Pharmacology RCR1 – Cardio

Anti-Coagulant Drugs
 Blood is a self-sealing liquid tissue, balance between thrombus and liquid,
liquid  haemorrhage but thrombus  thrombosis and embolism
 Virchow’s triad = composition of blood, quality of vessel wall and nature
of blood flow
 NB arterial is streamlined, clot is platelet dominant due to strong blood
flow so use anti-platelet drugs
 NB venous clots are mostly fibrin and have a fibrin tail so often lead to
embolism so use anti-coagulants
 Anti-coagulants work on thrombin and other clotting factors that
contribute to the act of fibrinogen changing into fibrin used in a thrombus
 PICTURE OF CLOTTING CASCADE
 Warfarin = in liver, vitamin K helps gamma glutamyl carboxylase change
incomplete clotting factors which are monocarboxylated into
dicarboxylated complete clotting factors that can then be activated fully
by the coagulation cascade in circulation, warfarin inhibits this by
competing with vitamin K (clot factors include 7, 10 and prothrombin)
 Warfarin Sodium = oral drug, works in vivo only, slow onset (2 days),
slow offset (4-7 days), narrow therapeutic index, metabolism is very
variable (by P450), lots of drug interactions, antidotes include vitamin K
and plasma, clotting test is the prothrombin time, SE include
haemorrhage and can cross placenta giving foetal warfarin syndrome
 Heparins = are antithrombin III enhancers, it accelerates the inhibitory
activity of antithrombin III by 1000-fold, heparin/ATIII complex binds to
active clotting factors (such as F10 and thrombin) and converts them into
an inactive factor/ATIII/heparin complex, the ATIII/inactive clotting
factor are then released
 Heparin = parenteral only, rapid onset (secs), short acting (hours),
accumulates due to liver metabolism, does not cross the placenta,
antidote is protamine, test is activated partial thromboplastin time, SE
include haemorrhage, osteoporosis (weeks use), heparin-induced
thrombocytopenia, HIT (antibodies cause platelet aggregation and
thrombosis)
 NB Low MW Heparins (dalteparin, enoxaparin), same but twice the
duration, predicted effects and less SE but no antidote, Oligosaccharides
(fondaparinux), long half life and even less risk of HIT
 Direct inhibitors of thrombin  independent of ATIII, no HIT, no
monitoring of clot time
 Gatrans eg Dabigatran, oral thrombin inhibitor
 Xabans eg rivaroxaban, inhibits factor Xa, prevents prothrombin to
thrombin, rapid acting, oral for DVT prophylaxis
 Risk factors for all these  recent fracture of major surgery of pelvis, legs,
hips, lower limb paralysis or amputation, major surgery and histry of PE
or DVT, recent IBD, MI, HF or cancer, trauma or burns
 Clinical uses:-
1. Prevention of DVT – lmw heparin
 2. Prevention of embolism – oral warfarin, direct thrombin/factor X
inhibitors
3. Treat DVT - LMW heparin, oral warfarin at same time (for 6 weeks)
4. INR = International Normalised Ratio = clotting time of blood from anti-
coagulated patient/clotting time for standard uncoagulated blood, need to
be INR of 2.0-3.5
5. In vitro, if testing for APPT put in green vacutainer, if for EDTA then
purple (for F10 or other clotting factors)

Anti-Platelet and Thrombolytic Drugs

ANTI-PLATELET
 Clot formation is of two parts, aggregation formed from thromboxane and
ADP leading to platelet aggregation, and then coagulation, the end of the
cascade being fibrin
 Platelets are non nucleated fragments of megakaryocytes in the bone
marrow, they last 5-9 days, and release growth factors to initiate
endothelial repair,
 Platelets are activated by sub-endothelial proteins (Von Willebrand factor
and Collagen), Thrombin, ADP and Thromboxane (TX)A2 which is made
by cyclo-oxygenase (COX-1)
 Platelets are inhibited by NO, a vasodilator, ADPase and prostacyclin
(PGI2), made by endothelian COX-1
 Anti-platelets drugs include clopidogrel, aspirin, abciximab, tirofiban

 ASPIRIN  high doses inhibit both COX-1 and COX-2 but low doses lead
to irreversible acetylation of COX-1, give 75mg daily, if for thrombolysis
give 150-300mg dose
  CLOPIDOGREL  pro-drug converted to active by cytochrome P450,
irreversible antagonist to platelet ADP receptors (P2Y12), and so reduces
expression of gp2b/3a, reducing aggregation
 Abciximab  fab fragments of a human-murine Ig against gp2b/3a, short
half of minutes, but blocks aggregation for days, given by IV infusion
 Tirofiban  non-peptide antagonist of gp2b/3a, given IV, mainly used in
angioplasty to prevent thrombosis (along with heparin and aspirin)
 Dipyridamole  inhibits platelet phosphodiesterase (PDE3), increasing
cAMP, and reducing aggregation
 Epoprostenol (synthetic PGI2)  mimic anti-aggregatory effects of
prostacyclin, increases cAMP via prostacyclin receptor
THROMBOLYTIC
 3 methods, so prevent reocclusion by using anti-platelet drugs and anti-
coagulants, but also use plasminogen activators to stimulate the lysis of
the thrombus
 Plasminogen activators increase plasminogen into plasmin and plasmin
changes fibrin into soluble degradable products
 STREPTOKINASE  from streptococcus, only used once
 ALTEPLASE/RETEPLASE  recombinant tissue-PA grown in bacteria,
human so no allergies, short-acting (15mins), given IV or IC, risk of
haemorrhage

Lipid-Lowering Drugs
 Hyperlipidaemias are either primary and therefore monogenic (severe
and rare) or polygenic (common and moderate) or secondary and due to
type 2 diabetes, diet, hypothyroidism, alcohol
 Classes include; statins (simvastatin), fibrates (clofibrate), nicotinic acid
and anion-exchange resins (cholestyramine)
 Chylomicron = gut to liver (3% chol, 90% TG)
 VLDL = liver to tissues (20% chol, 50% TG)
 LDL = liver to tissues (50% chol, 7% TG)
 HDL = tissues to liver (40% chol, 6% TG)
 Risk factors for atheroma are raised LDL (>5mmol/l); reduced HDL
(<3mmol/l); raised TG (1mmol/l) and raised total cholesterol
 Raised TG also causes acute pancreatitis
  STATINS  eg simvastatin, pravastatin, fluvastatin, atorvastatin, all
inhibit HMG CoA Reductase, leads to compensatory↑in hepatic LDL
receptors, so clears plasma LDL (20-50%), also↓in TG (25%) and↑in HDL
(15%), 1º hypercholesterolaemia, reduce progression of atherosclerosis,
prevent MI and stroke
 Every 10% drop in LDL cholesterol = 15% decrease in Heart Attack
 Also Statins↓prostate and colorectal cancer deaths, ↓vascular
inflammation and thrombosis, and↑endolethial function and plaque
stability, SE = myalgia, rhabdomyolysis (leads to acute renal failure)
 FIBRATES  eg clofibrate, fenofibrate, gemifibrozil, inhibit VLDL release
from liver and accelerate lipoprotein lipase (stimulated by insulin),
∆↓plasma TG (20-50%),↓LDL,↑HDL, SE = NVD, flu/myositis, gallstones, 1º
for hyper-TG to reduce pancreatitis
 NICOTONIC ACID  inhibits VLDL release, ↓plasma TG (30-50%),↓LDL
(10-20%), can use with fibrates for hyperTGaemia, SE = flushing, itching,
dizziness, palpitations, hyperglycemia, gout
 ANION EXCHANGE RESINS  eg cholestyramine, colestipol, stops dietary
lipids from being emulsified and so are excreted, as it forms a complex
with bile acids, less potent
 LIPASE INHIBITOR  eg orlistat, blocks breakdown of TG into FA within
gut
 Nutraceuticals  eg plant steroids, ↓ gut absorption of cholesterol but not
very potent

Pharmacology of Angina and MI

 Stable Angina = reduced coronary flow causing predictable chest pain on

exertion
 Unstable Angina = thin fibrous cap may rupture unpredictably, but clot
will resolve in 20 mins with no myocardial damage
 Angina occurs on exertion as O2 supply < O2 demand
 Drugs have a small effect on oxygen supply but anti-anginal drugs work
on reducing O2 demand, by changing contractility (less hard), rate (less
fast), preload (less in) and afterload (less pressure to pump out)

 Mostly it is done by manipulating Ca2+ interacting with SM in vasoclature

and heart muscle
 ß-ADRENOCEPTOR ANTAGONIST  or beta blockers, eg bisoprolol,
atenolol, metoprolol, all ß1 selective, competitive antagonists, ↓
spontaneous depolarsation at SA and AV node so↓heart rate, ↓
contractility, lengthen diastole so more time for coronary perfusion, ↓BP
by↓CO and↓renin release and so therefore↓afterload
 Occurs by binding to GPCR, so NA can’t bind, limits Ca2+ in cell and so less
contraction and can’t depolarize as fast
 SE = acute LVF, Bradycardia, raised TG and reduced HDL, do not use with
NDH Calcium Channel Blockers
 NON-DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS  eg
verapamil, diltiazem, block influx of Ca2+ through L-type channels in
myocardium, AV node and SM, reduces contractility and heart rate, also
vasodilatation and reduction in BP, short half life so modified release, SE =
exacervate HF, bradycardia
 SINUS NODE BLOCKER  Ivabradine, blocks ‘funny current’, IF channel,
only in SAN and eye, inhibits Na+ and K+ influx in diastole, bings to open
channel so dependent, ∆ better at higher heart rates, slow HR without
effecting contractility (SE = in eye mostly)
 ORGANIC NITRATES  eg Glyceryl Trinitrate, Isosorbide Mononitrate,
release NO which reduces availability of intracellular Ca2+ in vascular SM,
GTN is sublingual and works quickly, lasting 30mins, ISMN is orally taken,
with modified release, SE = postural hypotension, syncope, dizziness,
 reflex tachycardia, flushing, tolerance, DO NOT US WITH
PHOSPHOTDIESTERASES EG VIARGRA
 Effectively they dilate both arteriolar and venous vessels so decrease
afterload and preload, also stop spasms in vessels

 DIHYDROPYRIDINE CALCIUM BLOCKERS  eg amlopidine (mainly used),

nifedipine, felodipine, act on L-type channels but only in vascular SM so
no effect on heart, SE = ankle swelling, reflex tachycardia, flushing and
headache, decrease BP, vaso and venodilate, ↓ spasm in vessels
 POTASSIUM CHANNEL OPENER  Nicorandil, opens ATP-sensitive K+
channels so K+ efflux, inhibits voltage gated Ca2+ channels, so
vasodilatation, decreases afterload and improved myocardial blood
supply, also works on veins so reduces preload, SE = headache, dizziness
and mouth/anal ulcers
 LATE SODIUM CURRENT INHIBITION  Ranolazine, blocks late Na+ into
myocytes, usually increased in hypoxic tissue, decreases myocardial
oxygen demand and improved blood flow SE = headaches, GI upset
 NICE say firstly give beta blocker or calcium channel blocker, if one fails
give the other as well, if doesn’t help give ISMN or nicorandil or
ivabradine or ranolazine – only add a third agent if waiting or unable to
have revasculaeisation/stent
 If MI DO MONA  Morphine (5-10mg IV + metoclopramide 10mg),
Oxygen (15L/min if stats are low), Nitrates (2 puffs of GTN or GTN on IV),
Aspirin (300mg po)
 Also give fibrolytics such as streptokinase, alteplase, reteplase
 Additional approaches are PCTA, coronary stents or a coronary artery
bypass graft (using saphenous vein or mammary artery)
 NB Statins alos have anti-inflammatory effect so will stabilize plaques
after an MI

Pharmacology in Heart Failure

 Heart failure = complex clinical syndrome in which the heart is incapable
of maintaining a CO adequate to accommodate metabolic requirements
and the venous return --- can be acute or acute-on-chronic, or just a
chronic condition
 Two types HF with reduced ejection fraction, or with preserved ejection
fraction (2º is very rare)
 Symptoms = raised jugulo-venous pressure, peripheral oedema, ascites,
pulmonary oedema
 NB CO = HR X SV (SV is made up by preload, afterload and contractility)
 If LVF, LV pressure↑, LA pressure↑, pulmonary capillaries pressure↑ and
leads to pulmonary oedema
 Causes are ischaemic heart disease (35-40%), cardiomyopathy (30-34%),
hypertension (15-20%)

 Cardiac remodelling  myocardial hypertrophy leads to fibrosis and

stiffness so reduced relaxation in diastole, also dilatation of ventricles so
contractile inefficiency reducing stroke volume
 DIURETICS  used to relieve and prevent symptoms by reducing fluid
retention, improved exercise tolerance, but leads to electrolytes depletion
– loop diuretics (furosemide), thiazide diuretics both prevent Na +
reabsorption leading to naturieses and diuresis
 ACE INHIBITORS  eg capropril, ramipril, and AT1 Receptor Antagonists
(sartans eg losartan, cadesartan), ↓ vasoconstriction, ↓fluid retention,
↓cardiac remodeling and↑survival, decrease afterload and BP
 VASODILATORS  nitrates isosorbide dinitrate and hydralazine, direct
vasodilators, NO in vascular SM, good for Afro-Caribbean patients who
done respond to ACEI
 ß-BLOCKERS ß1 agonist eg dobutamine can stimulate heart in acute HF
but usually use ß-blockers to reduce CO, ↓cardiac work and ∆ damage to
cardiomyocytes, ↓arrhythmias, slows hypertrophy and fibrosis, inhibits
activstion os renin causes by SNS activation
 MINERALOCORTICOID RECEPTOR ANTAGONISTS  eg spironolactone,
epleronone, K+ sparing diuterics or aldosterone antafonists, compete with
aldosterone for receptor in DCT and collecting duct, ↓# of Na+/K+
exchange channels so↑sodium and water loss and potassium retention,
can lead to hypokalaemia, potassium and creatine levels should be
monitored
 DIGOXIN  is a +ve inotrope, ↑exercise tolerance and
haemodynamics,↑symptoms but no impact on survival and can cause
arrhythmias and MI
  Management for HF is Diuretic to control volume and then ACE inhibitor
and ß-blocker, if severe symptoms add mineralocorticoid receptor
antagonist and if still then digoxin
 Other things would be to lose weight, restrict fluid and salt intake, treat
sleep apnoea, or surgery
 Acute LV failure = Furosemide, Oxygen, Nitrates, Diamorphine, CPAP
(continuous positive airway pressure ventilation)
 NB Arterial BP = CO X Peripheral resistance
 ß1 = increase HR and force, activate RAAS
 ß2 = bronchodilatation, liver glycogen = blood glucose, vasodilatation in
vascular SM
 α1 = vasoconstriction of skin and gut blood vessels
 Types of ß-blockres include:-
1. Non-selective eg propranolol
2. Cardioselective eg atenolol and bisoprolol
3. With added vasodilator activity eg carvedilol (uses partial alpha
antagonism) and nibivolol (increases NO synthesis)
4. Partial agonist so intrinsic sympathomimetic activity eg celiprolol
and pindolol

SUMMARY OF DRUGS

Drug Class Peripheral Heart Rate Myocardial

vasodilation Contractility
Organic Nitrates √ = =
(GTN/ISMN)
ß-blockers = ↓ ↓
(atenolol)
CCB: non- √ ↓ ↓
dihydropyridine Arterial
(diltiasem,
verapamil)
CCB: √ = ↓/=
dihydropyridine Arterial
(nifedipine,
amlodipine)
K+ Channel √ = =
Activators Arterial
(nicorandil)

 After a MI, treatments include ABCD  ACE Inhibitors, Beta Blockers (less
so now), Ca2+ channel blockers, diuretics