antiplatelt drugs Flashcards
Coronary artery disease (CAD) is almost always due to atheromatous — and subsequent — of the an artery.
In affluent societies, CAD causes severe disability and more death than any other disease, including cancer.
It manifests as angina, silent ischaemia, unstable angina, myocardial infarction, arrhythmias, heart failure, and sudden death.
narrowing
occlusion
angina symptoms:
Clinical presentation
—- discomfort
—-like pain
may radiate down – or into —
occurs with exertion and —- by rest,
Pathophysiology:
Usually associated with the presence of significant
-obstructive — disease (stable disease)
-unstable disease associated with —
retrosternal
pressure
arm
neck
relieved
obstructive coronary disease
plaque repture
how does thrombus occur:
A thrombus is a blood clot that occurs as a natural response to the exposure of the blood to — blood vessel surfaces, altered blood — , or circulating thrombogenic provocateurs (Virchow 1902)
There are 3 biological events that determine the nature of a thrombus
1.— of the Coagulation Cascade
2- Activation of circulating —
3- The nature of the blood—
These are rigorously regulated by :
Carefully-controlled by a ‘Go-No-Go” biological assessment
A— assessment of the nature of the blood flow in the vicinity of the damage
A parallel — of a clot dissolution mechanism
dmaaged
flow
activation
platelt
blood flow
qualitative
mobilization
1- artiel thrombosis:
the formation of a thrombus within an — artery
Common causes of arterial thrombosis are:
- — (which causes disturbed blood flow); or
- —- (where the flowing blood encounters a damaged endothelial lining of a blood vessel)
Arterial thrombi are — RICH
2- venous. thrombosis:
the formation of a thrombus (blood clot) within an – vein.
Common causes of venous thrombosis are — or – blood flow
Usually classified by the veins that are affected
Deep vein thrombosis
Portal vein thrombosis
Renal vein thrombosis
Venous thrombi are — / — RICH
intact
arterial fibirllation
atherscolorsis
platelet
intact
stasis
reduced
protein/firbin
platelet function and treatment of risk of unwanted arterial thrombosis :
What are platelets?
How is their function regulated in normal homeostasis?
What tools to we have to inhibit / supress their activation in at-risk patients? 4 major drug types serve as anti-platelet agents
these are:
Aspirin
ADP Receptor antagonists
cAMP Signal inhibitors
GpIIb/IIIa inhibitors
Platelets are the — cellular component of blood.
They have nocell – (so technically not a cell!)
….but in all other aspects they resemble a — cell (Phospholipid bilayer, cell-surface receptors, cytoplasm, mitochondria, lysozomes, storage granules….)
They are cellular fragments derived from — in bone marrow, which then enter the circulation.
On average, —platelets are produced daily in a healthy adult
Platelet density is ~150 to 450 platelets X106/ ml blood (about 1/10th the density of Red Blood cells).
Circulating platelets are smooth — structures; diameter 2–3µm
The average life span of circulating platelets is —
Old platelets are destroyed byphagocytosisin the –
smallest
no nucleas
functional cell
megakarocyte
10 power 11
smooth discoid
8 to 10 days
spleen
role of platelet in haemostasis:
To survey blood vessels for signs of —
To — to sites of injury and prevent excessive —
To act as a — for the coagulation cascade
plalets contribute to disease:
Atherosclerosis and thrombotic disease
Unstable angina
Myocardial Infarction
Stroke
Peripheral arterial disease (Intermittent claudication)
Underlying ‘damage’ is atherosclerosis/ fragile endothelium
- info:
platelt aggregation depends on — and — of platelets
- 4 classes of antiplatelt:
1- aspirin
2- GpIIb/IIIa antagonist
3- Dipyridimole increases cAMP
4- Receptor Antagonists:
ADP antagonists: Clopidogrel
/ Prasugrel;
signs of damage
adhere
blood loss
catalyst
fibrinogen binding
cross linking
1- Aspirin – an inhibitor of — synthesis in platelets
2- ADP-receptor Blocking agents:
Clopidogrel
Prasugrel;
Ticagrelor
3- Inhibitors on intracellular signalling pathways in platelets:
Dipyridamole
4-GpIIb/IIIa antagonists
Eptifibatide
Tirofiban
prostaglandin
aspirin as anti platelet drug :
- Aspirin inhibits — synthesis throughout the body by — inhibiting the enzyme — , the first step in their synthesis.
-Prostaglandins are — that have a v – half-life.
-The actions pf Prostaglandins are – and —, and often involve mediation of – , — , or changes in blood vessel — .
-Prostaglandins also regulate core body—
Aspirin belongs to a class of drugs known as —
-NSAIDs are used in the treatment of fever (elevated core temperature), pain (headache, or pain associated with inflammation),and inflammation.
-Aspirin is the only NSAID to have therapeutic —- activity
-By careful management of its dosage, we can manipulate its actions to focus primarily on inhibiting platelet synthesis of TxA2
prostaglandin
irreversibly
cycloocygenase
local mediator
very short
local and transient
pain , inflammation , tone
temp
Non Steroidal Anti-inflammatory drugs (NSAIDs)
anti platelet
what are prostaglandins:
Prostaglandins are — involved in both — and — .
They are derived from — , a lipid stored in phospholipid membranes
They are synthesised in a — step process in response to cellular activation.
Different Prostaglandins exert different effects.
Their actions are — , and often involve mediation of pain, inflammation, or changes in blood vessel tone.
For example locally generated prostaglandins are responsible for the immediate — observed after tissue injury.
Platelets synthesise a platelet-specific prostaglandin, called — following platelet activation.
–>TxA2 recruits more platelets to an active platelet — and causes —
Vascular endothelial cells synthesise a different prostaglandin, called —
PgI2 — platelets activation and causes —
info:
step 1:The enzyme Cyclooxygenase (COX) is ubiquitously expressed in all cells. It catalyses the first step in Prostaglandin synthesis
step 2: Tissue-specific synthesis of prostaglandins such as Prostacyclin and Thromboxane
local mediators
homeostasis and inflammation
arachidonic acid
2 step
local
vasoscontrcction
Thromboxane A2 (TxA2)
platelet clot
vasoconstriction
Prostacyclin 2 (PgI2).
inhibit
vasodilation
Aspirin— inhibits the —
— is the rate-limiting step in the synthesis of prostaglandiins
-Arachidonate cyclooxygenase (COX) is also known as prostaglandin synthease (PHS) or prostaglandin endoperoxide synthetase (PES)
-COX — the first step in the synthesis of prostaglandins
The second step in the synthesis of prostaglandins is catalysed by a — enzyme. (pictorial version on next slide)
In Platelets, the enzyme is — and the product is —
In Endothelial cells, the enzyme is — and the product is —
In the – , the enzyme is prostaglandin E2Synthease and the product is PgE2
-TxA2 has 2 actions: it promotes — and it causes —
PgI2 has 2 actions: it inhibits — and it causes —
irreversibly
Cyclooxygenase (COX)
cox
catalyses
tissue specific enzyme
Thromboxane Synthease
Thromboxane (TxA2)
is Prostacyclin Synthease
Prostacyclin (PgI2)
stomach
platelet activation
vasocontrction
platelt activation
vasodilation
aspirin:
Aspirin= Acetyl salicylic Acid
First produced in 1897
It irreversibly acetylates — #529 in the COX active site, rendering the enzyme permanently —
Vane, Samuelsson, Bergström: Nobel Prize medicine 1982
Aspirin’s Half-life —
It is Metabolized in the —
Aspirin’s effect lasts for the life of the – and is overcome by the synthesis of new COX (—)
the vascular effect of aspirin:
-COX is irreversibly inhibited by Aspirin throughout the body
(Note other members of the NSAIDs, eg Ibuprofen also inhibit COX,; but they are not — !)
-Aspirin therefore inhibits — synthesis by — and so limits— of new platelets to a —
Platelets are anucleate. Therefore they cannot — COX activity for their full lifespan (—)
-Aspirin also inhibits – synthesis by — cells and enables greater — / — formation; prevents —
Note: DeNovo DNA synthesis of COX enzyme in the nucleated Endothelial cells, means that the effect recovers in ~ — hours
Note: Aspirin also inhibits PgE2 synthesis in the — cells of the—- responsible for managing the — : acid ratio-
Aspirin therefore causes — development in the stomach wall.
So: how can we manage the desired effect of Aspirin (to prevent TXA2 synthesis & platelet activation) and limit its effect on PgI2 and PgE2 synthesis ????
serin
inactive
4 hours
liver
4 hours
irreversible inhibitors
TXA2
platelets
recruitment
thrombus
recover
10 days
PgI2
endothelial cells
platelet activation
thrombus formation
vasodilation
4-8 hours
parietal cells
stomach
mucous
ulcer
specificity of aspirin:
COX -1 is a — enzyme involved in — synthesis in virtually every cell in the body.
COX-2 is induced in — conditions
Prostaglandins in CNS regulate — and body —
Prostaglandins in stomach regulate — secretion
Aspirin inhibits — activity
—- doses (—g/day)are effective as antiinflammatory agents (inhibits both COXI and COX II)
Intermediate doses (—mg to –g/day) have —- and — effects (Inhibits COXI).
Low doses (typically – to –mg/day)inhibits platelet — of thromboxane A2, resulting in an — effect.
ubiquitous
prostaglandin
inflammatory
vascular tone and temp
avid
COX
high
4-8g
650 mg / 4g
analgesic and antipyretic effect
75 to 81 mg
platelet generation
anti thrombotic effect
Platelet life-span is ~ — days
10% of Platelet population is replaced–
Platelets are — ie have —
They are therefore — to synthesise new proteins
Aspirin inhibits – irreversibly
Therefore, Aspirin treatment — inhibits platelet COX for the remaining life of the platelet
However, non-platelet COX can recover within — hours, as all other cells can regenerate new COX protein in this time
We can achieve platelet specificity-of-action of Aspirin by — manipulation
- manipualting aspirin dosage to achieve plaetelet specificity:
1- If a person is treated with 325mg Aspirin per day:
This dose of Aspirin will inhibit — prostaglandin formation in body
Most cells, except platelets, will recover within — hours by — synthesis of COX
repeated administration is likely to cause —and other side effects (Because prostaglandins eg PGE2 regulate acid / mucus balance in stomach)
2- In contrast, if a person is treated with 75mg Aspirin per day :
This dose of Aspirin will inhibit prostaglandin synthesis by only — throughout all cells in the body
most cells will recover within — hours
platelets will remain inhibited for their lifespan
daily dosage will cumulatively inhibit all — but non-platelet COX will only be— affected
gastric ulceration (and other side effects) is less likely to occur
10 days
daily
enucleate
no nuclease
unable
COX
irreversibly
4-8 hrs
pharmokinetics
all
4-8
de novo
gastric ulcerations
10-20%
4-8 hrs
platelet COX
minimally
effectiveness of aspirin:
Decreases incidence of death following — by approximately 25%
Has additive effect with — (not shown)
Has additive effect with — agents such as tPA or streptokinase
— prevention in patients for whom the risk of future vascular events is ≥0.6% per year and who are not at increased risk of gastrointestinal bleeding (≥0.1% per year).
side effects of aspirin:
Excessive—- due to — platelet function,
— symptoms (nausea, pain, bleeding into GIT) due to inhibition of COX in — mucosa
— disease in children- due to — of liver proteins
Note:
Aspirin is the only NSAID with potent and specific antiplatelet effects. Other NSAIDs are not irreversible
MI
heparin
thrombolytic agent
primary
bleeding
reduced
upper GI
gastric mucosa
reyes
acetylation
2- receptor antagonist : — receptor Antagonists
- —- inhibitors of ADP P2Y12 receptors on platelets
Clopidogrel (Plavix; off patent 2010)
Prasugrel (released on market 2009)
Ticagrelor (Released in 2016)
1- Clopidogrel (PLAVIX): Antagonist of Platelet ADP Receptor (P2Y12):
Mechanism of action:
— antagonist of ADP (P2Y12) receptors on platelets
Administered as a — , — binds to the adenosine phosphate (ADP) receptor on platelets (P2Y12)
Clopidogrel is metabolised to its active form in the – by — enzymes, specifically CYP2C19
Prevents ADP, released from activated platelets, from recruiting more platelets to the thrombus
adp
non competitive
non competitive
pro drug
covelently
liver
cytochrome p450
2- prasugrel : Antagonist of Platelet ADP Receptor (P2Y12):
Prasugrel is — member of this class of ADP receptor inhibitor
Like Clopidogrel, it is a — antagonist of ADP (P2Y12) receptors on platelets
Approved for the reduction of — cardiovascular events (including— ) in patients with —
Like clopidogrel, it is a — that needs activation by 000 enzymes
However, it is activated by different Cyt-P450 than Clopidogrel
There is a — incidence of drug resistance
info: prasugrel better than clopidigrel in reducing the combined rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (TRITON TIMI-38 investigators; 2007)
3- Ticagrelor: Antagonist of Platelet ADP Receptor (P2Y12):
Tricagrelor is the newest member of this class of — ADP receptor inhibitors
Mechanism of Action: — and — binds the adenosine diphosphate (ADP) P2Y12receptor on the platelet surface which prevents ADP-mediated activation of — .
Unlike Clopidogrel, and Prasugrel, Ticagrelor is not a — ;
-Note: Maintenance doses of aspirin above — mg — the effectiveness of ticagrelor and should be avoided.
-Used in the treatment of Acute & Chronic coronary syndrome (ACS)
Reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI.
Ticagrelor also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.
newer
non competitive
thrombotic cardiovascular events
stent thrombosis
acute coronary syndrom
pro drug
liver enzymes
lower
oral
reversibly and competitively
platelet aggregation
not a prodrug
100 mg
reduces
adverse effects of ADP receptor blocking drugs:
1- —- :
As with all drugs that may affect hemostasis, bleeding is associated with these drugs. — may occur at virtually any site. Risk is dependent on multiple variables, including the concurrent use of multiple agents that alter hemostasis (eg, aspirin, direct oral anticoagulants, nonsteroidal anti-inflammatory drugs, warfarin)
2- — reactions ( — and — ):
Drug discontinuation due to a pruritic – may occur in up to 1.5% of patients. Because of structural similarities, cross-reactivity has been reported among the thienopyridines (clopidogrel, prasugrel, ticlopidine)
3- Ventricular — and — ,
includingatrioventricular(AV)block, have been reported with the use of (ticagrelor); the precise mechanism of his effect is not fully understood as yet.
4- Failure to — : Noted with Clopidogrel due to genetic polymorphism in the CYP2C19 liver metabolic enzyme –(required to liberate the active compound from the prodrug) present in up to 14% of the US population.
bleeding
homrrhage
hypersensitivity
immediate and delayed
rash
ventricular pause and bradyarrthymias ( from ticagrelor)
failure to respond
anti platelet drug used clinically:
1- in the ACUTE treatment of patients with acute ST elevation myocardial infarction
acute non-ST elevation acute coronary syndromes
Ischemic stroke/transient ischemic attack
Antiplatelet drugs will supress platelet — and prevent the — of circulating platelets to a growing — .
Heparin, or an anti-coagulant drug is often used in parallel, to prevent / supress activation of the coagulation cascade
tPA, a thrombolytic drug, can also be used in —
Anti-platelet drugs are also used CHRONICALLY :
Following percutaneous coronary intervention for stable ischemic heart disease
Carotid artery atherosclerosis, symptomatic
Peripheral atherosclerotic disease
Stable ischemic heart disease
- anti platelt treatment regimen:
Often used as — drug: Aspirin or Clopidogrel for long term treatment of patients at risk of —; usually patients who have previously suffered a thrombotic event eg MI or thrombotic stroke.
For all patients who have undergone coronary artery stenting (irrespective of the need for anticoagulant), – antiplatelet therapy with aspirin AND an ADPreceptor (P2Y12 ) – is required for some period of time to lower the risk of stent thrombosis.
= Dual Antiplatelet Therapy (DAPT) has become standard treatment for —
At some point, the P2Y12receptor blocker is stopped and aspirin is continued indefinitely.
For AF patients who have undergone coronary stenting, there is a rationale to treat with an – anticoagulant and – antiplatelet agents for some period after stenting (=Triple Anti-thrombotic Therapy; TAT)
activation and recruitment
thrombus
parallel
single
thrombosis
intense
blocker
12 months
oral
2
