CVS Drugs 21 to 30
Describe the molecular action of digoxin?
Na+/K+ ATPase (“sodium pump”) inhibition
NOTES: Binds to alpha subunit which has different isoforms …differing affinities for digoxin in various tissues. Low concentrations occasionally stimulate the enzyme.
What are the cardiac effects?
PROMPT for autonomic effects: What are the autonomic effects of digoxin? Mechanical: Increased contractility due to increased intensity of interaction of actin and myosin filaments due to increased free calcium during systole Electrical: (i) Direct: Shortening of action potential and therefore shortened atrial and ventricular refractoriness At toxic levels, resting membrane potential reduced, then as toxicity progresses depolarizing afterpotentials (ii) Autonomic- at lower doses parasymp effects predominate NOTES: (i)increased intracellular Na+ and therefore (ii) relative decreased expulsion of Ca+ by NaCa exchanger Duration of contractile response neither shortened (as in case of ß blockers) nor lengthened (as in case of methylxanthines) Follows early brief prolongation of AP Probably due to increased K+conductance Overloaded intracell Ca+ stores Atropine —blockable effects: sensitization of baroreceptors, central vagal stim, facilitation of muscarinic transmission (mainly atria and AV node where rich cholinergic innerv’n) Sensitizes myocardium and exaggerates all toxic effects.
Increased contractility due to increased intensity of interaction of actin and myosin filaments due to increased free calcium during systole
(i) Direct: Shortening of action potential and therefore shortened atrial and ventricular refractoriness
At toxic levels, resting membrane potential reduced, then as toxicity progresses depolarizing afterpotentials
(ii) Autonomic- at lower doses parasymp effects predominate
NOTES: (i)increased intracellular Na+ and therefore (ii) relative decreased expulsion of Ca+ by NaCa exchanger
Duration of contractile response neither shortened (as in case of ß blockers) nor lengthened (as in case of methylxanthines)
Follows early brief prolongation of AP Probably due to increased K+conductance
Overloaded intracell Ca+ stores
Atropine —blockable effects: sensitization of baroreceptors, central vagal stim, facilitation
of muscarinic transmission (mainly atria and AV node where rich cholinergic innerv’n)
Sensitizes myocardium and exaggerates all toxic effects.
What are the non-cardiac manifestations of digoxin toxicity?
At toxic levels sympathetic outflow increased -all excitable tissue including smooth muscle and CNS
GIT nausea, vomiting, diarrhoea, anorexia CNS disorientation, hallucinations, visual disturbances, agitation and cornvulsions Gynaecomastia
1 GIT and 1 CNS example (prompt allowed) Hyperkalaemia
Relative low sensitivity of non-cardiac tissue due to differing enzyme isoforms
Nausea and vomiting a combination of direct and central effects
Describe the pharmacokinetics of digoxin?
Well absorbed orally
Moderate Volume of Distribution (6.3 L/kg)
Not extensively metabolized, 2/3 excreted unchanged by kidneys
NOTES: 10% population with enteric bacteria that reduce oral bioavailability
20-40%plasma protein bound
Describe succinylcholine and its metabolism?
Depolarizing neuromuscular blocking drug
Hydrolyzed by plasma cholinesterase to succinic acid & choline
NOTES: Two linked acetylcholine molecules Action at motor end plate terminated by diffusion away into ECF
What are the adverse effects of depolarising neuromuscular blockade?
- Renal Failure
- Burns > 24 hours
- Spinal Cord Injury
- Muscular Dystrophies
Increased IOP, intragastric & ICP (1 of)
Paralysis & prolonged Apnoea
CVS – negative inotrope & chronotrope
Describe the mechanism of action of amiodarone?
Potassium Channel Blocker (Class III)
Prolongs RP, APD
Na channel blockade
Weak Ca & adrenergic blocking
NOTES: Prolongs the effective refractory period by prolonging the action potential duration
Blocks inactivated sodium channels
Weak adrenergic (Class II) and calcium channel (Class IV) blocking actions
What are the clinical uses of amiodarone?
Atrial & ventricular arrhythmias
Maintaining normal sinus rhythm in AF Prevention of Recurrent VT
Describe the potential adverse effects of amiodarone?
Cardiac: Bradycardia, Heart block, hypotension, negative inotropy Pulmonary fibrosis,
Abnormal LFTs & hepatitis,
2 cardiac, 2 extracardiac
NOTES: photodermatitis and a gray-blue skin discoloration
-blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3)
What are the organ effects of nitrous oxide?
CNS: Analgesic, amnesic. Inc CBF
Renal: Decreased GFR, inc filtration fraction & inc renal vasc resistance
CVS: Dose dependant myocardial depression
Resp: Reduced resp response to CO2 & hypoxia
1 CNS and 1 non CNS
What is the mechanism of action of nitrous oxide?
Prompts: How does NO affect GABA. Any other mechanisms by which NO works?
Directly activate GABA A receptors
-GABA A receptor Cl channel. Facilitate GABA mediated inhibition at GABA receptor sites
-decreased duration of opening of nicotinic receptor activated channels. Decreased excitatory effect of Ach
Describe the pharmacodynamics of propranolol.
• Membrane stabilizing action,
• Antagonizes renin release from symp ns.
• Competitive, pure antagonist.
Inhibits sympathetic ns stimulation of lipolysis, Inhibits liver glycogenlysis, Reduces aqueous humour production, Increases VLDL, Decreases HDL. Blocks B2 receptor in bronchial smooth muscle increasing airway resistance.
Pass: (2 out of 4 + 1 of the rest in notes).
How does carvedilol differ from propranolol?
Carvedilol has no local anaesthetic action.
Causes Alpha 1 adrenoceptor block, but effect on Beta receptor > Alpha receptor.
Stereoselective metabolism of its 2 isomers occurs(with polymorphism influenced Cytochrome P450 2D6 affecting R isomer metabolism).
Pass: 1 out of 3
What are the effects of nitric oxide?
Smooth muscle relaxant
Pass: 1 of 4
What are potential therapeutic applications of nitricoxide.
– on vascular smooth muscle tone and B.P.
– may play a role in normal regulation of vascular tone -vasodilator action
-inhibits neutrophil adhesion to vascular endothelium
2. Hypertension associated with pregnancy
– resemble deficiency of NO and PG
– possible role of enhancing NO levels via nutritional supp.w/L-arginine
3. Respiratory disorders
– used via inhalation to newborns w/pulmonary hypertension and ARDS
– decreases pulmonary arterial pressure and improves blood oxygenation
– also used in open trials in adults with ARDS
– may act also act as bronchodilator by relaxing airway smooth muscle
4. Septic shock
-Urinary excretion of NO3, oxidative product of nitric oxide in 0- bacterial infection
– may act as antioxidant, blocking oxidation of LDL, preventing foam cell formation in the vascular wall
-nitric oxide = potent inhibitor of platelet adhesion and aggregation — as in vascular sm.muscle, cGMP mediates protective effect of NO in platelets
-may have additional effect on blood coagulation by enhancing fibrinolysis via effect on plasminogen
7. Organ transplantation
– NO reduces free radical toxicity, inhibits platelet and neutrophil aggregation and adhesion to vascular wall
– too high concentration of NO may be detrimental — so need to inhibit synthesis to prolong graft survival
-modifies neurotransmitter release in different areas of the brain
–also may have role in epileptic seizures
– also has negative effects
– causes destruction of photoreceptor cells in retina — prolonged increase in cGMP formation
9. Peripheral nervous system
– NO promotes relaxation of sm.muscle in corpora cavernosa — impotence trials with NTG ointment
and NTG patch (any 1)
What is the mechanism of action of glyceryl trinitrate in smooth muscle?
NO release, cGMP increases
How do nitrates relieve angina ?
Preload reduction decreases myocardial work
Describe the pharmacokinetics of propranolol.
High 1st pass, liver metabolism, lipid solubility high
Describe the cardiovascular effects of beta blockers
B blockade with variable selectivity, negative intropic and
What B-receptor types are there?
B1, B2 + B3
Pass: Need B1 + B2
What cellular processes do B-agonist - B- receptor coupling initiate?
Activation of all 3 receptor types results in stimulation of adenylyl cyclase and increased conversion of ATP to cAMP. Mediated by stimulatory coupling protein (Gs) via GDP and GTP
Pass: Need adenylyl cyclase
What are the clinical uses of B2 selective agonists?
Respiratory, uterine and vascular smooth muscle relaxation
Skeletal muscle K+ uptake
Pass: Need respiratory bronchodilation + one other
What is the mechanism of action of warfarin?
Warfarin inhibits reduction of inactive Vit K epoxide (KO) to active hydroquinone (KH2) form. Blocks gamma-carboxylation of glutamate residues in prothrombin ( Factor II) and factors VII, IX and X ,as well as endogenous anticoagulant protein C and S.
Notes: Need to know role of vitamin k
Why is there a delay in the onset of action of warfarin?
8-12 hr delay due to partially inhibited synthesis and unaltered degradation of 4 vit k dependent clotting factors and depends on degradation 1/2 life in circulation eg factor VII- 6 hrs, IX 24-hrs, X –
40 hrs and II- 60 hrs)
Notes: Need to have some idea of delay in onset
What pharmacological agents are used in the reversal of warfarin?
Vitamin K. FFP. Prothrombin Complex. Recombinant FVIIa
Optional: Describe the mechanisms of drug interactions with warfarin.
Pharmacokinetic: Enzyme induction + inhibition. Altered protein binding
Pharmacodymanic: Synergism. Competitive antagonism (Vitamin K)
Notes: 3 required