Inotropic Drugs (Dawes) Flashcards
What do Inotropic and Vasopressor Drugs do?
Both drugs result in increased BP (alpha and beta agonists) with very narrow therapeutic window.
- Inotropic drugs i_ncrease force of contraction._
- Vasopressor drugs increases vascular tone.
Define Inotropes
Inotrope is changing the force of (cardiac) muscle contraction. It can be positive or negative.
Define Shock
Shock is characterized by inadequate organ perfusion to meet the tissue’s oxygen demand, leading to organ dysfunction.
What are the categories of Shock
- Hypovolemic (e.g. haemorrhage, dehydration)
- Cardiogenic (e.g. heart failure)
-
Distributive (most common) (e.g. sepsis, anaphylaxis)
- Severe, overwhelming infection causes profound vasodilatation due to release of corticoids, cytokines etc.
- This leads to poor perfusion to organs (septic shock)
- Obstructive (e.g. cardiac tamponade, pulmonary embolism)
What are the features of Shock?
- Hypotension/hypovolemia
- LV impairment
- Changes in vascular resistance
- Poor renal/peripheral perfusion
- Confused/sedated
What are the goals of Shock resucitation?
- Restore blood pressure (ensure patient is euvolemic, maximise CO, measure centrally via intra-aortic balloon pump)
- Normalize systemic perfusion (inotropes and vasopressors, benefits outweighs risks in emergency revascularisation and initial medical stabilisation)
- Preserve organ function (renal perfusion)
- Treat underlying cause (antibiotics; relieve tamponade)
What is cardiogenic shock?
What is it characterized by?
Cardiogenic shock has multiple causes
- Ischaemic
- Valve dysfunction
- Acute VSD (ventricular septal defect)
It is characterized by high systemic resistance (sympathetic activity) and low cardiac output.
In cardiogenic shock it is important to…….
Why?
In impaired ventricular function, it is important to ensure that patient is euvolemic (normal body fluid) (maximises CO), because having fluid overload or underload can further impair ventricular output.
What are the mechanism of action of inotropoic agents?
Inotropic agents augments contractility, after preload established, thus improving cardiac output
Rationale is that increased cardiac output improves global perfusion
Risk includes tachycardia and increased myocardial oxygen consumption (risk of exacerbating myocardial ischemia)
Vasopressors/inotropic agents are __________________ (receptors)
Vasopressors/inotropic agents are alpha and beta adrenoceptor agonists.
Name some examples of Vassopressors/inotropic drugs
- They include norepinephrine, epinephrine, dobutamine, dopamine.
Whether drug acts preferentially as a vasopressor or a positive inotrope depends on…………..
- Whether drug acts preferentially as a vasopressor or a positive inotrope depends on their potency as alpha or beta agonist.
- Majority of a agonists are vasopressors
- Majority of b agonists are positive inotropes/chronotropes
Adrenergic receptors include…
What do they do?
Adrenergic receptors include:
- Alpha 1 on mostly vascular smooth muscle
- Alpha 2 on mostly presynaptic
- Beta 1 on mostly heart
- Beta 2 on respiratory and uterine smooth muscle
- Beta 3 on mostly adipocytes
- (Dopamine)
Compare between B-1 and A-1 receptors int he adrengergic system
Give an example of each
Beta-1 Receptors
Dobutamine is b1 agonist
- b1 receptors mostly in heart
- Increase contractility (positive inotrope)
- Increase heart rate (positive chronotrope)
Alpha-1 Receptors
Norepinephrine is a1 agonist
- a1 receptors mostly in blood vessels
- Increase tone/resistance (vasopressor)
Describe Norepinephrine
Norepinephrine (Noradrenaline)
Norepinephrine is first-choice vasopressor.
- It is potent a-adrenergic agonist (vasoconstriction)
- It has minimal b1 adrenergic agonism (minimal inotropic, chronotropic effect)
- Uptake 1 mechanism
- Pre-synaptic mechanism of rapid norepinephrine uptake, therefore short half-life of norepinephrine
- Uptake 1 mechanism
It increases peripheral resistance and increases systolic/diastolic BP
Its route via continuous intravenous infusion with dose of 1-100ug/min
- Start with low dose, titrate dosage according to BP
- Monitoring effects to reduce side effects such as coronary vasoconstriction
Decribe Epinephrine (adrenaline)
Epinephrine has mixed a and b adrenergic effects
- Can cause both v_asoconstriction and vasodilatation (_depends on adrenoceptor density in that organ),
- net effect of increasing BP
- It is _potent inotrope and chronotrop_e (used in cardiac arrest situations)
- Uptake 2 mechanism
- Post-synaptic mechanism of fast epinephrine uptake, therefore short half-life
- Uptake 2 mechanism
It i_ncreases myocardial oxygen consumption_ particularly in coronary heart disease
Its route via continuou_s intravenous infusion_ with dose 1-10ug/min.
What is Epinephrine used in?
Epinephrine is used in treatment of anaphylaxis and symptomatic treatment of anaphylactic shock (Epi-Pen IMI):
- Activates both a and b receptors
- Potent vasopressor
- BP increase
- Dilates bronchi
Describe Dobutamine
Dobutamine is b1 agonist.
- It is potent inotrope, variable chronotrope
- Half-life of ~2 minutes, IV dose 5-20ug/kg/min
- Hepatic metabolism (glucuronide)
- Caution in hypotension (inadequate volume) may precipitate tachycardia or worsen hypotension
Describe the role of Dopamine
Dopamine is metabolic precursor of norepinephrine.
It has short half-life (both uptake 1 and 2 mechanisms).
- Low dose (0.5-2ug/kg/min) is dopaminergic (increase renal blood flow) via D1 receptors
- Moderate dose (2-10ug/kg/min) has b-effects (positive inotropy and chronotropy)
- High dose (>10ug/kg/min) has a-effects (vasopressor)
What are the vasopressor side effects?
Patients in shock already have high sympathetic drive
It causes vasoconstriction (a agonism), hence risk of rschaemia (cardiac, limb, gut, cerebrovascular)
It has increased cardiac work (a and b agonism), hence can lead to cardiac ischaemia and arrhythmias
Describe the role of Amrinone/Milrinone
Amrinone/milrinone are phosphodiesterase III inhibitor:
- Vasodilation
- Positive inotrope (cardiac smooth muscle)
-
Increase cAMP, so activates protein kinase
- Increases Ca2+ flux in myocardium
- Ca2+ uptake into SR in vessels
Most often added with dobutamine as a second agent, need ITU environment and IV administration.
- Dobutamine increases ATP -> cAMP
- Phosphodiesterase III inhibitors increases cAMP -> AMP
Describe the Levosimendan drugs
Levosimendan is a new calcium sensitizer (emerging role in treatment of shock). It requires IV administration.
- It enhances troponin sensitivity to Ca2+
- Increases inotropy
Side effects include arrhythmias, increased mortality
Name a drug that is COMMONLY used for cardiac contractility
Digoxin
What are the indicators for Digoxin?
Digoxin indications include atrial fibrillation (rate control)
- Slows HR but also increases inotropy
- Improves cardiac work
- Treatment for acute/chronic heart failure
There is no effect on mortality, improves symptoms, reduces need for hospital admissions.
Describe how you would give digoxin
Digoxin has long half-life, so requires loading dose (if initiate with normal dose, take 2-5 half-lives to achieve therapeutic effect)
- Loading dose (long half-life) up to 1.5mg over 36hr (oral or IV)
- Maintenance dose of 0.0625-0.25mg per day (dependent on renal function due to renal elimination, caution with CKD)
Describe the mechanism of action of Digoxin
Increasing Inotropy
- Inhibition of Na+/K+ ATPase -> increased [Na+]i
- Increased [Na+]i is sensed by Na+/Ca2+ exchanger -? extrude Na+ and intrude Ca2+ -> increased [Ca]i
- Therefore, it i_ncreases contractility_
- Digoxin effect is more prominent in hypokalaemia since potassium competes with digoxin at Na+/K+ ATPase
Decreasing Chronotropy
- Augments vagal tone at AV node
- Slows AV conduction
- Slows ventricular rate
What are the clinical uses of digoxin
Digoxin Clinical Use
Clinical uses (ED, HDU) include:
- Acute congestive heart failure with fast atrial fibrillation (not useful in chronic CCF?)
- _AF rate control (_3rd line drug)
- 1st line is beta-blockers, 2nd line calcium channel blockers (diltiazem)
- Often need synergy between two of three drugs
What are the side effects of digoxin?
Cardiac Toxicity
- V_arious arrhythmias_
- Bigeminy, NSVT, VT
- 2nd or 3rd degree heart block
- Changes in ECG (increased PR, decreased QT, change P, change T, change ST)
Non-Cardiac Toxicity
- Nausea/vomiting/anorexia/diarrhoea
- Abdominal pains
- Fatigue
- Visual complaints
- Muscular weakness
- Dizziness
- Dreams
What are some Digoxin Interactions?
Metabolic
Metabolic interactions include include decreased K+ and decreased Mg2+
- Increases digoxin effects and side effects
- Care with use with diuretics
Drugs
Drug interactions include quinidine, amiodarone, verapamil, diltiazem, erythromycin, cyclosporin
- Increases plasma levels of digoxin
- Inhibit P-glycoprotein, which increase digoxin toxicity
Describe the P-Glycoprotein drugs
P-glycoprotein (PGP) is multi-drug transporter. PGP protects against digoxin toxicity by….
- Decreasing GI absorption
- Increasing biliary excretion
- Increasing renal excretion
- Decreasing CNS access
(Conclusions)
- Shock is proportional to high mortality
- Monitored on ITU, HDU, CCU
- Treatment tailored for individual (treat underlying cause)
- α and b agonists used to maintain BP and perfusion
- (different) Digoxin useful in acute CCF complicated with AF
