8. CVS drugs Flashcards
Digoxin
Where effects - nerve
Inhibits what
which leads to what
How is it exceted
what effect does this have
Toxicity increase with what
Avoided in what condition
signs of tx effect
bioavail
Vd
Side effects
Cardiac glycoside
used afib/flutter
Indirect effects via vagus nerve
Inhib Na/K ATPase incr sodium = displace calcium, + inotropic effect.
to cellular sodium overload and an increase in sarcoplasmic calcium content mediated by a Na/Ca exchanger. This increase in cellular calcium result in an increase in myocardial contractility.
Acetylcholine @ cardiac muscarinic receptors = prolongation - effective refractory
SA node
AV node
bundle of His.
Fifty per cent to 70% of digoxin is excreted unchanged in the urine and doses need to be altered in renal failure.
Toxicity is increased in hypokalaemia, hypomagnesaemia and hypernatraemia.
WPW - acclerate access path
Prolonged PR interval, ST segment depression, T wave flattening and shortened QT are therapeutic, not toxic ECG signs.
Po - 70%
Prot bind 20%
5-10 L/Kg.
10% hep met
70% excr unchanged
Junctional bradycardia
Ventricular bigeminy, and
Second/third degree heart blocks.
Phenytoin can b used to rx dig tox (vent tachyarryh)
AV nodal conduction agents in WPW
AV nodal conduction, such as adenosine, beta-blockers and calcium channel blockers, are also relatively contraindicated.
Aspirin Overdose features Stim what Blood gas + K early Late gas - why Paeads diff Urinary ph
Aspirin (salicylates) directly stimulate the respiratory centre causing an initial respiratory alkalosis.
The excretion of bicarbonate, potassium and water is increased which results in hypokalaemia (not hyperkalaemia), dehydration and eventually a metabolic acidosis.
The metabolic acidosis occurs later and is due to uncoupling of oxidative phosphorylation, increased fat metabolism and inhibition of the tricarboxylic acid cycle.
The metabolic acidosis tends to occur more rapidly and more commonly in children under the age of 12.
The urinary pH in aspirin overdosage is initially alkaline and then becomes acidic.
Aspirin potentiates - + why
Warfarin and sulphonamides are highly bound to plasma proteins and aspirin displaces them which increases their unbound proportion and potentiates their effect.
Asprin can cause hypoglycaemia by potentiating the effect of chlorpropamide.
Diazepam and the tetracyclines are unaffected by aspirin.
Adrenaline formulated as
Epinephrine is formulated as 1 ml of 1 in 1000 solution (1 mg) or 10 ml of 1 in 10,000 solution (1 mg).
1 in 1000 = 1g in 1000 ml of solution (1 g = 1000 mg).
Local anaesthetic agents and glucose containing solutions are expressed as a percentage.
A 1% solution is 1 g per 100 ml solution or 1000 mg per 100 ml solution.
10 ml of a 1% solution contains 100 mg of solute.
C/I to streptokinase
Pregnancy Bleeding (gut, menstrual) Recent stroke or surgery Uncontrolled severe hypertension GI malignancy, and Prolonged CPR. Prolife background diabetic retinopathy
LMWH
MOA
Bind to antithrombin = complex -> inactivates Xa
More readily v UFH
- shorter chain less likely bind Antithrombin & thrombin
Fewer chains pentasachh bind site vs UFH 15 vs 33%
Use >4 days UFH > risk HITTS
> bind w/ PF4
Excreted in urine & part hepatic metab
Monitoring in
Phentolamine
What is it
How work, where act
Uses
Presented+ Stored
Dosing
onset
duration
reflex
Non spec alpha antag
direct SM relax
A1 + A2 rec
Use
HTN crisis
clonidine w/drawl
hypotensive anaes
5mg/ml sol
Store 4’C
0.5-5mg bolus / infusion
Onset 2min
duration bolus 10-15 min
Drop in bp ~~ reflex tachy
Amiodarone
What is it
Class
Metab’ism
prot binding
Ite
Inhib by
S/E
Potentiate
benzofuran derivative
Class III antiarrhythmic
prolongs AP & refractory - block K slows phase 3, may prolong QT
Used for VT SVT WPW
Highly protein bound
bioavailability of amiodarone variable
22% to 95%.
Prot bind - 99% - long t 1/2
Amiodarone is extensively metabolised in the liver, and can affect the metabolism of numerous other drugs.
The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.
grapefruit juice, elevated amiodarone.
37.3% i lt use = accumulation of iodine. Thyroid disorder
Corneal microdeposits reversible
Pneumonitis
hepatitis
Neurological - tremor, ataxia, periph neurop, sleep
Amiodarone inhibits the metabolism of warfarin and so potentiates the anticoagulant effect.
1st line pharm CV - new onset AF
flecanidei if no struct hd
Toxicity related to dose
GTN
Metab
Bioavail
VD
High 1st past metab
- 90% of a dose of GTN is metabolised in the liver by glutathione organic nitrate reductase.
There is also an insignificant amount of metabolism in the intestinal mucosa.
Bioavailability is 38% after sublingual and 1% for oral administration.
GTN is well absorbed by the gastrointestinal tract and is not known to cause gastric irritation.
The volume of distribution GTN is relatively high at 2.1 to 4.5 L/kg.
Sodium nitroprusside
organic nitrate that produces nitric oxide PROdrug
NO, 5 CN- ions and methaemoglobin.
↑cyclic guanosine monophosphate (cGMP), which in turn decreases intracellular calcium levels causing relaxation of smooth muscle and vasodilation
Act GC - Relax SM
Venous and arterial vasodilatation
SE:
Cyanide toxicity:
5 cyanide moieties for every nitric oxide moiety, so cyanide toxicity and a metabolic acidosis
Tachyphylaxis & mix ven Po2 elevated
coronary steal of blood
Atten HPV - Drop PaO2
Platelet aggregation - >16mg infusion
Decreased renin release - overshoot when d/c
It is presented as a reddish-brown powder and requires reconstitution with dextrose to a straw-coloured solution. Exposure to sunlight causes a dark brown or blue discolouration due to the liberation of cyanide ions that are responsible for its toxic effects.
Tachyphylaxis can occur but the mechanism is unclear.
Enoximone
MOA
use
se
Enoximone is a competitive and selective inhibitor of type III isoenzyme of phopshpodiesterase.
Consequenrtly, it casues increased intracellular cAMP - with vasodilatation and inotropic effects.
It is used in cardiac failure.
Side effects include arrhthymias, deranged LFTs and thrombocytopenia.
Salmeterol - LABA
15x >potent @ b2
4x< potent @b1
Salmeterol is a long acting beta-2 receptor agonist, which has a structure similar to salbutamol.
It has a long onset time and so is unsuitable for treating acute asthma.
It is fifteen times more potent than salbutamol at the beta-2 receptor and four times less potent at the beta-1 receptor.
equipotent to isoprenaline as a bronchodilator
Tachyphylaxis to the unwanted side effects commonly occurs, but not to bronchodilation.
Salmeterol has been shown to protect against bronchoconstriction caused by histamine, methacholine and exercise, and may have some degree of anti-inflammatory activity in addition to its bronchodilator role.
Salmeterol has a slower onset of action than other ß2 agonists but its duration of action is up to 12 hours (longer than salbutamol) so that twice daily dosing is sufficient to control the symptoms of mild asthma.
Salmeterol is rapidly absorbed from the lung and is rapidly eliminated with a plasma half life of between two to eight hours. It is extensively metabolised.
The action of salmeterol can be competitively reversed by ß2-antagonists, but when the antagonist is removed, the muscle relaxant activity returns without further dosing with salmeterol, suggesting that it may be permanently anchored near the ß2-receptor site.
Normal SV
SVR
Normal CI
CO/HR x 1000 60 – 100 ml/beat
80 x (MAP – RAP)/CO 800 – 1200 dynes · sec/cm5
Cardiac Index (CI) CO/BSA 2.5 – 4.0 l/min/m2
Verapamil
what is it
How does it work
which leads to what
C/I in what
Calcium antagonist , antiarrhythmic
Prolongs A-V nodal refractoriness
depresses amplitude, velocity of depolarisation and conduction in depressed atrial fibres.
Interrupts re-entrant pathways and slows the ventricular rate.
Depression of SAN activity paradoxically, using verapamil in the aberrant conduction associated with WPW may speed up AF and produce VF.
Not useful in VT.VF
Adenosine
AVRT AVNRT
purine nucleoside which blocks the atrioventricular node.
Bronchoconstriction and is competitively inhibited by xanthine derivatives
Vasodilatation with a reduction in blood pressure
Antiplatelet
Clopidogrel inhibits platelet aggregation through inhibition of the adenosine diphosphate (ADP) receptors on the platelets.
Aspirin has a similar function but mediated through inhibition of cyclo-oxygenase.
Calcium ch antagonists
What channel
Nifedeipine - acts
Veraparmil bio avail
Nimodipine
lip sol v nifed
use
effects on NDMR
L type channel
Nifedipine acts by reducing coronary and peripheral arterial tones, reducing peripheral resistance and may cause a reflex tachycardia.
Verapamil is well absorbed but has a high first-pass metabolism. Its oral bioavailability is only 20%.
Nimodipine is a more lipid-soluble analogue of nifedipine and is used in the treatment after subarachnoid haemorrhage to reduce cerebral vasospasm.
All calcium channel antagonists can potentiate the effects of non-depolarising muscle relaxants.
Phenylephrine
Acting
causes
lasts
Other sites?
Vs ephedrine in obs
direct acting sympathomimetic.
Alpha-adrenergic
vasoconstriction, rise in blood pressure and reflex bradycardia.
lasts for five to 10 minutes
Intramuscular or subcutaneous administration has a slower onset but effects last for up to one hour.
a better umbilical cord gas profile when used in obstetrics compared with ephedrine
The precursors of adrenaline in order are:
Phenylalanine Tyrosine DOPA Dopamine Noradrenaline Adrenaline.
Ephedrine
action
uses
Ephedrine has both direct and indirect actions on alpha- and beta-adrenergic receptors. It also inhibits monoamine oxidase (MAO) and may interact with other MAO inhibitors, precipitating a hypertensive crisis.
Ephedrine is commonly used to treat hypotension but other indications include nasal congestion, nocturnal enuresis and narcolepsy and it can be given orally or intramuscularly.
Alpha + beta
beta-blockers have intrinsic sympathomimetic activity?
beta-blockers have intrinsic sympathomimetic activity?
Labetolol
Pindolol
Not Atenolol
Esmolol
Metop
Beta-blockers that are partial agonists may have agonistic activity leading to sympathomimetic effects when the endogenous catecholamine levels are low but act as antagonists when levels are high.
Torsades treatment
Torsades de pointes is predisposed to by prolonged QT and a magnesium infusion is an appropriate therapy.
Lidocaine C/I
Cox inhibitors
Aspirin like most NSAIDs acts through inhibition of cyclo-oxygenase.
Rofecoxib is a selective COX-II inhibitor and is used specifically as it is not associated with the inhibition of COX-I responsible for the production of mucosal protection in the stomach.
Clopidogrel is an ADP receptor antagonist and responsible for inhibtion of platelet aggregation through this route.
Amiodraone and the thyroid class t1/2 Contains Inhibits Reduces Decrease sensitivity Inhibs release
Amiodarone is a class III antiarrhythmic drug that acts by prolonging the cardiac action potential and refractory period.
It has a half life of over four weeks and prolonged administration may result in numerous side effects including interference with thyroid function causing hyper- or hypothyroidism.
Amiodarone contains iodine and inhibits thyroid hormone synthesis and reduces the peripheral conversion of thyroxine (T4) to tri-iodothyronine (T3).
It also decreases the sensitivity of the pituitary to T4 and T3, and inhibits the release of thyroid stimulating hormone.
Atropine
- derivative
Act on what
What type of molecule is it
how does this affect its crossing of bbb
Elderly increased risk off
which symptoms include
Initial affect on HR odd time
d.t
Atropine and its derivative ipratropium bromide (Atrovent) are bronchodilators, due to competitive inhibition of bronchial muscarinic receptors. Atropine is a tertiary amine (that is, uncharged) and it crosses the blood brain barrier readily.
Central anticholinergic syndrome is seen, particularly in the elderly and the symptoms include
Agitation Hallucination Drowsiness Somnolence Amnesia Dysarthria and Ataxia (although the stimulatory effects are more common with atropine).
An initial bradycardia may occasionally follow atropine administration. It is most likely to occcur if administered by I.M or S.C routes. It causes a transient inhibition of presynaptic M1 receptors before the M2 in the sino atrial node are inhibited.
Atropine is a competitive muscarinic antagonist (not non-competitive), although there may be nicotinic effects at very high doses, this remains competitive antagonism.
Neostigmine is a
Effects include
followed by
Severe can cause
Effect on block -
Side effects include
HR
Lungs
Eyes
? cross BBB
Neostigmine is a quaternary ammonium anticholinesterase compound.
The nicotinic effects include initial skeletal muscle fasciculations (involuntary irregular, violent muscle contractions) followed by the inability to repolarize cell membranes resulting in weakness and paralysis. Severe reactions can lead to ventilatory failure and death secondary to a cholinergic crisis.
It has no effect on phase I block caused by suxamethonium but it does transiently antagonise phase II block.
Bradycardia is the predominant effect on heart rate leading to a decrease in cardiac output.
It causes bronchospasm and constriction of the pupillary sphincter muscle leading to miosis (not mydriasis).
Neostigmine does not cross the blood brain barrier due to the quaternary ammonium group rendering it lipid insoluble.
Aspirin poisoning
Hyperventilation Nausea and vomiting Hypoglycaemia (particularly in children), hyperglycaemia has also been reported Acute renal failure (rare) Rhabdomyolysis GI perforation Hypotension Tinnitus and Hearing loss.
VW class 1
Class 1 drugs (membrane stabilisers) inhibit the rapid influx of sodium ions responsible for phase 0 of the action potential, and reduce the rate of phase 4 depolarisation in pacemaker cells. They are further divided into three sub-groups: 1a, 1b and 1c.
VW class 2
Class 2 drugs (beta adrenoreceptor antagonists) antagonise the effects of increased sympathetic tone on the heart by depressing (reducing the slope of) phase 4 depolarisation, decreasing the maximum rate of depolarisation (phase 0), and prolonging the duration of the action potential.
VW Class 3
Class 3 drugs prolong the duration of the action potential and the relative refractory period
VW class 4
Class 4 drugs (calcium channel antagonists) modify the plateau phase in non-pacemaker cells and inhibit the rapid depolarisation (phase 0) of pacemaker cells.
QT prolongation
a/w
Drugs
QT prolongation is seen with a QT interval above 0.45 ms on the ECG, and may lead to torsades de pointes.
It is associated with:
Hypokalaemia
Hypocalcaemia
Hypothermia, and
Hypomagnesaemia (although hypermagnesaemia can also prolong QRS complex and by default QT interval)
It is also seen with drug therapies such as:
Tricyclic antidepressants Major tranquilisers Amiodarone Antihistamines Erythromycin, and Ciprofloxacin.
It is not associated with Digoxin, Gentamicin, or Atropine.
Norad terminated by
80% active re-uptake by postganglionic nerve terminals for reuse.
The remaining 20% is metabolised by catechol-O methyltransferase (COMT) and monoamine oxidase (MAO).
The initial enzymatic action is deamination (MAO) and methylation (COMT) rather than decarboxylation.
Clonidine
acts where
x3
Where are these located
saliva
sedation?
Agonist - central acting a2-
Agonist for imidazoline (I1) receptors
Dopamine antagonist.
Locus ceruleus BS
noradrenergic outpuT
control of blood pressure.
Sympathetic stimulation reduces salivary flow.
Clonidine and the superselective alpha-2 adrenoreceptor agonist (dexmedetomidine) produce sedation, have nociceptive actions and can reduce the MAC of the volatile anaesthetic agents.
Clonidine is known to improve the efficacy of the non-steroidal anti-inflammatory drugs and has anti-nociceptive activity at a spinal level.
Clonidine acts through a secondary neurone system which reduces the effects of dopamine receptor stimulation.
Enoximone
Mechanism
Effects
Metabol
S.E
Enoximone is a phosphodiesterase inhibitor and acts through selective and competitive inhibition of the type III isoenzyme.
It is a vasodilator and produces increased cardiac output. It is used in the treatment of severe cardiac failure and typically these patients are hypotensive.
It is administered IV through infusion with an onset of action between 2 - 5 minutes.
It is hepatically metabolised.
Side effects include
Arrhythmias
Deranged liver function tests
Thrombocytopenia.
Prazosin is a
Causes
t1/2
PD -
selective alpha1 adrenergic blocker.
It produces a fall in blood pressure that is generally unaccompanied by any significant rise in heart rate or fall in cardiac output.
Its half life is approximately three hours.
It is extensively plasma bound and excreted primarily through bile and faeces.
Class 1 antiarrhythmic
How do they work
What is the affect
How are they subclassified
Class 1 antiarrhythmic agents block phase 0 of the cardiac action potential by reversibly blocking the Na+ channel; so called “membrane stabilisers”.
They all inhibit the influx of sodium via voltage-gated channels and slow the maximum rate of phase 0 depolarisation, are negatively inotropic and slow conduction velocity.
The sub-classes of the type I antiarrhythmic agents having different effects on the refractory period and length of action potential:
Class Ia (quinidine, procainamide and disopyramide) - Increase the refractory period.
Class Ib (lidocaine, phenytoin and bretylium) - Shorten the action potential and reduce the refractory period.
Class Ic (flecainide and propafenone) - Have minimal effect on action potential duration and the refractory period.
Dopamine acts where and at what doses
Can it cross bbb
does it make you feel nauseated
opamine acts predominately at
The dopamine receptors at low dose (1-5 mcg/kg/min)
Beta adrenoceptors at intermediate doses (5-10 mcg/kg/min) and
Alpha receptors at high doses (10-15 mcg/kg/min).
Its use does not affect the progression to renal failure, although urinary output is often increased by its use.
It has marked emetogenic effects (not antiemetic) by the action at the chemoreceptor trigger zone, which is outside the blood brain barrier.
However, L-dopa does cross the blood brain barrier and is therefore used in the treatment of Parkinson’s disease.
