties with minimal effect on heart rate and myocardial oxygen consumption
Milrinone
Better than inamrinone
Action of Milrinone : Increased are _____and _______
Decreased are :
Unchanged or slightly increased?
CO, Contractility
SVR, PVR, (mean pulmonary artery pressure)
afterload, preload, venous return
HR.
Mechanism of action of Milrinone
-positive lusitropic (myocardial relaxation) effect
facilitates diastolic relaxation, decreases right and left ventricular end- diastolic pressures (right and left heart filling pressures decreased)
decreases pulmonary capillary wedge pressure
decreased wall tension
Effects of milrinone on SV :
Decreased:
Afterload
Preload and venous return to the heart.
Compared with dobutamine, as
less tachycardia
move vasodilation
Greater decreases SVR and BP
More effective at decreasing cardiac filling
Compared with dobutamine, as Milrinone
less tachycardia
move vasodilation
Greater decreases SVR and BP
More effective at decreasing cardiac filling
Milrinone not used in
Severe obstructive aortic or pulmonic valvular disease
The inotropic effects of milrinone are decreased by _____? why?
ACIDOSIS; Presumably reflecting decreased cAMP formation in acidotic muscle
Milrinone should be avoided in severe Chronic HF why
Increased morbidity and mortality with chronic use.
Loading dose of milrinone
50mcg/kg administered over 10 MINUTES
followd by continuous infusion 0.375 -0.75 mcg/kg/min
Elimination half life of milrinone
- 3 hours
Elimination organ is ______ and_____ of milrinone is excreted ______. Therefore, dose should be decreased in patients with _________
Kidneys ; 80% unchanged in urine;
Renal insufficiency.
Adverse effects of MILRINONE
HYPOTENSION
What increases the risk of hypotension
What decreases the risk?
Loading dose
Slow administration
Milrinone can cause
Atrial or ventricular arrythmia
Nonsustained vtach or vfib
Inamrinone
Agent of choice is
does everything milrinone
Milrinone does it better
MILRINONE
Non-selective Phosphodiesterase Inhibitors
Theophylline and Aminophylline
Is structurally in the class of ________medications and is similar in structure to
methylxanthine ; Caffeine
Is a bronchodilating agent that also has anti-inflammatory, immunomodulatory and stimulatory properties
bronchodilating
Theophylline has______and is available in both ____ and ______routes
several mechanism of actions; IV and PO
Theophylline is recommended IV for the treatment of ________ and _________
bronchospasm due to an acute exacerbation of asthma and for reversible airflow obstruction.
Treat primary _______of prematurity
stimulates respiratory medullary centers
apnea
Inhibition of these isoenzymes
mediates_______
mediates smooth muscle relaxation through accumulation of both intracellular cGMP & cAMP, resulting in bronchodilation of airway smooth muscle
Is a ________ -________ inhibitor of phosphodiesterase enzymes (primarily PDE III and, to a lesser extent, PDE IV).
weak, nonselective, competitive
Theophilline puts the patients
risk for aspiration
Theophilline Is a competitive antagonist of _____ -_________receptors, resulting in antagonism of ____________ leading to smooth muscle relaxation and bronchodilation
A1 and A2 adenosine receptors; bronchoconstriction
Theophilline has several anti-inflammatory effects
Inhibits the release of histamine and leukotrienes
Reduces the number of eosinophils and neutrophils
Reversal of glucocorticoid resistance by theophylline
Theophylline: Mechanism of Action
Is a CNS ________
Increases the force of contraction of DIAPHRAGMATIC MUSCLES (because of enhanced calcium uptake through adenosine mediated channel)
-stimulant
Theophylline : Is a cardiovascular stimulant by ______ ______therefore HR and CO are _____
stimulating the release of endogenous catecholamines ; increased.
Theophylline on heart side effects
tachycardia
Theophylline has a ______TI
Narrow
Theophylline metabolized throught the liver
CYP 450
What speeds up the metabolism of Theophylline? Clear better
RPPCSC - SMOKING
Theophylline excretion
<10%
Aminophylline is _______Theophylline
80%
Both theophylline and aminophylline pass freely across the p_____ _______ _______ and produce ______ in ______
placenta, into breast milk and into cerebrospinal fluid and can produce toxicity to neonates
Mechanism of action of aminophylline
Same as theophylline.
Therapeutic range of Theophylline
5-15 mg/L
Affect clearance of theophylline
both the clinical status of the patient and medication will alter clearance of theophylline
THeophylline 15-25mg/L
Tachycardia and palpitations
THeophylline 15-25mg/L
Tachycardia and palpitations
Theophylline. >25mg/L
Tachyarrhythmias- PVCs, Vtach
Drugs that increase theophylline clearance
CYP 450 inducers
Drugs that decrease theophylline clearance
CYP 450 inhibitors
ANESTHASIA Considerations
Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines
and results in increased risk of ventricular arrhythmias
Theophylline =? Crosses the placental barrier
toxic to neonates
Ketamine and theophylline
lower theophylline seizure threshold and increase risk of seizures in patients taking theophylline
Discontinuing theophylline without reducing the dose of benzo may lead to
Respiratory depression
Benzodiazepines such as diazepam and midazolam, Theophylline can decrease the effectiveness of diazepam or midazolam WHY? Therefore
-increase CNS concentrations of adenosine which is a potent CNS depressant, while theophylline blocks adenosine receptors.
- Larger doses of these agents may be required to
achieve neuromuscular blockade
______ diazepam/midazolam doses may be required to produce a desired level of sedation.
Larger
Discontinuation of theophylline without reduction of diazepam/midazolam dose may result in ______________
respiratory depression
The inotropic effects of calcium are enhanced in patients with preexisting _______ or ______
-hypocalcemia or hyperkalemia
With calcium, ________ in HR and systemic vascular resistance can be seen as well as ________ in systemic vascular resistance and MAP
Decreases; increases
Calcium when given IV can produce an __________ effect and increased____ _____
-positive inotropic; stroke volume
Duration of action calcium: ____minutes
10-20 minutes
The risk of cardiac arrhythmias exist with calcium when _____especially if _______ is present.
when IV calcium is given to patients receiving digoxin, especially if hypokalemia is present
Calcium chloride contain ______ more elemental calcium than calcium gluconate salt solutions. Typical dose of Calcium chloride is
~3 times; 5-10mcg/kg IV.
1 gram of calcium chloride________amount of elemental calcium as giving 1gram of calcium gluconate
IS NOT THE SAME
Calcium is used to :
Used to treat cardiac/myocardial depression that
-may follow termination of cardiopulmonary bypass
-may accompany the delivery of volatile anesthetics, the transfusion of citrated
blood or the use of potassium containing cardioplegia solutions
Adverse reactions (3)
Rapid injection may cause hypotension, a tingling sensation, or a
sense of oppression or “heat wave”
Local “burning” sensation
Irritating to veins and local infiltration may occur
PDE-III is found in high concentration in the
Myocardium and Vascular Smooth Muscle (VSM)
PDE III INhbitors are : (class)
non-catecholamine and non-glycoside compounds
PDE III inhibitors decreases the degradation of cellular cAMP which results in (ACTION IN SMOOTH MUSCLE)
In smooth muscle, increased levels of cAMP produce vasodilation of resistance and capacitance vessels.
PDE–III Inhibition improves CO through _______ AND by _______ preload and afterload (aka ______)
INOTROPY
DECREASED
Inodilators.
Selective PDEIII inhibitors will act _______ of beta adrenergic receptors and will increase ________ in those 3 types of patients?
Independently
- Patients with myocardial depsression from Beta adrenergic blockers
- Pt with down regulation of beta adrenergic receptors
- Patient who have become refractory to catecholamine therapy
The hemodynamic response produced by PDE inhibitors exceeds that of ______and are _______with catecholamines, therefore, can be used in conjuction with ______
Digitalis
synergistic
Digoxin
Why was INAMRINONE replaced by milrinone?
MORE frequent occurence of THROMBOCYTOPENIA
Compared to Inamrinone, milrinone is
- 20 times more potent as inotrope
- has enhanced vasodilatory properties causing a greater decrease in the LVP and BP
Which medication has been shown to reverse VASOSPAMS in arterial grafts and is thought to have anti-inflammatory effects?
Milrinone
Important to know that Theophylline is _____Effective than B2 adrenergic agonist and should only be used______
Less; when selective beta 2 adrenergic agonist and corticosteroid fail to produce adequate response.
Phosphiesterase enzyme inhbition lead to ?
Smooth muscle relaxation through accumulation of both intracellular cGMP and cAMP, resulting in bronchodilation of airway smooth muscle.
Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE and include?
inhibition of PDE III Hypotension Tachycardia Headache Emesis
Theophylline on CNS
Increased alertness
Increased ability to concentrate
Stimulates the medullary respiratory centers by
Increasing the sensitivity of these centers to CO2
Factors decreasing clearance of theophylline?
Age (reduced in neonates&Elderly)
Cirrhosis, CHF and fever
Which has the most significant factor on increasing clearance for theophylline?
SMOKING
Adverse effects of theophylline are related to plasma concentrations and at serum concentration greater than
20 mcg/ml
Adverse effects of theophylline when levels are 15-25
NVHTP(Nausea vomiting headache, tachy and palpitation)
Adverse effects of theophylline when levels are >25
Severe NVHTP
Tachyarrhythmias (PVCs, VTACH)
Seizures and deaths.
Theophylline and neuromuscular blockade consideration
May antagoniz nondepolarizing neuromuscular blocking effects due to phosphodiesterase inhibition. Larger doses may be needed.
Pentoxifylline is used to treat
intermittent claudication due to chronic occlusive arterial disease of the limbs.
What is pentoxifulline?
Side effect
Methylxantine derivative which is a Hemorrheologic agent that increases flexibiltiy of erythrocytes and decreases viscosity of blood , therefore improving capillary blood flow and tissue oxygenation.
Nausea.
Glucagon is a
polypeptide hormone produced by the alpha cells of the pancreas
Glucagon is anti_______and has (effects on heart)
When given as a drug______
Tissues with glucagon receptor_______
Antihypoglycemic; Positive inotropic and chronotropic effects
**work as inotrope
Heart.
Glucagon interacts with a __________ that stimulates _____ _______which increases the______ _______
G protein-coupled receptor (Gs on
the heart that stimulates ADENYLATE CYCLASE which increases the production of cAMP.
With glucagon, the increased cAMP in the heart promotes _________
calcium ion influx which increases intracellular calcium concentrations and results in positive chronotropic and positive inotropic effects on the heart
Does glucagon activate
or bind to beta-adrenergic receptors OR inhibit PDE ?
It does not; no
Glucagon also evokes and tell nerves to release what?_______
Can be given in GI procedure to
The release of catecholamines
Reversing spasms of the sphincter of oddi
The principle cardiac indication of glucagon:
is to increase myocardial contractility and heart rate in the presence of beta-adrenergic blockade (Used in the treatment of beta-blocker overdose)
This drug is used in the treatment of beta-blocker overdose
GLUCAGON
Rapid IV administration of 1-5mg of glucagon or a continuous infusion of 1-5 mg/hour results in increased
____________
increased
stroke volume (increased force of contraction) and heart rate
independent of beta-adrenergic stimulation
CV adverse effects of Glucagon :
3
- Tachycardia that is great enough to interfere with cardiac output may occur
- Abrupt increases in heart rate may occur when glucagon is
given to patients in atrial fibrillation - MAP may increased whereas SVR may stay same or decreased
not effective in evoking a sustained positive inotropic and chronotropic effect
The chronic administration of glucagon
Glucagon side effects
Nausea and vomiting that is dose- dependent
Monitor for pulmonary aspiration
Tachycardia and hypertension
HYPOGLYCEMIA (may occur in patients that lack glycogen stores)
HYPOKALEMIA (increased secretion of insulin and subsequent intracellular shift of K+)
Glucagon stimulates the release of catecholamines and may cause
hypertension in patients with unrecognized
pheochromocytoma’s
