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PA20321 Retake > (chan) 3. Pharmacology (the second half) > Flashcards

(chan) 3. Pharmacology (the second half) Flashcards

1
Q

High BP is a risk factor for CHD and stroke.

If BP is left untreated, it may lead to…?

A
  • Endothelial cell damages
    : Atherosclerosis
  • Internal organ damage (kidneys, eyes, nerves)
  • Extra strain on the heart
    : Left Ventricular Hypertrophy (Pulmonary oedema)
    : Congestive Heart Failure (Peripheral oedema)
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2
Q

What are the examples of modifiable Cardiovascular Risk Factors?

A
  • High BP
  • Smoking
  • High salt intake
  • Alcohol
  • Lack of exercise
  • Obesity
  • DYSLIPIDAEMIAS
  • Diabetes
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3
Q

What are the types and causes of systemic hypertension?

A
  1. Essential (primary) hypertension
    - 90-95%; no apparent cause
  2. Secondary hypertension
    - endocrine gland disorder
    - kidney diseases
    - drugs induced
  3. White-coat hypertension
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4
Q

What are the stages of systemic hypertension & treatment initiation developed by BHS (British Hypertension Society)?

A 
Stage 1 (lifestyle changes)
\: ≥140/90mmHg AND ABPM/HBPM ≥135/85mmHg
Stage 2 (treatment initiated)
\: ≥160/100mmHg AND ABPM/HBPM ≥150/95mmHg
Stage 3 (treatment initiated)
\: ≥180/110mmHg
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5
Q

BP(Blood Pressure) = __ x __

A

CO x TPR

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6
Q

CO(Cardiac Output) = __ x __

A

HR x SV

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7
Q

What are the antihypertensive drugs acting on the RAAS & In the kidney?

A

RAAS

  • ACE inhibitors (ACEi)
  • AT1 receptor blockers (ARB)
  • Renin inhibitors
  • Aldosterone antagonists

Kidney
- Diuretics

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8
Q

What are the antihypertensive drugs acting on Blood Vessels?

A

Direct-acting vasodilators

  • calcium channel blockers
  • potassium channel openers
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9
Q

What are the antihypertensive drugs that target the sympathetic NS?

A

Acting on peripheral adrenergic receptors

  • beta-blockers (heart, kidney)
  • a1-adrenoceptor antagonists (blood vessels)

Central-acting (brainstem)

  • a2-adrenoceptor agonists
  • imidazoline receptor agonist
  • ganglion blockers
  • adrenergic neuron blockers
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10
Q

What is the function of Renin?

A
  • Cause an increase in blood pressure leading to restoration of perfusion pressure in the kidneys
  • Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin i which is further converted into angiotensin ii by ACE
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11
Q

How is Angiotensin II formed and what is its effect?

A

Angiotensin I is produced by the action of renin (an enzyme produced by the kidneys) on a protein called angiotensinogen, which is formed by the liver.

Angiotensin I is transformed into angiotensin II in the blood by the action of angiotensin-converting enzyme (ACE).

Angiotensin II acts directly on blood vessels, causing their constriction and thereby raising blood pressure.

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12
Q

How does ACEi work?

A

Angiotensin converting enzyme inhibitors (ACE inhibitors) are medications that slow (inhibit) the activity of the enzyme ACE, which decreases the production of angiotensin II.

As a result, blood vessels enlarge or dilate, and blood pressure is reduced.

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13
Q

ACEi are often used together with diuretics.

Which adverse effects could the combination of an ACEi with a diuretic and an NSAID have?

A
  • dangerously reduced GFR and renal failure (triple whammy)
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14
Q

What are the adverse effects of ACEi?

A
  • Hypotension
  • Taste disturbance
  • Dry cough
  • Angioedema
  • Hyperkalaemia
  • Reversible renal failure in patients
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15
Q

Drugs that act on the RAAS are not the first choice of therapy in some patients. Who are they?

A
  • Elderly (over 55 yrs old)
  • Patients of African or Caribbean family origin (Due to low activity of RAAS)
  • Pregnancy
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16
Q

What is the Calcium Channel Blocker’s mechanism of antihypertensive action and its systemic effect?

A
  • Block of the L-type Voltage-Activated calcium influx in vascular smooth muscle cells
  • Arterial Dilation (decrease in TPR & Cardiac afterload)
  • Venodilation
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17
Q

Which patients is Calcium Channel Blocker (CCB) preferred first-line treatment in?

A
  • Elderly (over 55 yrs old)
  • Patients of African-American or Caribbean family origin of any age
  • Severe hypertension in pregnancy
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18
Q

What are the common adverse effects of CCBs?

A
  • Postural hypotension
  • Tachycardia
  • Hypotension
  • Ankle oedema
  • Headache & Flushes
  • Myocardial ischaemia
  • Constipation
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19
Q

What is the Potassium Channel Activator’s mechanism of action?

A
  • Activation of ATP-sensitive potassium channels in vascular smooth muscle
  • Inducing Membrane hyperpolarisation
  • Closure of L-type VACCs
  • Reduced Calcium influx
  • Vasorelaxation
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20
Q

What are the adverse effects of Potassium channel activators?

A
  • Reflex tachycardia
  • Fluid retention
  • Diabetes mellites
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21
Q

What is Hydralazine’s systemic effects and mechanismo of action?

A
  • Dilation of arteries and arterioles, decrease in TPR & cardiac afterload
  • MoA not clear
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22
Q

What are the antihypertensive drugs that act on the sympathetic NS?

A
  • ß-BLOCKERS (-olol)

- α1 –ADRENOCEPTOR ANTAGONISTS

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23
Q

What is the mechanism of ß-BLOCKERS and its benefit as hypertensive therapy?

A
  • Block ß1 receptors in the heart
  • Reduces reflex tachycardia
  • Reduces renin release and activation of the RAAS
  • Reduces central sympathetic activity
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24
Q

What are the adverse effects of ß-BLOCKERS?

A
  • Bronchoconstriction
  • Hypoglycaemia
  • Bardycardia
  • Fatigue
  • Erectile dysfunction
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25
Q

What is the machanism of α1-Adrenoceptor antagonists and its systemic effect?

A
  • Inhibition of postsynaptic α1-adrenoceptors on vascular smooth muscle cells
  • Arterial dilation: reduced TPR and cardiac afterload
  • Venodilation: reduced cardiac preload and SV
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26
Q

Adverse effects of α1-Adrenoceptor antagonist?

A
  • First-dose hypotension
  • Dizziness
  • Fatigue
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27
Q

what is the mechanism of action of central-acting drugs as antihypertensives?

A
  • Reduction in the activity of vasomotor centre in the brain, leading to decrease in sympathetic activity and increase in parasympathetic outflow
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28
Q

How does Ganglion Blocking Drugs (antihypertensives on sympathetic NS) work?

A
  • Competitive nicotinic acetylcholine receptor antagonist at the autonomic ganglia
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29
Q

Define Atherosclerosis

A
  • progressive disease of large and medium-sized muscular arteries characterised by inflammation and dysfunction of the lining of the involved blood vessels and the build up of cholesterol, lipids and cellular debris
  • this results in formation of a plaque, obstruction of blood flow and diminished oxygen supply to target organs
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30
Q

What are the clinical signs and symptoms of Atherosclerosis?

A
  • In many cases asymptomatic

- CHD, leading angina, ACS & MI

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31
Q

What are the normal levels of cholesterol and triglycerides in blood plasma?

A

TC: ≤ 5mmol/L

TC:HDL-C ratio ≤ 6

Non HDL-cholesterol: ≤ 4 mmol/L

LDL-cholesterol: ≤ 3 mmol/L

HDL-Cholesterol:
≥ 1mmol/L (men)
≥ 1.2mmol/L (women)

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32
Q

What are the modifiable and non-modifiable risk factors of Atherosclerosis?

A

Modifiable

  • Hypertension
  • Diabetes Mellitus
  • Smoking
  • Alcohol excess
  • High-fat diet
  • Lack of exercise
  • Obesity

Non-modifiable

  • Gender
  • Age
  • Genetics
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33
Q

What is Chylomicrons (CM)?

A
  • Mainly dietary triglycerides + esterified cholesterol
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34
Q

What is VLDL (Very Low-density lipoprotein)

A
  • Cholesterol esters + newly synthesised triglyceride
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35
Q

How is cholesterol transported in the blood?

A
  • Cholesterol is insoluble in the blood

- It is transported to and from the cells by carriers known as lipoproteins

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36
Q

What do you understand about LDL and HDL?

A

LDL

  • Bad cholesterol
  • major cholesterol carrier in the blood
  • If too much LDL cholesterol circulates in the blood, it can slowly build up in the walls of the arteries feeding the heart and brain
  • Together with other substances it can form plaque, a thick hard deposit that can clog those arteries
  • A clot forming near this plaque can block the blood flow to part of the heart muscles resulting in a heart attack or it can block blood flow to the brain causing a stroke

HDL

  • Good cholesterol
  • Carries 1/3 to 1/4 of blood cholesterol
  • It is believed that HDL tends to carry cholesterol away from the arteries and back to the liver where it is metabolised and removed
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37
Q

Describe Formation of atheromatous plaque in the blood vessel

A

Endotherlial cell dysfunction (initiation)

  • Reduced bioavailability of NO
  • Upregulation of endothelial adheision receptors
  • Increase endothelial permeability to LDL particles
  • Release of chemokines and cytokines

Lipid accumulation and oxidation

  • LDL particles accumulate in sub-endothelial space
  • LDL retained by ApoB100 binds to negatively charged extracellular matrix proteoglycans
  • LDL oxidised by reactive oxygen species or enzymes secreted from inflammatory cells
  • Formation of oxidised LDL particles
  • Formation of non-esterified cholesterol crystals
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38
Q

Describe formation of a stable fibrious cap in the blood vessel

A
  • Proliferation & migration of SMC into sub-endothelial space
  • Increased matrix protein synthesis & deposition
  • Formation of a stable fibrous cap
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39
Q

What do you understand about ‘Lipoprotein(a)’

A
  • cholesterol-rich LDL-like APO-B and an additional protein, apolipoprotein(a), attached via a disulphide bond
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40
Q

What is the Cholesterol Targets in the UK in CHD patients?

A

TC < 4mmol/L

HDL ≥ 1 mmol/L

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41
Q

What are the examples of Lipid-Lowering Drugs?

A
  • Statins
  • Ezetimibe
  • Fibrates
  • Bile Acid-binding resins
  • Nicotinic Acid
  • Fish oil derivatives
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42
Q

What is the mechanism of action of Statins and its main lipid-lowering effect?

A
  • Specific, reversible and competitive inhibition of HMG-CoA reductase
  • Reduction of circulating LDL (due to increased LDL surface receptors & LDL particle clearance)
  • Modest increase in plasma HDL
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43
Q

What are the 2 types of statins used in the UK?

A

Type I
- Fungal (fermentation) derived statins

Type II
- Synthetically-derived statins

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44
Q

What CYP enzmyes do Lovastatin, Simvastatin, Atorvastatin’ interact with?
and their oral bioavailability?

A
  • CYP3A4

Lovastatin <5%
Simvastatin 5%
Atorvastatin 12%

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45
Q

What are the metabolism, excretion and drug interactions of Statins?

A

Liver CYP metabolism
- mainly by CYP3A4 and CTP 2C9

Excretion
- mainly faecal (mostly via bile and GI route)

Drug interactions
- CYP3A4 inhibitor
: increase levels of statin
: anti-fungal, antibiotics (erythromycin), CCB, immunisuppresants, grapefruit juice

  • CYP3A4 inducers
    : reduce statin levels
    : antibiotics (rifampicin), anticonvulsants
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46
Q

What is the therapeutic uses of Statins?

A
  • Primary prevention of CHD in patients with other risk factors
    : Chronic Kidney Disease
    : Diabetes
  • Secondary prevention of CHD
  • In familiar hypercholesterolaemia
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47
Q

Statin uses cautions in patients with ..?

A
  • Liver disease
  • Hypothyrodism
  • Pregnancy
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48
Q

Other than lipid lowering effect, what other CV benefits does statin have?

A
  • Improvement of endothelial function
  • Anti-inflammatory
  • Anti-thrombic and antiplatelet effects
  • Increase in vasodilation
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49
Q

What are the adverse reactions of statins?

A
  • Muscle pain
  • Rare: Myopathies
  • Very rare: Hepatitis
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50
Q

What is the mechanism of action of Ezetimibe and its main lipid-lowering effects?

A
  • Inhibition of NPC1L1 membrane transport protein in enterocytes in the gut
  • Inhibition of cholesterol absorption in the gut
  • Reduction of LDL
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51
Q

What are clinical use & adverse effects of Ezetimibe?

A
  • In combination with a statin
  • Alone when statins are contraindicated

Adverse effects

  • Diarrhoea
  • Abdominal pain
  • Headache
  • Myalgia
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52
Q

What are the mechanism of action and main lipid-lowering effects of Fibrates?

A

Mechanism
- agonists at PPARa (Peroximal Proliferator Activator Receptor a), a nuclear transcription factor

  • Bind and activate PPARa
  • Activated PPARa dimerises with the RXR
  • PPARa/RXR heterodimer activates transcription of LPL(Lipoprotein lipase)
  • also increased expression of HDL lipoproteins
Main lipid-lowering effects
- Increased expression of LPL and HDL apolipoprotein results in
\: ↑ Lipoprotein lipase activity
\: ↑ Plasma HDL
\: ↑ LDL uptake
\: ↑ b-oxidation of fatty acids
\: ↓ plasma VLDL &amp; ↓ triglycerides
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53
Q

What are the therapeutic uses of Fibrates?

A
  • In mixed dyslipidaemia
  • In patients with high risk of atherosclerosis and low HDL
  • In severe treatment-resistant dyslipidaemia
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54
Q

What are the adverse effects of Fibrates?

GA YAU GA YAU
HWAITING

A

Common

- Abdominal distension, anorexia, diarrhoea, nausea

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55
Q

What are the mechanism of action and lipid-lowering effects of Bile Acid-binding resins?

A

Mechanism
- Bind bile acids in the guy and reduce reabsorption of cholesterol via enterohepatic circulation

Lipid-lowering effects
- Decrease in LDL

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56
Q

What are the clinical use and adverse effects of bile acid-binding resins?

A

Clinical use

  • In patients with liver diseases
  • In dyslipidaemia non-responsive to diet
  • In pregnancy with caution

Adverse effects

  • GI disturbances
  • Constipation
  • Bleeding
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57
Q

What is the mechanism of action and lipid-lowering effects of nicotinic acid?

A

Lipid-lowering mechanism
- Activates on the Gi/o coupled HCA2 receptor in adipocytes

Lipid-lowering effects
- Inhibition of lipolysis
: ↓ triglyceride = ↓ VLDL = ↓ LDL
- Increase apo-A1 = ↑ HDL

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58
Q

What lipid-lowering effects does Fish oil derivatives have?

A
  • Reduction of triglycerides

- Reduction in LDL cholesterol

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59
Q

Effects of Insulin and Glucagon?

A

Insulin decreases plasma..

  • glucose
  • amino acids
  • FFAs
  • ‘anabolic’

Glucagon increases plasma

  • glucose
  • ketones
  • ‘catabolic’
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60
Q

What do you understand about T1DM?

A
  • Autoimmune disease
  • T-cell mediated autoimmune disease with circulating auto-antibodies to various islet cell antigens
  • Cause: Genetic risk factor (HLA), Environmental factors (viral infection)
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61
Q

What do you understand about T2DM?

A
  • Insulin resistance: body cannot produce enough insulin
  • Can go undiagnosed for a long time
  • accounts for between 85-95% of all people with diabetes
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62
Q

Who is insulin needed to?

A
  • Required for treatment of T1DM: no insulin produced

- Needed for T2DM where other methods have failed to achieve good control

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63
Q

What are the 3 types of insulin?

A
  1. Short-acting insulin
    : before meals
  2. Intermediate-acting insulins
    : once or twice dialy, before meals
  3. Long-acting insulins
    : once or twice daily, before meals
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64
Q

What is the traetment aim with insulin?

A
  • to maintain blood glucose levels 4-9 mmol/L

- to avoid hypoglycaemia

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65
Q

How does insulin increase glucose uptake?

A
  • In muscle and fat cells, insulin triggers the translocation of GLUT4 to the plasma membrane
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66
Q

How does insulin affect metabolism?

A

Insulin stimulates glucose utilisation via glycolysis and glycogenesis
- upragulates transcription of enzymes involved in rate limiting steps of glycolysis
: glucokinase, phosphofructokinase, pyruvate kinase

  • increases glycogenesis by activating glycogen synthase, the enzyme which adds glucose units to make glycogen
  • increases glycogenensis by inactivating glucose synthase kindase 3 (GSK-3) which inhibits glycogen synthase

Insulin inhibits glucose production by inhibiting gluconeogenesis and glycogenolysis
- inactivates glycogen phosphorylase, responsible for the subsequential removal of glucose monomers from glycogen

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67
Q

What are the consequences of insulin resistance?

A
  • Hyperglycaemia
  • Increased thirst/urination
  • Fatigue & changes in appetite
  • Low ‘HDL’ cholesterol
  • Hypertension
  • Atherosclerosis & increased risk of CVD
68
Q

What is Sulfonylureas used for?

A
  • ‘oral antidiabetic drug’ or ‘oral hypoglycaemic drug’ used for the treatment of T2DM
  • stimulate insulin secretion
  • examples include tolbutamide, gliclazide
69
Q

How do sulfonylureas stimulate insulin secretion?

A
  • Insulin is found in small packets inside the beta cells of the pancreas
  • The release of these packets is set off by rising calcium concentration inside the cells
  • Sulfonylureas trigger a rise in calcium and the subsequent release of insulin by inhibiting the action of a protein that brings potassium meolcule into the cells
70
Q

What is the potential adverse effects of sulfonylureas?

A
  • Major adverse side effect is hypoglycaemia

- May stimulate weight gain due to fat storage promotion

71
Q

What is Meglitanides used for?

A
  • Examples are repaglinide, nateglinide
  • insulin secretagogues: act by blockade of Katp channels
  • More rapidly absorbed than sulfonylureas so faster onset of action
72
Q

What is Biguanides used for?

A
  • Oral antidiabetic drug used for treatment of T2DM
  • Acts only in the presence of endogenous insulin: insulin-sensitizing drug
  • metformin
  • Drug of choice in overweight patients
73
Q

What is the antihyperglycaemic MoA of metformin (biguanides)?

A
  • Main action is to decrease hepatic glucose production by inhibiting gluconeogenesis
  • Molecular target is AMP-activated protein kinase(AMPK)
74
Q

What are the benefits of metformin over sulfonylureas?

A
  • Lack of weight gain
  • No increase in plasma insulin, and resultant hypoglycaemia
  • Persistent efficacy (2-5 yrs) when used alone or in combination
  • Positive changes in lipid profiles (decreased TG, increased HDL)
  • Reduction of blood pressure
  • Delay in moving to insulin injections
75
Q

What are the potential adverse effects of metformin?

A
  • GI tract effects
    : metallic taste, diarrhoea, nausea
  • Lactic acidosis
    : occurs because of excessive lactate production because of blockade of mitochondrial respiratory chain complex
76
Q

What do you understand about α-glucosidase inhibitors

A
  • Acarbose is an example
  • Reduces the digestion of complex carbohydrates, slows their absorption from the gut
  • Reduces postprandial glycaemia
77
Q

What is Thiazolidinediones (TZDs, glitazones) used for?

A
  • Targets insulin resistant patients

- ‘insulin sensitizing drug

78
Q

What do you understand about Peroxisome Proliferator-activated receptors (PPARs)

A
  • Thiazolidinediones (TZDs) are PPARγ agonists
  • Effects may take several weeks to be fully expressed
  • Net increase in insulin sensitivitiy

PPARγ has two mechanisms
1. Transactivation
: activates gene expression

  1. Transrepression
    : represses gene transcription
79
Q

What are the potential adverse effects of thiazolidinediones

A
  • minimal hypoglycaemia

- Weight gain

80
Q

What is incretin?

A
  • hormones released in the GI tract postprandially to stimulate glucose-induced insulin release from the pancreas
  • GLP-1(Glucagon-like peptide) and GIP(Gastric inhibitory polypeptide) are ‘incretins’
  • GLP-1 affects insulin biosynthesis and secretion, only under hyperglycaemic conditions
  • GLP-1 inhibits glucagon release
  • GLP-1 levels are reduced in T2DM
81
Q

Following a meal, the increase in blood glucose is dampened by..

A
  • Satiety signals to the brain
  • GLP-1 stimulated insulin secretion
  • GLP-1 inhibition of glucagon
82
Q

What are incretin mimetics?

A
  • analogues of incretins
  • administered via subcutaneous injection
  • main adverse effect is nausea which deters use
  • GLP-1 therapy is aimed at overweight T2DM patients
83
Q

What are Gliptins?

A
  • DDP-4 inhibitors
  • DDP-4 is the enzyme responsible for rapid degradation of GLP-1 and GIP
  • Effects are to enhance insulin secretion, suppress glucagon secretion and slowed gastric emptying
84
Q

What does GLP-1 do to brain, stomach and pancreatic islets?

A

Brain
- Satiety

Stomach
- Delay in gastric emptying

Pancreatic islets

  • stimulation of insulin secretion
  • stimulation of b-cell proliferation
  • inihibition of b-cell apoptosis
  • inhibition of glucagon secretion
85
Q

What are SGLT2 inhibitors?

A
  • Reversibly inhibit SGLT2 in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
86
Q

Presence of glucose in the urine is a market for diabetes.

Why is that?

A
  • Kidney plays a key role in regulating glucose homeostasis

- In a non-diabetic person, virtually all of the glucose filtered is reabsorbed, and non appears in the urine

87
Q

What are the energy sources of cardiac metabolism?

A
  • Fatty acid oxidation (major 60-70%)

- Oxidation of carbohydrates

88
Q

Describe energy usuage in cardiac metabolism

A
  • Myocardial contraction 50%
  • Basal resting activity 20-30%
  • Cardiac relaxation 20%
  • cardiac excitation small
89
Q

Describe Coronary Blood Flow (CBF)

A
  • Left coronary artery supplies the left & right heart (~85% of CBF)
  • Right coronary artery supplies the SAN & AVN & right heart
  • Venous blood returns into
    : RA (95%) via the coronary sinus & anterior cardiac vein
    : heart chambers directly via thebesian veins
90
Q

How does Coronary Blood Flow increase when you exercise?

A
  • Release of catecholamines
  • Increase in heart rate
  • Increase in cardiac workload
  • Increase in cardiac metabolism
  • Local release of metabolites(Adenosine/Potassium) & hypoxia(decreased pO2)
  • Vasodilation of coronary arteries
  • Increase in coronary blood flow
91
Q

Metabolic autoregulation of CBF

: What is the effect of adenosine?

A
  1. Induces increase in cAMP
  2. Vasodilation
  3. Increase in CBF
92
Q

Metabolic autoregulation of CBF: What effects do hypoxia & potassium have?

A
  1. Hyperpolarisation of coronary SM
  2. Vasodilation
  3. Increase in CBF
93
Q

What is the underlying cause and symptoms of Angina Pectoris/Stable angina?

A

Underlying cause
- Atheromatous disease of the coronary arteries

Symptoms

  • main symptom of angina is chest pain
  • feels tight, dull or heavy
  • spreads to your left arm, neck, jaw or back
  • is triggered by physical exertion or stress
  • Stops within a few minutes of resting
94
Q

What are the therapeutic strategies for treatment of stable angina?

A

Reduce oxygen demand

  • reduce the HR
  • reduce cardiac preload

Increase oxygen supply

  • increase coronary blood flow
  • increase regional collateral blood flow
95
Q

What is the first-line and second-line treatment of stable angina?

A

First-line
- Beta blockers

  • Calcium channel blockers (CCBs)

Second-line
- Organic Nitrate vasodilator

96
Q

What are the systemic effects of organic nitrates?

A 
Systemic vasodilation
- Veins
\: ↓ Preload (main net effect)
- Arteries
\: ↓ Afterload
= ↓ Cardiac Oxygen Demand

Dilation of collateral vessels
= ↑ Oxygen supply to ischaemic myocardium

97
Q

Common adverse effects of organic nitrates?

A
  • diziness
  • postural hypotension
  • Reflex tachycardia
  • Headache
98
Q

What are the MoA and main systemic effect of Nicorandil?

A
  • activator of vascular ATP-sensitive potassium channels
  • Sytemic venodilation (decrease of cardiac preload)
  • Arteriodilation (increase in CBF)
99
Q

What are the MoA and main systemic effect of ivabradine?

A
  • inhibition of the pacemaker i.f current in the Sinoatrial Node
  • decrease in HR
100
Q

What are the MoA and main systemic effect of Ranolazine?

A
  • inhibits the late sodium current that is activated by ischaemia in cardiac myocytes
  • protect cardiac muscles from ischaemic damage
101
Q

Describe ACS: Unstable Angina

A

Symptoms

  • Unstable chest pain occurring at rest
  • Urgent hospitalisation required

Causes
- Ischaemia due to thrombus formation

Partial artery occlusion
- NSTEMI

Complete artery blockade
- STEMI

102
Q

What is the main aim of early treatment of unstable angina & NSTEMI?

A
  • To prevent future adverse cardiovascular events

: MI, repeated revascularisation or death

103
Q

What is the acute management of MI with STEMI?

A
  • Primary Percutaneous Coronary Intervention (PCI)

- Coronary Artery Bypass Greating (CABG)

104
Q

What is the prevention of secondary MI

A

Changing lifestyle
- mediterranean-type diet

  • regular exercise
  • alcohol consumption within the limits
  • quit smoking
  • weight control

Preventive drug therapy
- ACE inhibitors

  • Dual antiplatelet therapy
  • b-blockers
  • Statins
105
Q

What are the 7 stages of platelet activation, aggregation and thrombus formation?

A
  1. Triggered
    - by the damaged vascular endothelium, exposure of collagen and release of von Willebrand factor by endothelial cells
  2. Platelet adhesion
    - via von Willebrand factor bridging between subendothelial macromolecules and paltelet glycoprotein GPlb receptors
  3. Platelet shape changes
    - from smooth discs to spiny spheres with protruding pseudopodia
  4. Secretion
    - of the granule contents. From dense granules ADP, ATP, calcium, 5-HT, histamine are released. From alpha granules IGF-1, PDFG, TGFb, platelet factor 4 and coagulation factors are released
  5. Synthesis and release
    - of platelet -activating factor (PAF) and thromboxane A2 (TXA2)
  6. Aggregation
    - is promoted by various agonists such as collagen, thrombin, ADP, 5-hydroxytryptamine and TXA2 followed by expression of GPllb/llla receptors that bind fibrinogen, which links adjacent platelets to form aggregates
  7. Exposure of acidic phospholipid
    - on the platelet surface, promoting thrombin formation
106
Q

Describe cellular mechanisms of action of COX inhibitors (aspirin)

A
  • Cox-1 produces prostaglandins that activate platelets

- NSAIDs block the COX enzymes and reduce production of prostaglandin

107
Q

Describe cellular mechanisms of action of P2Y12 receptor antagonists (-GREL/-GRELOR)

A
  • P2Y12 (Gi) RECEPTORS plays a central role in amplification and stabilization of ADP-induced platelet aggregation
  • Active metabolite contains thiol group
  • Forms a disulfide bond with cysteine residues of the receptor
  • irreversible inhibition
108
Q

What is Ticagrelor?

A
  • Direct-acting, reversible P2Y12 receptor antagonist
  • non-competitive and reversible
  • hepatic metabolism by CYP3A4(main), CYP3A5
  • produces active metabolite
109
Q

Describe cellular mechanisms of action of Glycoprotein llb/llla receptor inhibitors (eg, ABCIXIMAB, EPTIFIBATIDE, TIROFIBAN)

A
  • Glycoprotein llb/llla receptor antagonist binds to glycoprotein llb/llla receptor and prevent the receptor being bound by fibrinogen which forms bridges between adjacent platelets
110
Q

Describe cellular mechanisms of action of Phosphodiesterase inhibitors (DIPYRIDAMOLE)

A
  • Blocks PDE and increase cAMP & cGMP
  • DP Increases local concentration of adenosine, which stimulates Adenylyl cyclase (AC) in platelets leading to increased intracellular cAMP levels
  • In addition, by inhibiting PDE, DP prevents the breakdown of cAMP
  • Increased cAMP keep platelets from being activated
  • Also, increases PGI2 production and vascular smooth muscle cGMP leaving to vasodilation
111
Q

What is the common adverse reaction of antiplatelet drugs?

A
  • Haemorrhage
  • GI bleeding
  • Bronchospasm
  • Hypersensitivity
112
Q

Describe conduction system of the heart and ECG
: P-wave, QRS complex, T-wave
: PR-segment, ST-segment, PR interval, QT-interval

A

P-wave
- depolarisation of the atria

QRS complex
- depolarisation of the ventricles

T-wave
- repolariation of the ventricles

PR-segment
- AV delay

ST-segment
- Ventricular plateau

PR interval
- Atrial depolarisation & AV delay

QT interval
- Ventricular depolarisation & repolarisation

113
Q

Describe the phases of the Cardiac AP

A

Phase 0

  • Rapid depolarisation
  • Rapid Na+ influx via voltage-activated sodium channels

Phase 1

  • Rapid repolarisation
  • Transient K+ efflux

Phase 2

  • Plateau
  • Ca2+ influx via L-type voltage-activated calcium channels

Phase 3

  • Repolarisation
  • K+ efflux via slow & rapid delayed rectifier potassium channels

Phase 4

  • Stable baseline
  • K+ efflux via inwardly rectifying potassium channels
114
Q

Duration of the Cardiac AP determines the Refractoriness of the heart.

What are Absolute/Effective refractory & Relative refractory period?

A

Absolute/Effective
- when generation of the 2nd AP is not possible even at the strongest consecutive stimulus

Relative
- when generation of the 2nd AP is possible but requires a stronger stimuli

115
Q

Describe the phases of the Pacemaker AP

A

Phase 4

  • Pacemaker current
  • Mainly sodium influx

Phase early 0
- Voltage-activated T-type calcium influx

Phase 0
- Voltage-activated L-type calcium influx

Phase 3
- Voltage-activated potassium efflux

116
Q

What are the key features of l.f ‘funny’ ‘pacemaker’ current?

A

Channel type
- Hyperpolarisation-activated Cyclic Nucleotide-Gated channel (HCN)

Selectivity

  • Non-selective cation current , permeable to both Na+ and K+
  • But physiological potentials mainly sodium influx

Activation

  • By membrane repolarisation
  • Directly by cAMP

Modulation

  • Sympathetic +ve via b1 and b2 adrenoceptors
  • Parasympathetic -ve via muscarinic M2 receptors

Role in the normal heart

  • Cardiac automaticity
  • Heart rate control by the autonomic NS & by circulating adrenaline

Pharmacology
- selectively inhibited by Ivabradine (anti-anginal)

117
Q

How is the pacemaker potential modulated by sympathetic and parasympathetic stimulation?

A

Sympathetic stimulation
- Increased AP frequency, increased HR

Parasympathetic stimulation

  • Vagus stimulation
  • Reduced AP frequency, reduced HR
118
Q

What is the LQT syndrome?

A
  • disorder of the heart’s electrical activity

- causes sudden, uncontrollable dangerous arrhythmias in response to exercise or stress

119
Q

Symptoms of Cardiac Arrhythmia?

A
  • Feeling heartbeats (palpitation)
  • Diziness, feeling faint
  • Fainting
120
Q

What can cause cardiac arrhythmia?

A
  1. Myocardial ischaemia and existing heart diseases
    - Ischaemic heart disease (IHD)
    - Acute myocardial infarction (AMI)
    - Congestive Heart failure (CHF)
  2. Drugs
    - Antipsychotics, antibiotics, antidysrhythmics, digoxin
  3. Electrolyte disturbance
    - Hypokalaemia
    - Hypercalcaemia
  4. Hyper/Hypothyroidism
  5. Genetic disorders
    - Channelopaties
    - Storage & release of calcium from the SR
    - Abnormal conduction pathways in the heart
121
Q

What are the different classification and types of cardiac arrhythmia?

A

By the site of origin in the heart

  • Supraventricular
  • Ventricular

By the effect on the heart rate

  • Bradycardia (<60 bpm)
  • Tachycardia/Tachyarrhythmia (>100bpm)

By the effect on the heart rhythm

  • Regular
  • Irregular

By the type of QRS complex

  • Narrow complex
  • Broad complex
122
Q

What are the drugs that act on the cardiac and pacemaker AP?

A

The Pacemaker AP (SAN&AVN)

  • Rate control drugs
  • Calcium-channel blocker
  • B-blocker
  • Digoxin
The Cardiac AP
(Atrial&amp;Ventricular myocytes, his bundles, purkinje fibres)
- Rhythm control drugs
- Sodium-channel blockers
- Calcium-Channel blockers
- Potassium-channel blockers
123
Q

What are the 4 different Vaughan Williams Classifications of Antiarrhythmatic drugs?

A

Class I
- Sodium channel blockers

Class ll
- Beta-blockers

Class lll
- Drugs that prolong the AP duration

Class lV
- Calcium channel blockers

124
Q

What is the mechanism of Antiarrhythmatic action of Class l Sodium channel blockers?

A
  • Block the fast voltage-activated sodium channels
  • Slow down the upstroke of the cardiac AP, hence slow down AP conduction
  • Most effective in ventricular myocytes, pPurkinje fibres and in the atria
  • The block is use-dependent and increased with increased HR, hence reducing AP frequency
125
Q

What is the mechanism of Antiarrhythmatic action of Class ll Beta-blockers?

A
  • Block cardiac β1-adrenoceptors

- Slow down conduction at the AVN

126
Q

What is the mechanism of Antiarrhythmatic action of Class lll drugs that prolong the AP duration?

A
  • Block of voltage-activated potassium chanenls in repolarisation phase 3 of the action potential
  • prolong the duration of the cardiac AP
  • Prolong the QT interval
  • Increase refractoriness of the heart
127
Q

What is the mechanism of Antiarrhythmatic action of Class lV Calcium-channel blockers?

A
  • Block L-type voltage-activated calcium channels

- Slow down conduction of the AV node

128
Q

What are the physiological and pathological causes of bradycardia?

A

Sinus bradycardia (Physiological causes)

  • Increased vagal tone
  • In trained atheletes

Extrinsic (non-cardiac) causes

  • Hypothermia (not responsive to atropine)
  • Endocrine disorders (hypothyroidism)
  • Electrolyte imbalance
  • Drugs

Intrinsic (degeneration & diseases of the SAN, the atrium and the AVN)

  • Sick Sinus Syndrome
  • Atrioventricular blockade or heart block
129
Q

What is Sick Sinus Syndrome?

A

Group of heart rhythm disorders due to malfunction of the SA node that may present on the ECG as
- Sinus pause

  • Sinus arrest (pause for >3s)
  • Bradycardia-Tachycardia syndrome
130
Q

What are the 3 degrees of AV block?

A

First-degree
- slowed av conduction

Second-degree
- missed beats to the ventricles

Third-degree
- complete block

131
Q

What is the treatment for the AV block?

A

In emergencies
- Atropine (IV - antimuscarinic) or Isoprenaline (IV)

Long-term solution
- Implantable transcutaneous pacemaker (TCP)

132
Q

what is the Mechanisms of Tachyarrhythmia?

A

Automaticity

  • Enhanced: due to sympathetic overactivity
  • Abnormal: ectopic pacemaker
Triggered
- Re-entry
\: AVNRT, micro re-entry, 
\: AVRT(macro re-entry)
- Early after-depolarisation (EAD)
- Delayed after-depolarisation (DAD)
133
Q

What are the factors that can promote EAD(Early After-Depolarisation) and DAD(Delayed After-Depolarisation)

A

EADs

  • Slow HR
  • Drugs that prolong the QT interval
  • Genetics (LQT syndrome)

DADs

  • Fast HR
  • Drugs that increase cytosolic Ca2+
  • Genetics (CPVT)
134
Q

what is Atrial Fibrillation (AF)

& Atrial ‘Flutter’ and its cause?

A

AF
- Fast irregualrly irregular heartbeat

  • Random ectopic activity from the pulmonary vein in left atrium

Atial ‘Flutter’
- Fast regular heartbeat

  • One or more foci of re-entrant excitation in atria
135
Q

What is the treatment strategy for AF?

A

Rate control

  • Class ll: beta-blockers
  • Class lV: Verapamil, diltiazem
  • Digoxin

Rhythm control

  • Electrical cardioversion
  • Class ll: beta-blockers
  • Class lc: Flecainide
  • Class lll: Amiodarone
136
Q

Describe extrinsic coagulation cascade at the site of action of anticoagulant drugs

A
  • Tissue factor (TF) released by leukocytes due to EC layer damage
  • TF receptor of Factor Vlla
  • TF: FVlla complex activates FX
  • FXa activates Flla (thrombin)
  • Thrombin converts Fibronogen to Fibrin
  • Thrombin activates FXll
  • FXllla cross-links soluble fibrin into matrix
137
Q

What are the common therapeutic uses of anticoagulants?

A
  • Treatment of unstable angina and prevention of STEMI
  • Prophylaxis of stroke in patients with non-vulvar AF
  • Prophylaxis after insertion of prosthetic heart valve & in rheumatic heart disease
  • Prophylaxis and treatment of DVT & PE
138
Q

What are the common adverse effects of anticoagulants?

A
  • Bleeding

- Haemorrhage

139
Q

What is the role of Factor Xa in coagulation?

A
  • Factor Xa is the activated form of the coagulation factor throbokinase
  • Acts by cleaving prothrombin in two places which yields the active thrombin
140
Q

what is the MoA of anticoagulant action of Heparin & LMWH?

A
  • UNF & LMWH bind to antithrombin lll (ATlll) & enhance ATlll binding activity to Factor Xa
  • UFH also inhibits thrombin but LMWH do not
141
Q

What is the MoA of Novel Oral anticoagulatns (NOACs)?

A
  • Selective direct inhibitors of factor Xa
142
Q

What is Dabigatran?

A
  • Synthetic oral anticoagulant
  • Hydrolysed to active dabigatran
  • Inhibits bot hfree and fibrin-bound forms of thrombin
  • Inhibits thrombin-induced platelet aggregation
143
Q

What is the MoA of Warfarin?

A
  • inhibits vitamin-k dependent synthesis of biologically active forms of various clotting factors in addition to several regulatory factors.
144
Q

What are the factors that can affect action of Warfarin?

A
  • Polymorphisms of VKORC1
  • Polymorphisms of CYP450
  • Plasma levels of warfarin can be increased by
    : Acute alcoholism
    : Drugs that displace warfarin from albumin
    : Diseases (liver, hyperthroidism)
  • Plasma levels of warfarin can be decreased by
    : Drugs that reduce GI absorption
    : Chronic alcoholism
    : Hypothyroidism
145
Q

What is Fibrinolytic(Thrombolytic) drug?

A
  • drugs that dissolve (lyse) blood clots (thrombi) by activating plasminogen, which forms a cleaved product called plasmin
  • Plasmin is proteolytic enzyme that is capable of breaking cross-links between fibrin molecules which provide structural integrity of blood clots
146
Q

What are the therapeutic uses of Fibrinolytic (thrombolytic) agents?

A
  • In Acute Myocardial Infarction (main use)

- In acute thrombotic stroke

147
Q

Describe the processes of Cardiac Contraction

A
  1. Rapid depolarisation due to fast Na+ influx (phase 0) via Na+ channels (Stimulus)
  2. Activation of L-VACCs by rapid membrane depolarisation and influx of extracellular Ca2+ (Trigger)
  3. Activation of ryanodine receptors (RyR2) on the SR by Ca2+ and Ca2+-induced Ca2+ (Main source)
  4. Ca2+ influx via Na+Ca2+ exchanger (NCX) via the reverse mode of NCX (minor role)
148
Q

What is Cardiac Ryanodine Receptor (RyR2) and its features?

A
  • Protein found primarily in cardiac muscle
  • In the process of cardiac calcium-induced calcium release, RyR2 is the major mediator for sacroplasmic release of stored calcium ions
  • A large homotetrameric protein complex
  • An intracellular Ca release channel
  • Contains Ca binding sites
  • Contains endogenous stabiliser Calstabin to keep channel closed
  • Contains phosphorylation sites for PKA, CaMKll and PKG
149
Q

What are the 3 main isoforms of RyR?

A

RyR1
- skeletal muscles

RyR2
- cardiac muscle

RyR3
- brain & other tissues

150
Q

Describe the steps of Ca2+ induced Ca2+ release (CICR)

A
  1. Ca2+ enter via L-VACC
  2. Activation of cluster of RyRs
  3. Local Ca2+ release (Calcium Spark)
  4. Rapid summation of local events
  5. Global raise in Ca2+ (Calcium Wave)
  6. Contraction
151
Q

Build-up of cytosolic calcium could trigger DAD (Delayed AfterDepolarisation) leading to cardiac arrhythmia

What factors can may RyR leaky?

A

Drugs which make RyR leaky

  • Excess of caffeine
  • Immunosuppressants

Genetics; abnormal

  • Cardiac RyR2
  • Calsequestrin-2
152
Q

Describe the processes of Cardiac Relaxation

A
  1. Ca2+ reuptake into SR by Sacroplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) - 70-80%
  2. Ca2+ extrusion by the Na+Ca2+ exchanger - 20-30%
153
Q

How is SERCA (Sacroplasmic/Endoplasmic Reticulum Calcium ATPase) activated and regulated?

A

Cardiac isoform
: SERCA2a

Activation
: ↑ Cytosolic Ca2+

Regulation
: by phosphorylation of phospholamban (PLN) by PKA (main) and CaMKll

154
Q

Describe both Forward/Reverse mode of Ca2+ extrusion by the NCX

A

Forward (normal) mode

  • Activated by increased cytosolic Ca2+
  • Removes 1 cytosolic Ca2+ in exchange for 3 Na+
  • Reduces [Ca2+] by 20-30%

Reverse Mode

  • Activated by increased cytosolic Na+
  • Expels 3 Na+ in exchange for 1 Ca2+
  • Increases [Ca2+] (minor)
155
Q

What is an inotrope?

A

Inotrope is an agent that alters the force or energy of muscular contractions

  • Negatively inotropic agents weaken the force of muscular contractions while positively inotropic agents increase the strength of muscular contraction
156
Q

What are the 4 main positive inotropic agents?

A
  1. Catecholamines
  2. Phosphodiesterase type-3 inhibitors (PDE3 inhibitor)
  3. Calcium sensitisers
  4. Cardiac glycosides
157
Q

Describe the Positive inotropic & lusitropic effects of catecholamines

A

Inotropic (contraction)

  • Increase of [Ca2+]cyt
  • via PKA-mediated of phosphorylation
  • ↑ Ca influx via L-VACC
  • ↑ Ca release via RyR2

Lusitropic (relaxation)

  • Increase of Ca reuptake into SR
  • via PKA-mediated phosphorylation
  • ↑ PLN - SERCA
158
Q

Describe the positive inotropic effect of PDE3 inhibitor

A
  1. PDE3 inhibitor inhibits conversion of cAMP to AMP
  2. ↑ cAMP induced
  3. ↑ PKA
  4. ↑ Force of contraction
159
Q

Describe the positive inotropic effect of Calcium sensitiser

A
  • Binds to TnC in Ca2+-dependent manner and prolongs its action
  • Benefits
    : do not increase ATP consumption, cytosolic calcium
    : can synergise with PKA-dependent phosphorylation of Tnl
    : inhibits PDE3a (↑cAMP)
160
Q

Describe the positive inotropic effect of Cardiac Glycoside

A
  1. Inhibition of the Na+/K+ ATPase (Na-pump) by binding competitively to an extracellular K+ binding site
  2. Cellular sodium build-up induced
  3. Activates the reverse mode of NCX
  4. Increases intracellular calcium and hence more stored in the SR and available for release upon stimuli (CICR)
  5. Force of contraction is increased
161
Q

What are the adverse effects of Digoxin?

A
  • Cardiac arrhythmias
  • GI (irritation, diarrhoea, nausea, vomitting)
  • CNS (Yellow vision, blurred vision, diziness, headache)
162
Q

What is the treatment and prevention of Digoxin toxicity?

A
  • Use lower dose or withdrawal; monitoring plasma levels
  • Use oral K+ supplements
  • Steroid-bidning resins, activated charcoal
  • Digoxin-specific antibody fragments
163
Q

Define Heart Failure

A
  • Complex clinical syndrome of symptoms and signs that suggest the efficiency of the heart as a pump is impared
  • It is caused by structural or functional abnormalities of the heart
164
Q

What are the pathogenesis of heart failure?

A
  • Increased sympathetic activity and raised catecholamine levels
  • Impaired cardiac contractility & reduced CO
  • Activation of RAAS
  • Fluid and salt retention
165
Q

what is the first line therapy for CHF?

A
  • Ace inhibitor + beta-blocker + Diuretic
  • Acei and beta-blockers should be dose titrated in ‘start low go slow’ manner until achieve
    1. The highest tolerant dose
    2. The desired therapeutic dose

PA20321 Retake (5 decks)

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