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?


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
  • Demyelination
  • Spinal Cord Injury
  • Muscular Dystrophies
  • CVA

Increased IOP, intragastric & ICP (1 of)

Paralysis & prolonged Apnoea
CVS – negative inotrope & chronotrope
Muscle Pain


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

(Class I)

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,

Skin deposits

Corneal microdeposits


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

-membrane hyperpolarisation

-decreased duration of opening of nicotinic receptor activated channels. Decreased excitatory effect of Ach


Describe the pharmacodynamics of propranolol.

•             Non-selective action on Beta receptors,

•             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

Platelet inhibitor

Immune regulator


Pass: 1 of 4

What are potential therapeutic applications of nitricoxide.

1.Vascular effects
– 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

5. Atherosclerosis

– may act as antioxidant, blocking oxidation of LDL, preventing foam cell formation in the vascular wall

6. Platelets

-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

8. CNS

-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

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