Pharmacology - CVS Flashcards
What is the mechanism, clinical effect and pharmacokinetics of GTN
**-mechanism:
converted to nitric oxide, taken up by smooth muscle (all types, including vascular), causes increased cGMP
prevents interaction between myosin and actin, leading to SMC relaxation
-clinical effect: reduces myocardial oxygen demand
vascular =** venodilation** at low concentration, causing reduced venous return–> reduced LVEDV/ventricular pre-load–> decreased LV wall tension–> reduced myocardial oxygen.
arteries dilated at high concentration, causing reduced BP and dilation of epicardial artery
overall effect: reduce CO and myocardial oxygen demand and improved delivery of oxygen to heart
other: relax bronchi, GI tract, GU tract, decrease platelet aggregation
-pharmacokinetics: Administration: SL/IV/Transdermal/Buccal
GTN rapidly absorbed but high first pass metabolism, bioavailability <10-20% (ISMN oral bioavailability of 100%)
SL route avoids hepatic metabolism,
onset 1-3 minutes, doa 10-30 minutes
excretion via kidneys
2/3; 2/3
What are the indications, side effects and contraindications of GTN
-indications:
angina, acs, hypertensive emergencies, APO, aortic dissection
-adverse effects:
orthostatic hypotension, tachycardia, headache, methaemoglobinaemia
-contraindications:
hypotension, inferior and posterior MI or right ventricular infarct, fixed cardiac output(Aortic stenosis, tamponade etc.); Raised ICP
What is tachyphylaxis as it relates to GTN
-continuous exposure to GTN causes SMC to develop tolerance, seen with continuous infusions
-require a drug free interval of at least 8 hours between doses
-theory: diminished release of nitric oxide and systemic compensation
When should GTN be used with caution
hypotension
inferior/posterior MI
raised ICP
significant tachycardia
What are the effects of nitric oxide
- smooth muscle relaxant
- platelet inhibition
- immune regulator
- neurotransmitter
(Nitro for a SPIN)
What are the therapeutic applications of nitric oxide
-vascular effects: angina
-hypertension associated with pregnancy
-respiratory disorders: newborns with pulmonary hypertension
-atherosclerosis: may act as an antioxidant and preventing foam cell formation in the vascular wall
-platelets: inhibitor of platelet aggregation
-CNS: may have a role in epileptic seizures
What drugs are used in hypertensive emergencies
GTN
nifedipine
diazoxide
hydralazine
nitroprusside
esmolol
labetalol
What is the mechanism of action, pharmackinetics and side effects of sodium nitroprusside?
Pharmacodynamics:
- release of NO leading to increased cGMP, causing smc relaxation
- affects arteries and veins equally
Pharmacokinetics:
- only parental form available
- onset 1 minute, half life 2 minutes, duration of action 5 minutes
- rapidly metabolised by uptake into RBC, release NO and cyanide
- sensitive to light
Side effects:
- accumulation of cyanide
- hypotension
- metabolic acidosis
- arrhythmia
What is the mechanism of action, pharmacokinetics, indications and adverse effects of Adenosine; Drug interactions
-mechanism:
Blocks AV conduction
act on the Adenosine receptor
activating inward rectifier K+ current and inhibit Ca+2 currents causing hyperpolarisation of AV node and suppresion of calcium dependent AP.
directly inhibits AV nodal conduction and increases AV nodal refractory period, less effect on SA node. Interrupts re-entry through AV node
-pharmacokinetics:
very rapid metabolism by adenosine deaminase in RBC and endothelial cells
t1/2 <10 seconds, doa 30 seconds, must be given by rapid IV bolus
-indications: conversion of SVT to sinus rythm
-adverse effects: flushing, Bronchospasm, chest tightness, sense of impending doom, Arrythmia
-contraindications: AV block, SSS, acute asthma
-Drug interactions: Theophylline inhibits adenosine rc
Dipyrridamole enhances;blocks adenosine re-uptake
How do you classify anti-arrhythmic drugs and give an example of each
-class 1 = Na+ channel blockers
a - procainamide, quinidine (prolongs AP)
b - lidocaine (shortens AP)
c - flecainide (minimal effect on AP)
-class 2 = beta blockers - propranolol
-class 3 = K+ channel blockers - amiodarone, sotalol
-class 4 = Ca+2 channel blockers - verapamil, diltiazem
What antiarrhythmic drugs can be used in the management of AF
class 1c (flecainide)
class 2 (metoprolol)
class 3 (amiodarone)
class 4 (verapamil)
unclassified (digoxin)
What is the mechanism of action and cardiac effects of Amiodarone?
-mechanism:
class 3 antiarrhythmic medication (potassium channel blocker)
blocks rapidly activating potassium current, causing markedly prolonged AP duration and QT interval
also: blocks Na+ channel, weak beta blocker, noncompetitive alpha blocker, weak Ca+ blocker
-effects:
prolongs AP duration, decreases HR and AV nodal automaticity, slows AV nodal conduction
Indications, side effects and drug interactions of Amiodarone
-indications: ventricular (vt) and supraventricular (af) arrhythmias
-adverse effects: heart block, pulmonary toxicity, hepatitis, hypo/hyperthyroidism, photodermatitis, torsades (rare)
-drug interactions:
amiodarone is a substrate for CYP3A4
inhibitors (cimetidine) - increase level of amiodarone
inducers (rifampicin) - decrease level of amiodarone
amiodarone inhibits several P450 enzymes, causing increased levels of - digoxin, warfarin, statin
What is the mechanism of action and pharmacokinetics of digoxin
-mechanism:
increases cardiac contractile force and decreases HR
mechanical =
inhibit Na+/K+ ATPase, causing increased intracellular Na+ and decreased intracellular K+
this causes decreased Ca+2 expulsion via Na+/Ca+2 exchange
increased concentration of Ca+2 causing increased contraction of cardiac sarcomere
electrical = indirectly modifies autonomic activity and increases efferent vagal activity
this causes decreased firing rate at SA node and increased refractory period at AV node
-pharmacokinetics:
well absorbed orally, moderate VOD, t1/2 36-40 hours, 2/3 excreted unchanged by kidneys
Are the parasympathetic effects of digoxin uniform throughout the heart
No
The atria and SA/AV node are more affected than purkinje or ventricular function
What are the features of toxicity of digoxin, antidote and why are patients in heart failure more prone
Features of Digoxin Toxicity:
- Cardiac: hyperkalaemia, enhanced automaticity + decreased AV nodal conduction -> arrhythmia (AVJR, PVC, VT, bigeminy, 2nd degree HB, bradycardia with R on T)
- Neurological: disorientation, hallucination, green and yellow vision
- Gastrointestinal: anorexia, nausea/vomiting/diarrhoea, abdominal pain
Antidote for Digoxin Toxicity: digoxin-specific antibody fragments (Digibind), 1 vial covers 500mcg digoxin
Predisposition:
- Reduced kidney function: renal clearance requires dose adjustment, patients in heart failure have poor renal perfusion from lower CO, K+ competes with binding of digoxin, so toxicity increased in setting of low K+ (may be on diuretics)
- Drug interaction: increased digoxin level by NSAIDs, (impairing renal clearance), thiazides and loop diuretics (depleting K), aitiarrhythmics (amiodarone, quinidine), verapamil (CCBs), macrolide antibiotics (increased bioavailability)
- Electrolyte disturbance: low K, low Mg, high Ca
What is the mechanism of action, pharmacokinetics and contraindications of flecainide
- mechanism: class 1c antiarrhythmic (sodium channel blocker)
blocks Na+ and K+ channels with slow unblocking kinetics, prolongs QRS but no effect on AP duration - pharmacokinetics: well absorbed orally, t1/2 20 hours, eliminated via liver and kidneys, dose 100-200mg OD
- indications: supraventricular arrhythmias in normal hearts
- contraindications: pre-existing ventricular tachyarrhythmia or IHD
What distinguishes lidocaine from other class 1 antiarrhythmics?
- shortens AP duration
- dissociates with rapid kinetics and has little effect on the ECG in NSR
What is the mechanism of action of lidocaine on the heart
Mechanism:
- class 1b antiarrhythmic (sodium channel blocker), greater effect on ischaemic tissue
- blocks activated and inactivated Na+ channels with rapid kinetics
- binds refractory channels, shortens AP
Indications: arrhythmia associated with MI, local anaesthetic, post herpetic neuralgia Adverse effects: hypotension, bradycardia, paraesthesia, tremor, nausea, tinnitus, visual disturbance
Describe the pharmacodynamics, pharmacokinetics and side effects of propranolol
Beta blocker. Class II antiarrythmic.
Dynamics:
- MOI: non-selective beta-blocker, direct membrane effects with Na+ channel block, prolongation of AP duration
- cardiovascular: negative inotrope, negative chronotrope, increase PR interval by increasing AV nodal refractory period, antagonises renin release, lower blood pressure
- respiratory: bronchospasm
- ophthalmological: decrease IOP
- metabolic: decrease glycogenolysis
- endocrine: reduce peripheral conversion of T4 to T3
Kinetics:
- high first pass metabolism, 25% bioavailability
- high lipid solubility, large VD, readily crosses the BBB
- t1/2 4 hours
ADR:
bradycardia, AV blockage, ventricular arrythmia/death, hypotension, bronchospasm, sedation, reduced hypoglycaemia response
(in high doses, Na channel blocking effects similar to TCAs: seizures, cardiac conduction block)
How does carvedilol differ from propranolol
carvedilol has no local anaesthetic action but has alpha 1 block
Describe the mechanism of action, pharmacokinetics and effects of metoprolol
-mechanism:
beta 1 selective beta blocker
-pharmacokinetics:
PO or IV, well absorbed, bioavailability 50% (first pass effect), large VOD, metabolised by liver
-effects:
negative chronotropic and inotropic, slows AV node conduction
Why do beta blockers lower BP?
- BP is determined by cardiac output (HR x SV) and TPR
- beta blockers lower HR and reduce force of contraction
How does metoprolol differ from propranolol
equipotent at B1
metoprolol is 50-100 times less potent at B2
Describe the pharmacodynamics/kinetics and side effects of sotalol
-pharmacodynamics:
class 2 and 3 antiarrhythmic
non-selective beta blocker causing decreased HR
blocks K+ channels causing a prolonged AP duration
used in ventricular arrhythmias, maintenance of SR in AF, decreases cardiac threshold for defib
-pharmacokinetics:
well absorbed, bioavailability of 100%, low lipid solubility, no protein binding, not metabolised, half-life 12 hours, excreted unchanged by kidneys
-side effects:
prolongs QT and TdP, AV blockade, reduction in LV function in CCF, asthma exacerbation
What drug interactions occur with sotalol to prolong the QT
phenothiazines
macrolides
antidepressants
drugs that cause hypokalaemia
What are the pharmacokinetic principles, effects and side effects of beta blockers
-well absorbed, low bioavailability, large VOD, most metabolised in liver
-effects: negative chronotropic and inotropic, AV block, increased survival after MI, bronchospasm
-side effects: hypotension, bradycardia, cardiogenic shock, bronchospasm, seizure
What are the effects of calcium channel blockers on smooth muscle
smc relaxation
arterioles are more sensitive than veins but both are dilated
How do calcium channel blockers control angina and what are the toxic effects
-voltage-gated L-type calcium channels is dominant in cardiac and smooth muscle
blocking these channels cause decrease opening and decreased calcium current, leading to:
-reduced myocardial contractility - causing reduced oxygen demand
-decreased SA node rate and AV node conduction velocity
-relaxation of vascular smooth muscle - causing decreased afterload
-toxicity: cardiac depression, bradycardia, AV block, cardiac arrest, heart failure, peripheral edema
Differentiate verapamil from other calcium channel blockers
-verapamil and diltiazem are mainly antiarrhythmic (more marked in tissues that fire frequently)
side effects: bradycardia
-nifedipine and nimodipine (dihydropyridines) are predominantly vasodilating
side effects: flushing, headache, tachycardia
What is the mechanism of action and uses of verapamil
-mechanism:
class 4 antiarrhythmic, blocks activated and inactivated slow L-type Ca+2 channels
works on vascular smc, cardiac myocytes and cardiac nodal tissue
AV node conduction time and effective refractory period are prolonged
directly dilates coronary arteries
-indications:
angina, hypertension, atrial arrhythmia, migraine
-side effects:
hypotension, bradycardia, AV block, constipation, edema
-antidotes in toxicity:
calcium, insulin
What are the sites of action of antihypertensive drugs
-diuretics: lower BP by depleting Na+
example. frusemide, thiazide, spironolactone
-centrally active: lower BP by reducing sympathetic outflow from vasomotor centers in the brain
example. methyldopa, clonidine, moxonidine
-beta-blockers: lower blood pressure by beta antagonism causing negative inotropic and chronotropic effects
example. metoprolol
-alpha-blockers: lower BP by alpha antagonism dilating capacitance and resistance vessels
example. prazosin
-vasodilators: lower BP but sympathetic reflexes remain intact, no orthostatic hypotension
example. hydralazine (dilate arteries only), GTN (dilate veins>arteries), nifedipine (dilate arteries>veins)
-angiotensin modulators: lower BP by inhibiting RAS
example. ACE inhibitor (enalapril), angiotensin II blocker (losartan)
Describe the mechanism of action of ACE inhibitors (also asked as Catalopril and Ramipril)
-mechanism:
competitively block conversion of angiotensin I to angiotensin II
inhibits RAS: normally would cause arteriolar vasoconstriction, Na+/Cl- reabsorption, aldosterone/ADH secretion
stops inactivation of the kallikrein-kinin system
-effects: decreased vascular tone, decreased BP
Describe the pharmacokinetics, uses and side effects of ACE inhibitors
-pharmacokinetics: eliminated mainly by the kidneys, need renal adjusted dosing
-uses: CHF, post MI, diabetic nephropathy to stabilise renal function, hypertension
-adverse effects: AKI, hyperkalaemia, dry cough, dizziness, hypotension, angioedema
-interaction: hypotension with diuretics, lithium toxicity with lithium, hyperkalaemia with potassium sparing diuretics
Describe the pharmacodynamics of medications that modulate the effect of angiotensin
-ACE inhibitors:
reversibly block conversion of angiotensin I to angiotensin II
-angiotensin blockers:
competitive antagonists at AII receptors, does not increase level of bradykinin
What are the advantages of angiotensin receptor blockers over ACE inhibitors
- ACE also breaks down bradykinin, ARB has no effect on bradykinin, so reduced incidence of cough and angioedema
- more complete inhibition of actions of angiotensin II
What is the mechanism of action and side effects of prazosin
-mechanism: selective alpha 1 blocker affecting arterioles and venules
reduces arterial pressure by dilating both resistance and capacitance vessels
-side effects: dizziness, palpitations, headache, fatigue, first dose hypotension, postural hypotension
What is the mechanism and effect of acetazolamide
-mechanism: inhibition of carbonic anhydrase enzyme
causes reduced H+ excretion and increased Na+/K+ excretion leading to diuresis
-toxic effect: hyperchloraemic normal anion gap metabolic acidosis, renal K+ wasting, low pH of CSF, renal stones
What is the mechanism of action, indications and adverse effects of thiazide
-mechanism:
inhibits the Na+/Cl- cotransporter on the luminal side of the early distal convoluted tubule
prevents re-absortion of NaCl and promotes diuresis
-indications:
hypertension, heart failure, nephrogenic diabetes insipidus, edema, nephrotic syndrome, cirrhosis
-adverse effects:
hypokalaemic metabolic alkalosis, hyperlipidaemia, hyponatraemia, hyperuricaemia
What are the pharmacokinetics and side effects of frusemide
-mechanism
loop diuretic, acting by inhibiting Na+/K+/2Cl- transporter on luminal side of ascending loop
prevents reabsorption of Na+ and Cl- and causes diuresis
-pharmacokinetics:
rapidly absorbed, onset post oral 1-3 hours/post IV 15-30 minutes, t1/2 1.5-2 hours
highly protein bound, 50% conjugated in kidney, 50% excreted in urine unchanged
-side effects:
electrolyte = hypokalaemic metabolic alkalosis, hyponatraemia, hypomagnesaemia, hyperuricaemia
others = orthostatic hypotension, dehydration, ototoxicity (reversible)
-drug interactions:
nsaid, aminoglycosides, digoxin, lithium, propranolol, thiazides
Why is mannitol used in management of head injury and what are the toxic effects
-used to reduce intracranial pressure
-mechanism: osmotic diuretic, does not cross BBB, draws water out of cells and reduced intracellular volume
-freely filtered by glomeruli, not reabsorbed
-other clinical effect: reduces rate of CSF production, reduces intraocular pressure
-dose in raised intracranial pressure: 1-2g/kg as IV bolus over 15 minutes
-toxic effects: extracellular volume expansion, hypovolaemia, hyponatraemia, hypokalaemia
