CVS Drugs 1 to 10
Describe the mechanism of action of glyceryl trinitrate?
- Taken up by vascular smooth muscle
- Interacts with tissue sulfhydryl groups
- Releases free radical nitric oxide
- Activates cGMP
- Dephosphorylates myosin light chains
- Reduces intracellular Ca levels
- Smooth muscle relaxation & vasodilation
- Vascular smooth muscle
- Nitric oxide
What are the clinical effects of nitrates?
(Prompt if needed: What other clinical effects may be seen?
- Low doses – venodilation leads to decreased preload & stroke volume
- Higher doses – arterial dilation leads to decreased blood pressure as well as decreased cardiac output & decreased myocardial oxygen demand + dilation of coronary arteries/redistribution of perfusion
- Improved oxygen delivery to myocardium & resolution of ischaemic pain
- Adverse effects include:
- Postural hypotension, tachycardia, dizziness, headache, flushing, blurred vision, dry mouth, rash
- Decreased BP
- Decreased Myocardial oxygen demand
- PLUS 2 listed other effects
Describe the mechanism of action of ACE inhibitors.
- Competitive block conversion of angiotensin I to II
- Decreased vascular tone from prevention of vasoconstrictor effects of Ang II (main effect)
- Inhibition of aldosterone secretion caused by Ang II leading to reduced Na & H2 resorption resulting in decreased BP
- 3 in bold to pass
What are the adverse effects of ACE inhibitors?
- Dizziness, hypotension
- Headaches, weakness
- Loss of taste, nausea, diarrhoea
- Rash, fever, joint pain
- Mild hyperkalaemia due to decrease in aldosterone secretion
- Acute renal failure
- Hypotension or dizziness
- PLUS 2 others
What are some drug interactions that occur with ACE inhibitors?
- Diuretics Þ hypotension
- General anaesthetics Þ hypotension
- Lithium: lithium toxicity
- NSAIDS: hyperkalaemia & reduced effects of ACE inhibitor
- Potassium sparing diuretics / potassium supplements – hyperkalaemia
- 2 to pass
Describe the pharmacodynamics of therapeutic drugs that modulate the effect of angiotensin?
- ACE inhibitors – bind ACE reversibly preventing conversion of AI to AII.
- Inhibitory action on the renin-angiotensin system Stimulating action on the kallikrein-kinin system
What are the advantages of Angiotensin 2 receptor antagonists over ACE inhibitors?
- Angiotensin II inhibitors – competitive antagonists at A II receptor
- As AII inhibitors do not result in production of bradykinins, there is a decreased incidence of cough and angioedema.
- Potentially greater effect as enzymes other than ACE can generate AII
- Able to describe actions and basic effects of ACE inhibitors
- AND understanding that AII receptor antagonists and ACE inhibitors have different mechanisms
What is the cellular mechanism of action of GTN?
- Denitration by glutathione S-transferase.
- Free nitrite ions released and form NO.
- NO activates guanylyl cyclise leading to increased cGMP and dephosphorylation of myosin and smooth muscle relaxation (precise mechanism unknown)
- Production of NO leading to smooth muscle relaxation
How does GTN relieve angina pain?
- Venodilation leads to reduced venous return, reduce ventricular volume and reduced heart wall tension.
- This reduces myocardial O2 requirement
- Know that venodilation and reduced venous is major factor reducing myocardial o2 requirement
Outline the pharmacokinetics of sublingual GTN
- Oral bioavailability is low due to extensive first pass hepatic metabolism by high capacity organic nitrate reductase.
- Rapid and efficient absorption by sublingual or intranasal routes but rapid elimination (t1/2 2-8 mins) and duration of action (15-30 mins) due to high capacity hepatic metabolism.
- Denitrited metabolites conjugated to to glucuronide and excreted in urine.
- Poor oral bioavailability due extensive first pass metabolism and effective alternative routes of administration
How does GTN exert its effect on smooth muscle?
- Nitrite -> NO -> increased cGMP -> relaxation.
- Prostaglandins also involved
What are the clinical effects of GTN?
- Venodilation -> reduced venous return -> reduced LVEDV -> reduced LV wall tension -> reduced myocardial oxygen consumption (-> reduced cardiac output in normal people, possibly increased in pathological conditions where pretreatment preload is abnormally high)
- Arterial dilation -> throbbing headache (relatively ineffective on resistance vessels)
- Other smooth muscle relaxation (eg amyl nitrite + enhanced erection) less important
- Decreased platelet aggregation, but no apparent beneficial therapeutic effect in this regard
- Methaemoglobinaemia from nitrite but not from GTN
- Able to discuss pros and cons of at least two
What are the pharmacokinetic features of Beta Blockers?
- Well absorbed
- Low bioavailability
- Large volume of distribution.
- Most are metabolized in liver
- At least 2
What are the effects of beta blockers?
- Decrease in hypertension, negative chronotrope and negative ionotrope, atrioventricular block, increased survival after AMI, Bronchospasm, decreased IO pressure
- At least 2
What are the effects of beta blocker in overdose?
- Hypotension, bradycardia, cardiogenic shock, bronchospasm, seizures (cerebrotoxic),
- NB Propanolol causes arrhythmias through Type 1 antiarrhythmic effects (Na channel block)
- At least 3
What is the mechanism of action of atropine?
- Reversible block of cholinergic muscarinic receptors
Give examples of the organ effects of atropine?
- CNS: decrease tremor and rigidity in Parkinson’s disease
- Eye:– mydriasis and cycloplegia
- Cardiovascular: SA ( and AV) node; blocks vagal slowing -> rel tachycardia and incr conduction ( shorten PR )_, block coronary vasodilation
- Respiratory: blocks M receptors on smooth muscle and secretions
- Gastrointestinal: Blocks motility and secretions
- Genitourinary Relaxes smooth muscle in ureters and bladder wall ( spasm) and slows voiding ( retention)
- Skin: decreases sweating
- At least 3
What are the features of atropine poisoning?
- Agitation and delerium
- Raised temp
- Blurred vision / mydriasis
- Dry mouth / flushed skin
- At least 4
At a cellular level, describe the action of calcium channel blockers.
- Bind at intracellular L type calcium channel
What are the differences in pharmacodynamics between dihydropyridines and other Ca channel blockers?
- Dihydropyridines are vascular smooth muscle selective
- Verapamil / Diltiazem greater effect on cardiac/conducting tissue
How are these differing pharmacodynamics reflected in their side effect profile?
- Dihydropyridines cause flushing, headache & tachycardia
- Verapamil causes bradycardia
- Both can cause hypotension
What is the mechanism of action of captopril?
- Inhibit converting enzyme peptidyl dipeptidase which
- Hydrolyzes AI to AII – get decreases peripheral vasc. resistance; CO and HR same
- inactivates bradykinin – therefore get vasodilation, decreased Peripheral vascular resistance and decreased BP
What are the clinical uses of captopril?
- CHF, after MI (better preservation of LVF – reduce post MI remodeling)
- Diabetic nephropathy: diminish proteinuria, stabilize renal function – improved intrarenal hemodynamics
What are the adverse effects of captopril?
- Hypotension after 1st dose if hypovolemic, diuretics, NaCl restriction, GI loss
- ARF (bilateral renal a. stenosis)
- Hyperkalemia – if renal insufficiency, DM
- Dry cough, angioedema (bradykinin, substance P)
- Fetal problems if 2nd, 3rd trimester
- Neutropenia, proteinuria from high dose captopril
- Minor – change taste, skin rash, drug fever
What is the mechanism of action of adenosine?
- Enhanced K+ conductance – marked hyperpolarisation
- Inhibition of cAMP induced Ca2+ influx – suppression of calcium dependant AP
What effect does this have on cardiac conduction?
- Inhibits AV node conduction (at least )
- Increases AV node refractory period
- Lesser effect on SA node