Pharmacology Flashcards
B1-adrenoceptor couples to the g-protein….
Gs
The sympathetic nervous system releases noradrenaline as a __________ _____________ and adrenaline as a ___________ ___________
Post-ganglionic transmitter
Adrenomedullary hormone
B1-adrenoceptors are activated in which locations? (2)
Nodal cells
Myocardial cells
Activations of b1-adrecopteors NASA positive/negative chronotropic force
Positive
Chronotropic is an increase in
Rate
Ionotropic is…
Force
Increase in heart rate in presence of noradrenaline is due to what?
Increase in slope of phase 4 of action potential
Reduction in threshold for AP initiation due to enhanced Ica
Increase in contractility in the presence of noradrenaline is due to?
Increased in phase 2 of AP
Sensitisation of contractile proteins to calcium
The duration of systole is ______in the presence of noradrenaline
Decreased - this is a positive lusitropic reaction
Noradrenaline causes a ______ in the efficiency of the heart muscle
Decrease - heart starts to use oxygen less efficiently
Effect of noradrenaline on the Na-K-ATPase
Increases activity which is important for the normal balance of ions across the membrane
Parasympathetic system releases ___ to the cardiac muscle
ACh
In the heart, ACh acts on ____ muscarinic cholinoceptors largely in the ______ cells
M2
Nodal
The M2 receptor couples to the ____ g-protein
Gi
Coupling through Gi decreases the activity of ______ _______ thus reducing _______. The ________ potassium channel is opened causing a hyperpolarisation mediated by _________
Adenylate cyclase, cAMP.
GIRK, G-by subunits
Parasympathetic action of the cardiac muscle is…. (3)
Decreased chronotropic effect
Slight decrease in contractility
Decreased conduction in AV node
Why does the parasympathetic stimulation of the heart have little/no effect on ventricular contractility?
There is no parasympathetic stimulation on the ventricles
Parasympathetic stimulation of the heart may cause ….
Arrhythmias to occur in the atria
Vagal manoeuvres can can be used to…
Suppress atrial tachycardia
The funny current is mediated by channels that are activated by….(2)
hyperpolarisation and cAMP
other name for funny current channels
HCN
Blocking HCN channels causes what?
decrease of slope of pacemaker potential and reduces HR
Drug used to block HCN channels
Ivabradine
Ivabradine
Selectively blocks HCN Channels - slows HR in angina and reduces cardiac O2 consumption
cAMP is converted to 5’AMP by …
PDE - phosphodiesterase
Inhibition of PDE has a positive/negative inotropic
positive
Drug which inhibit PDE in acute heart failure
milrinone
Catecholamines that act as b-adrenoceptor agonists (3)
dobutamine, adrenaline, noradrenaline
Actions of b-adrenoceptor agonists
increase rate, force and CO and O2 consumption
Medical situations for use of adrenaline
Cardiac arrest; anaphylactic shock
Dobutamine is used in what medical situation?
acute but potentially reversible Heart Failure
Adrenaline is administered…
IC, IM, SC or IV infusion
Dobutamine is administered…
as an IV infusion
Advantage of dobutamine
causes less tachycardia than other b1 agonists
Examples of b-adrenoceptor antagonists
Propanolol, atenolol, bisoprolol, metoprolol
non-selective and partial agonist b-adrenoceptor drug
alprenolol
Effects of b-blockers at rest
little effect
Effect of b-blockers during exercise
cardiac stress, rate, force, CO are significantly reduced
Disadvantage of b-blockers during exercise
can reduce maximal exercise tolerance
Use of b-blockers in medical situations (4)
Disturbance of cardiac rhythm; treatment of angina; treatment of HF; treatment of HBP
How do b-blockers act in A-fib and SVT
delay conduction through the AV node
Use of b-blockers in angina
Alternative to calcium entry blockers
Treatment of HF with b-blockers
must be low-dose to prevent cardiac death
Another suggested drug in HF
carvedilol
Carvedilol is…
a1 - antagonist, b-blocker
Adverse effects of b-blockers (6)
Bronchospasm; Aggravation of HF; Bradycardia/Heart Block; Hypoglycaemia; Fatigue; Cold extremities
What is atropine?
Non-selective muscarinic ACh receptor antagonist
When is atropine used first line?
In severe or symptomatic bradycardia, particularly following MI. Also used in anticholinesterase poisoning
What type of drug is digoxin?
cardiac glycoside
What does digoxin bind?
a-subunit of Na-K ATPase
What is the end effect of digoxin binding the Na-K ATPase?
Increases the Calcium in the cell and thus the calcium uptake into the sarcoplasmic reticulum and increase CICR
Where should digoxin be used with caution?
In those with hypokalaemia or on diuretics
Half life of digoxin
40 hours
Digoxin is a chronotropic agent - True or False?
False - it is an inotropic agent - it increases contractility by increasing calcium available for CICR
Direct effects of digoxin on the heart (2)
shortens the AP and refractory period.
Indirect effects of digoxin on the heart
- increased vagal activity
- slows SAN discharge
- increased refractory period
Adverse effects of digoxin on the heart? (2)
excessive depression of AV node conduction - heart block
Propensity to cause arrhythmias
Non-cardiac adverse effects of digoxin (4)
nausea
vomiting
diarrhoea
disturbance of colour vision
Calcium sensitiser
Levosimendan
Mechanism of action of levosimendan
binds to troponin C and increases sensitivity to calcium
where is levosimendan used?
in acute decompensated heart failure
Amrinone and Milrinone act to…
inhibit PDE in cardiac and smooth muscle cells and hence increase cAMP
Why is it suspected that amrinone and milrinone decrease survival?
Increase arrhythmias
Where are amrinone and milrinone used?
limited to acute heart failure
Which molecule is important in the activation of PKG to cause VSM relaxation?
cGMP
___ stimulates the production of cGMP
Nitric Oxide - NO
Substances that activate the production of NO (3)
bradykinin, ADP, 5-HT
3 effects of organic nitrates
Venorelaxation; arteriolar dilation; increased coronary blood flow
When are organic nitrates used?
in stable angina and ACS
Benefits in angina from using GTNs (3)
decreased preload, decreased afterload and improved perfusion
common organic nitrates used
GTN
isosorbide mononitrate
longer acting organic nitrate
isosorbide mononitrate
GTN sprays do not undergo first pass metabolism - true or false?
false - they undergo first pass metabolism, ISMN does not undergo first pass metabolism
Drug used orally for prophylaxis of angina
ISMN
Adverse effects of organic nitrates
postural hypotension;
headaches; formation of methaemoglobin; tolerance
Molecules that stimulate endothelin production
Adrenaline
AngII
ADH
situations where renin is released (3)
decreased renal perfusion pressure; increased renal sympathetic activity; decreased glomerular filtration
where is angiotensinogen produced?
liver
The AT1 receptor causes smooth muscle relaxation - true or false
false - it causes smooth muscle contraction
the RAAS overall contributes to a(n) _______ in MABP and blood volume
increase
Where does aldosterone originate?
the zona glomerulosa of the adrenal cortex
Aldosterone causes the tubular _______ of Na
reabsorption
Aldosterona production leads to a(n) _______ in blood volume and MABP
increase
Example of an ACE inhibitor
lisonopril
ACE converts AngI to AngII - true or false
true
example of an AT1 receptor blocker
losartan
ACE acts to … (2)
inactivate bradykinin
convert AngI to AngII
ACE inhibitors have an effect on cardiac contractility - true or false?
false - the mechanism of action means that ACEIs will cause venodilation and vasodilation - this reduces the strain on the heart but does not affect the heart contractility
Where is the greatest effects of ACEIs?
Brain, kidneys, heart
Main adverse effects of ACEIs
hypotension
dry cough
ARBs are useful in patients who…
find the ACEIs dry cough intolerable
ACEIs and ARBS are contraindicated in which two groups?
Pregnancy
Bilateral renal artery stenosis
3 clinical uses of ACEIs and ARBs
Hypertension
Cardiac Failure
Following MI
a1-adrenoceptors act to…
constrict vascular smooth muscle
b1-adrenoceptors act to…
increased cardiac rate, force and AV node conduction velocity
b2-adrenoceptors act to…
relaxes bronchial and vascular smooth muscle
b1- adrenoceptor antagonists can be used in the treatment of (3)
Angina pectors; hypertension; heart failure
action of b-blockers in angina pectoris?
decreases O2 requirements; counter-elevated sympathetic activity; increase the amount of time spent in diastole
Action of b-blockers in hypertension?
reduce CO; reduce renin release from kidney; a CNS action that reduces sympathetic outflow
Arrhythmias can be formed from defects in which two ways?
defects in impulse conduction or impulse formation
Types of defects in impulse formation (2)
Altered Automaticity
Triggered Activity
Pathological reasons for altered automaticity
SAN firing frequency is pathologically low (escape beats); latent pacemaker fires faster than the SAN (ectopic beats)
Causes of ectopic rhythms
ischaemia, hypokalaemia, increased sympathetic activity
Triggered Activity can be either of…?
EAD
DAD
Where do EADs come from?
Phase 2 (Ca) and Phase 3 (Na); associated with prolonged AP and drugs prolonging the QT interval
Where do DADs appear?
after complete repolarisation
Where do EADs appear?
during the inciting AP
What is DAD associated with?
Ca overload provoked by catecholamines, digoxin, heart failure
What are the 3 defects in impulse conduction?
Re-entry; conduction block; Accessory tract pathways
What are re-entry arrhythmias?
self-sustaining electrical circuit where action potentials can create a self-sustaining loop
Types of partial block?
Mobitz type I
Mobitz type II
Mobitz type I conduction block
PR interval gradually increases from cycle to cycle until a beat is missed
Mobitz type II conduction block
PR interval is constant but every n-th beat is mossed
Complete block is…
when the atria and ventricles beat independently
Example accessory tract
Bundle of Kent
What do accessory tracts predispose patients to?
tachyarrhythmias
Class I agents are what?
Sodium channel blockers
Class II agents are what?
b-adrenoceptor antagonists
Class III act on?
Voltage gated K+ channels
Class IV agents act on?
Calcium channel
How do Class I agents work?
they act on the SAN in a use dependent manner; there are varying degrees of block from short acting to long acting
Action of adenosine?
activates A1-adenosine receptors coupled to Gi/o - opens ACh sensitive K channels
When is Adenosine used?
to terminate paroxysmal SVT - atrial firing of 140-250bpm
Action of Digoxin?
stimulates vagal activity; slows conduction and prolongs refractory period in AV node
What is digoxin used to treat?
used to treat AF
What is the action of Verapamil?
type IV agents - blocks LTCC; slows conduction and prolongs refractory period in AV node and bundle of His
When is verapamil used to treat?
Atrial flutter, AF
Two types of diuretics
Loop and thiazide
Action of thiazide diuretics
block the reabsorption of sodium and chlorine in the distal convoluted tubule
Action of loop diuretics
block the Na-K-Cl symporter in the ascending loop of henle
Potential side effect with Loop diuretics?
hypokaleamia
Because of the side effects of loop diuretics, which drug should they be used with caution with?
Digoxin
Diuretics are used in which conditions?
hypertension and heart failure
Example of a thiazide diuretic
Bendrofluazide
Example of a loop diuretic
Furosemide
General side effects of diuretics
hypokalaemia, tiredness, arrhythmias, hyperglycaemia in diabetics, gout, impotence
Where are cardioselective beta-blockers used?
angina, hypertension, heart failure
Effect of b-blockers on the heart?
increased rate, contractility and decreased O2 efficiency
Example of cardioselective b-blockers
atenolol, metoprolol, bisoprolol
Side effects of b-blockers in general
tired, bronchospasm, heart failure, cold peripheries,
Two main groups of calcium antagonists
dihydropyridines; rate limiting calcium antagonists
Action of dihydropyridine CCBs?
L-type CC blockers which are more vascular in their action
Where are dihydropyridines preferentially used?
in hypertension and angina
Side effect of dihydropyridines?
innocent ankle oedema
Example of dihydropyridine CCB
amlodipine
Where are rate limiting CCBs used?
angina, hypertension and supraventricular arrhythmias
Where are rate limiting CCBs more selective for?
myocardium
Why should rate limiting CCBs be avoided with b-blockers?
they cause a degree of heart block which would cause bradycardia when combined
Examples of rate limiting CCBs?
verapamil, diltiazem
a-adrenoceptor antagonists cause what?
vasodilation
Example of an a-adrenoceptor antagonist
doxazosin
Action of ACE inhibitors
blocks conversion of Ang I to Ang II thus preventing vasoconstriction
Indications for the use of ACEIs
hypertension, heart failure, diabetic nephropathy (hypertension)
Contraindications for ACEIs
renal artery stenosis
Examples of ACEIs
lisinopril, Ramipril
Side effects of ACEIs
cough, renal dysfunction, angioedema
Why should ACEIs never be used in pregnancy?
causes foetal kidney abnormalities
Alternative to ACEIs if they are not tolerated?
Angiotensin receptor blockers
Example of ARB
Losartan
Action of nitrates?
venodilators and nitric oxide donors
When are nitrates used?
in angina, acute HF and MI
Main side effects of nitrates?
headache and hypotension, tolerance is also an issue
Examples of nitrates?
Isosorbide mononitrate, glyceryl trinitrate
Action of anti-platelets?
prevent new thrombosis
Indications for use of anti-platelets?
angina, MI, cerebrovascular attacks, TIA
Examples of anti-platelets
aspirin, clopidegrel, ticagrlor, prasugrel
Main side-effects of anti-platelets
haemorrhage, peptic ulcer haemorrhage, aspirin sensitivity in asthma
Actions of anti-coagulants
prevent new thrombosis
Examples of anticoagulants
heparin (IV only); Warfarin (oral only); Rivaroxaban; Dabigatran
Warfarin blocks which clotting factors?
2,5,7,9,10
When is warfarin used?
DVT, PE, NSTEMI, AF
Risks of using warfarin?
haemorrhage - needs careful INR monitoring
How can warfarin be reversed?
Vitamin K
Action of rivaroxaban?
inhibits factor X
Action of dabigatran?
thrombin factor IIa inhibitor
Action of fibrinolytics
dissolve formed clots but not liked due to risk of haemorrhage
Where are fibrinolytics used?
STEMI, PE and CVA in selected cases
Examples of fibrinolytics
Streptokinase, tissue plasminogen activator
Anti-cholesterol agents?
Statins
Fibrates
Action of statins
block HMG CoA reductase
Where are statins used?
hypercholesterolaemia, diabetes, angina, MI, CVA, TIA, high risk of MI or CVA
Example of statin
simvastatin
Side effects of statins?
muscle pain, myopathy, rhabdomyolysis
Indications for fibrates?
hypertriglyceridaemia, low HDL
Example of a fibrate
benzofibrate
Drug used in supraventricular arrhythmias
adenosine
Drugs used in SV arrhythmias and ventricular arrhythmias
amiodarone, beta-blockers, flecainide
side effects of amiodarone
phototoxicity, pulmonary fibrosis, thyroid abnormalities
Two actions of digoxin
blocks AV node conduction, increases ventricular irritability
What is digoxin useful for treating?
atrial fibrillation
Side effects of digoxin?
nausea, vomiting, yellow vision, bradycardia, heart block, ventricular arrhythmias
vascular wall damage exposes (2)
collagen and tissue factor
primary haemostasis causes what 3 things?
local vasoconstriction, platelet adhesion and acitvation, stabilised soft plug
Fibrinogen is converted to fibrin by?
thrombin
activated platelets secrete thromboxane A2 mediated by which enzyme?
COX 1
Exposed collagen binds the platelet __ ______ _____ to which glycoprotein __ receptors also bind
von willibrand factor, Ib
Fibrinogen is converted to fibrin by?
thrombin
vascular wall damage exposes (2)
collagen and tissue factor
activated platelets secrete ___ which is mediated by the COX 1 enzyme
thromboxane A2
Exposed collagen binds the platelet __ ______ _____ to which glycoprotein __ receptors also bind
von willibrand factor, Ib
thrombin is also known as factor__
II
cells bearing tissue factor are exposed to factor ___ from the plasma to form a complex ____
VIIa, VIIa:TF
The TF:VIIa complex activates factor __
X
Factor X works with factor _ to activate prothrombin to thrombin (factor II)
factor V, implicated in factor V leiden thrombophilia
Factor II activates further platelets and causes the release of ______ _ from platelet granules
factor V
Factor II liberates factor ___ from von willebrand factor
factor VIII - normally bound to vWF
Factor XI or TF:VII activate factor
IX
factor IX forms a complex with factor ___ which powerfully activates factor II
VIII
Factor VIII activated by thrombin cross-links the fibrin polymer to…
form a fibrin fibre network and a solid clot
What is a thrombosis?
a haematological plug in the absence of bleeding
Chances of thrombosis are increased in…
virchows triad
Virchows triad consists of?
injury to vessel wall (atheromatous plaque rupture), abnormal blood flow, increased coagulability of the blood
An arterial thrombus is also known as a (white/red) thrombus
white
Why is an arterial thrombus white?
many platelets in a fibrin mesh
Where is an arterial embolus likely to travel?
artery of brain or other organs depending on site of origin
A venous thrombus is also known as a (white/red) thrombus
red
Where is a venous embolus likely to travel?
the lung (PE)
How are arterial thrombi usually treated?
anti-platelets
How are venous thrombi usually treated?
anti-coagulants
anti-platelets are used to treat which type of thrombus?
arterial
anti-coagulants are used to treat which type of thrombus?
venous
A venous thrombus is also known as a (white/red) thrombus
Red
An arterial thrombus is also known as a (white/red) thrombus
white
A venous thrombus is rich in…
fibrin
Warfarin blocks the modification of which 2 factors?
X and II
Rivaroxaban inhibits which factor within prothrombinase
Xa
prothrombinase is made up of which two factors
Xa/Va
Heparin, LMWH and fondaparinux inactivate factor Xa via…
antithrombin III
antithrombin III inactivates…
factor Xa
Heparin inactivates factor __a via….
IIa via antithrombin III
Dabigatran directly inhibits
IIa
Heparin inactivates factor __a via….
IIa via antithrombin III
Heparin, LMWH and fondaparinux inactivate factor Xa via…
antithrombin III
prothrombinase is made up of which two factors
Xa/Va
antithrombin III inactivates…
factor Xa
Rivaroxaban inhibits which factor within prothrombinase
Factor Xa
factors dependent on vitamin K
II, VII, IX and X
warfarin blocks what enzyme essential in recycling vitamin K
vitamin K reductase
II, VII, IX and X are all factors dependent on…
vitamin K
vitamin K reductase is inhibited by
warfarin
anticoagulants can be used to prevent and treat:
DVT, post-operative thrombosis, in artificial heart valves, atrial fibrillation
Warfarin is an…
anti-coagulant
The effects of warfarin should be monitored using…
the international normalised ration - prothrombin time
plasma half-life of warfarin
40 hours
Factors potentiating the effects of warfarin
Liver disease, high metabolic rate, drug interactions (inhibition of platelets)
Factors lessing warfarin action
pregnancy, hypothyroidism, vitamin K consumption, drug interactions
To inhibit factor IIa, heparin needs to bind?
Antithrombin III and IIa
to inhibit factor Xa, heparin needs to bind?
just antithrombin III
Examples of LMWHs
Exoaparin, Dalteparin
LMWHs are administered…
subcutaneously
fondaparinux is…
chemically related to the LMWHs
Advantage of elimination of LMWHs
first order rather than zero order
Heparin is preferred over LMWHs in which situation?
renal failure
Adverse effects of Heparin and LMWHs
Haemorrhage, osteoporosis, hypoaldosteronism, hypersensitivity reactions
dabigatran, and rivaroxaban are administered
orally
Advantages to dabigatran and rivaroxaban are?
they have a predictable level of anti-coagulation and a convenient administration route
Clopidogrel blocks ADP P2Y receptor irreversibly
Clopidogrel blocks ADP P2Y receptor irreversibly
Clopidogrel blocks _____receptor irreversibly
Clopidogrel blocks ADP P2Y receptor irreversibly
Aspirin blocks _____ irreversibly
COX -1
Tirofiban blocks GPIIb/IIa receptor whose expression is increased by ADP and TXA2
Tirofiban blocks GPIIb/IIa receptor whose expression is increased by ADP and TXA2
Tirofiban is given IV in short term treatment to prevent MI in high risk patients with unstable angina
Tirofiban is given IV in short term treatment to prevent MI in high risk patients with unstable angina
Anti-platelet drugs are used in what type of thrombus
arterial
Examples of the main anti-platelets
aspirin, clopidogrel, tirogiban
Clopidogrel is given when…
patients are intolerant to aspirin
Fibrinolytics are used…
to reopen occluded arteries in MI or stroke
Examples of fibrinolytics
Streptokinase, alteplase, duteplase
Fibrinolytics act to activate…
plasminogen
Streptokinase is not…
an enzyme
Streptokinase shouldnt be given in patients with a recent
streptococcal infection
Ateplase and Duteplase are…
recombinant tissue plasminogen tissue activator
Alteplase and duteplase advantages…
less allergic reactions, more selective for clots
haemorrhage due to fibrinolytics can be controlled by…
oral tranexamic acid
tranexamic acid inhibits
plasminogen activation
