CORNARY HEART DISEASE

How does a CHD process start?

Cornary artery obstruction or constriction > Loss of blood flow to the heart > depleting
oxygen & nutrients, build up of waste toxins > metabolic dysfunction, contractile dysfunction,
electrical instability, myocardial infarction (cell death)
What are 3 process of obstruction?
Atherosclerosis: LDL gets deposit into the sub-endothelial space > LDL gets modified to
oxidised LDL & recruit monocytes > monocytes releases macrophages and joins with OLDL >
foam cell formation > SMC migrate, proliferation & de-defferentiation. > fibrous plaque
formation and atheroma
Coronary Thrombosis: Rupture or ulceration of the atherosclerosis plaque > blood gets in
contact with collagen and tissue factors > activation of platelet aggregation & activation along
with coagulation cascade activation forming fibrinogen to fibrin > thrombus/clot
Coronary Spasm: endothelial injury = increase reactivity of vasoconstriction, vascular
dysfunction = imbalance of vasoconstriction & dilation
What are the consequences of each obstruction?
Atherosclerosis: Partial coronary occlusion = stable angina, vascular dysfunction = coronary
artery spasm, or rupture or ulceration of plaque = coronary thrombosis
Coronary thrombosis: complete & permanent occlusion of the coronary artery = STEMI,
intermittent occlusion of the CA = NSTEM/UA, or thromboembolism in a distal artery.
Coronary spasm: subtotal or intermittent occlusion of coronary artery OR complete focal
occlusion of coronary artery.
What are the modifiable risk?
-Hypertension
-smoking
-diabetes
-Obesity
-Hypercholesterolaemia

ANGINA
Describe the causes and underlying coronary pathology of stable coronary artery
disease (SCAD)
- Myocardial ischaemia of REVERSIBLE myocardial demand/supply mismatch (hypoxia
without cell necrosis)
-Imbalance b/w oxygen demand & supply
-Due to atherosclerotic plaque-related obstruction of epicardial coronary arteries = classic
angina
-Due to focal or diffuse spasm of mildly disease coronary arteries = variant angina
-Due to primary dysfunction of small diameter (500um) coronary arteries = microvascular
spasm
Describe the main clinical signs & symptoms, and the distinguishing features of the
subtypes of stable CAD
Clinical subtypes:
Angina with obstructive CAD
1. Classic or Stable Angina
- Chest pain on exertion
 - ST depression
- Fixed obstructive CAD (atherosclerotic plaque)
Angina without obstructive CAD
2. Varient Angina
- Chest pain at rest OR at night
- ST elevation
- Focal or diffuse spontaneous coronary artery spasm
- Arrhythmias
3. Microvascular Angina
- Chest pain at rest or exertion (poor response to GTN
- Positive stress test - ST depression during exercise
- No angiographic evidence of obstructive CAD
- Microvascular dysfunction
Signs & Symptoms
-Angina pain with various characteristics; discomfort in the front of the chest, neck, shoulder,
jaw or arms. RELIEVED by rest and/or GTN within about 5 minutes
-SOB, dizziness, syncope (from ishemia-induced transient LV dysfunction
-Increase myocardial lactate production & net ATP breakdown due to anaerobic metabolism
-ST depression (subendocardial ischemia)
-ST elevation (transmural ischemia)
Give an account of the non-pharmacological & pharmacological management of stable
CAD
Management Aim= control symptoms, reduce ischaemic burden, improve prognosis
1. Lifestyle modification:
-dietary control
-smoking cessation
-physical activity
-weight loss
2. Pharmacological therapy:
-organic nitrates
-beta blockers
-calcium channel blockers
-miscellaneous agents - nicorandil, ivabradine, ranolazin
3. Risk factor modification (secondary prevention)
-aspirin 75mg daily
-statin
-ACEis
-blood pressure control
-diabetes control
4. Revascularization procedures
-Percutaneous coronary intervention (PCI)
-Coronary artery by-pass graft (CABG)
Give an account of how the major classes of anti-anginal drugs act to produce their
beneficial effects
Nitrates
Pharm action = direct action on blood vessels > vasorelaxation > systemic vasodilation >
therapeutic effects.
M.O.A = converts NO2 > NO > NO & thiol combines > nitrosothiols enzyme > activates
guanylate cyclase to convert GTP to cGMP > activates PKG > vasorelaxation
Mechanism of anti-anginal effect (decrease preload) = peripheral venodilation > peripheral
pooling of the blood > reduces venous return > reduces ventricular volume &
intraventricular pressure > reduce cardiac output > reduces myocardial oxygen demand.
Adverse effects:
-Throbbing
-Flushing
-Headaches
-Hypotension

Beta-Blockers
Pharm action = inhibits the SNS effect and acts on the beta andrenoceptors
M.O.A = B1 decreases cardiac output causing skeletal muscle relaxation
B2 increases peripheral vaoconstriction & brooch-constriction
selective & non-selective
Mechanism of anti-anginal effect:
haemodynamic effect:
-lower myocardial contractility
-lower HR
-lower BP
ancillary effect:
-increase diastolic filling time = increase myocardial perfusion
-anti-arrythmia = increase electrical stability
-antiatherogenic & antithrombotic
Adverse effects:
-exacerbation of asthma
-cold extremities
-1st dose hypotension
-masking of hypoglycaemia
-sleep disturbance (nightmares)
-rebound phenomenon

Calcium Channel Blockers

Pharm action = inhibit Ca influx from voltage gated calcium ion channels, main effects on
heart and vascular smooth muscles.
MOA = Cardiac effects: inhibit Ca from myocardial cells - lowering contractility & inhibit Ca
from nodal & conduction cells - lower HR (phenylalkylamine & benzothiazepines)
vascular effects: inhibit Ca from arterioles - arteriolar dilation = peripheral vasodilation >
lower SVR > lower arterial BP
coronary dilation > increase coronary blood flow, reverse spasm, prevention of spasm
Mechanism of anti-anginal effects:
Reduce myocardial demand:
-lower arterial BP (after load)
-lower heart rate
-lower myocardial contractility
increase myocardial blood
-coronary vasodilation > increase CBF spasm reverse/prevention
Adverse effects:
-hypotension
-peripheral edema
-cardiac depression (phenylalkylamine & benzothiazepine)

Miscellaneous Agents:
Potassium channel openers - Nicorandil > venodilation > lower preload > low myocardial
oxygen demand
arterialdilation > lower after load > low myocardial oxygen demand

Sinus Node (If current) inhibitor - Ivabradine > inhibition of If > lower HR > lower
myocardial oxygen demand

Late sodium current blockers - ranolazine > inhibition of late l-na > anti-ischaemic effect
Describe the current NICE care pathway for stable angina
1. Symptom controle
-Short acting nitrate/GTN
-BB or CCB
-BB & CCB
-Long acting nitrates

ACUTE CORNARY SYNDROME

Define & describe the 3 major clinical subtypes of acute coronary syndromes
Definition: result from acute plaque rupture in the wall of a coronary artery leading to
reduction in coronary blood flow.

3 clinical subtypes:
1. Unstable Angina:
-acceleration in frequency of chest pain
-new onset of anginal pain
-chest pain occurs at rest
-incomplete and/or transient/intermittent occlusion of the culprit artery
-presence of an active prothombotic surface area present at the site of plaque rupture.
2. Non-ST elevation myocardial infarction (NSTEMI)
-due to unstable plaque rupture & thrombosis > significant partial occlusion of an epicardial
coronary artery
-presence of an persistent prothombotic surface area present at the site of plaque
rupture.
-evidence of myocardial cell necrosis
3. ST-segment elevation myocardial infarction (STEMI)
-unstable plaque rupture & thrombosis leading to complete occlusion of an epicardial
coronary artery
-transmural myocardial cell necrosis (infarction)
Describe the causes, underlying coronary pathology, major clinical features &
diagnosis of acute coronary syndromes
Describe the causes
Triggered by a atheromatous plaque disruption (rupture/erosion) > coronary thrombosis >
formation of intravascular thrombus or clot.

Underlying coronary pathology

UA or NSTEMI: incomplete and/or transient/intermittent occlusion of the culprit artery
difference in duration & severity of ischaemia/symptoms
STEM: complete and sustained occlusion of culprit artery

Major clinical features

-Pain
Haemodynamic = breathlessness, hypotension, dizziness, syncope
Serial ECG changes
-ST-segment changes = depression or elevation
-T-wave inversion
-Pathological Q wave development
STEMI
-ST segment elevation
-Pathological Q wave development
NSTEMI/UA
-ST segment depression
-T wave inversion (often persistent in NSTEMI & usually transient in UA)
Serum cardiac Biomarker Changes
-Serum levels of myoglobin, CK-MB & troponin
-biomarkers of myocardial cell necrosis/infarction

Diagnosis of acute coronary syndromes

-Symptoms of myocardial ischaemia
-ECG changes (ST/T wave changes)
-Development of pathological Q waves on ECG
-Imaging evidence of new loss of viable myocardium or regional wall motion abnormality
-Angiographic or autopsy evidence of coronary thrombus

Give an account of the non-pharmacological &

pharmacological management of ACS
Immediate management:
Aspirin 300mg
Heparin (anticoagulant)
Diamorphine (angina pectoris reliever)
GTN-sublingual/ followed by IV
Beta-blocker IV

STEMI
Mechanical repercussion: Revascularization with PCI (FIRST LINE)
Pharmacological reperfusion: Thrombolytic or Fibrinolytic therapy (clot-busters)
by adjunctive anti platelet & antithrombin therapy
-antiplatelet & anticoagulant therapy (aspirin & heparin)

Give an account of mechanisms of action of the major classes of drugs used in the
management of ACS
Thrombolytic Therapy
Activation of endogenous plasminogen fibrinolytic system
-help to avoid irreversible transmural myocardial damage
Drug
Streptokinase - indirectly activates plasminogen present in the blood stream but binding to
a plasminogen causing a confirmation change to convert to activation of free plasminogen.
Tissue type plasminogen activator: directly acting plasminogen activator or TPA that
convert plasminogen which is inactive to plasmin and plasmin would dissolve the fibrin
mesh on the clot therefore dissolve the cot
What is preferred for a thrombolytic agent
Clot selective
immediate duration of action
non-antigenic
reduce risk of bleeding

Antiplatelet agents

Anticoagulant
indirect thrombin inhibitor (via activation of antithrombin III)
Unfractionated heparin (UFH): increase inactivation of thrombin (FIIa), FXa & FIXa
-binds to antithrombin III and thrombin
LMW heparin: increase inactivation of FXa
-bind to antithrombin III but not to thrombin with FXa
-binds to ATIII with Xa
Fondaparinux: increase inactivation of FXa

binds to the inactive antithrombin this binding allows activation of antithrombin to bind &
interact with FXa leading to its effect in the plasma to stop the conversion of thrombin from
prothrombin thereby inhibiting the producing of fibrin from fibrinogen preventing any
formation of clot.

in the same way, binds & causes confirmation to active antithrombin. unfrantionated heparin
serves as a catalyst template to block b/w thrombin to fibrinogen.
LMW binds to inactive antithrombin > activate it > this in turn accerlates the interaction b/w
active antithrombin and factor Xa > decrease prothrombin to thrombin which further
decrease fibrin > prevents clot

Describe the consensus care pathways for ACS

HEART FAILURE
HF:
Define HF & Cardinal features
Cardinal feautures: two things that are majorly highlighted to be impaired
1. Forward failure: reduced cardiac output due to impaired cardiac pumping
2. Backward failure: elevated A/V filling pressure - impeded venous return (impaired arterial
pressure to enable perfusion) which lead to pooling of blood causing systemic and/or
pulmonary venous congestion
True definition: a clinical syndrome characterised by impaired cardiac pumping, leading to
inability of the heart to deliver blood to the body (peripheral tissue) with metabolic, oxygen
& nutrient supply, with impeded venous return, leading to systemic and/or pulmonary
venous congestion.
Classification of HF and their clinical subtypes
Classification scheme 1: Left ventricular ejection fraction (LVEF) fraction of blood that is
ejected by the left ventricle into the aorta during systolic.
1.HF-REF
-reduced (LVEF <40%)
-inability of the heart to contract effectively (overload pressure - systolic dysfunction -
impaired ventricular contraction & ejection)
2. HF-PEF
-normal (LVEF >50%)
-inability of the heart to relax effectively after contraction (diastolic dysfunction - impaired
relaxation and ventricular filling)
Classification scheme 2: Based on clinical status & time course of symptoms
1. Acute Heart Failure (decompensated failure)
-rapid onsets of heart failure
-sudden decline in cardiac dysfunction that can be life threatening
-may result in acute myocardial infraction or due to sepsis or an exacerbation of chronic HF
2. Chronic Heart Failure (compensated failure)
-gradual insidious process because when the heart function is compromised you get reflect
activated of compensatory mechanism that deals with the reduced cardiac output, to
stabilise the function of the heart.
-signs and symptoms are masked due to the compensatory mechanism.
Describe cause & patho of HF-REF & HF-PEF
Causes of HF-REF
1.Intrinsic damage to the heart -
-coronary artery disease (MI): myocardium are now not fully functioning due to necrosis,
-cardio-mypoathy: if its lacks the ability to contract muscle of the heart
2.Pressure overload: condition that put too much pressure on the heart and therefore
increases workload
-hypertension: elevates after load (left ventricular has to contract more forcibly to eject
blood into the aorta) leads to ventricular hypertrophy.
-pulmonary HPT: elevated blood pressure in the pulmonary artery (>25mmHG) causes right-
sided HF
-Aortic stenosis: .narrowing of the aorta, so when LV contract, it has to contract forcibly
3.Volume load: deals with excessively large amount of blood due to valve disease
-Mitral valve regurgitation - defect (located-b/w left atrium & left ventricle. when LV
contract, mitral valve closes but if this is dysfunction, then metal valve does not close and
blood goes back into the left atrium. causing dilation due to large amount of pooling of blood.
-Aortic regurgitation, open when LV contract to enter aorta and close when LV relaxes. but if
this is impaired, blood flows back from the aorta and the LV, LV will be dealing with large
amount of blood leading to HF.
-Ventricula septum effect (the serrate b/w left ventricle and right ventricle is affected)
4.Inadequate filling
-AF: heart not getting enough filling in diastole time
-Constrictive pericarditis: pericardium surrounding the heart, the fluid, when the heart
contracts there is no friction b/w heart and pericardium causing inflammation/infection and
harden, prevent heart to not relax or expand properly
Causes of HF-PEF
-Associated with many comorbities - e.g obesity, hypertension, type 2 diabetes, arterial
fibrillation, etc
Underlying pathology mechanism of HF-REF -
-helps rational of drug therapy
-Neurohormonal model describes the human’s physiological response to activate
compensatory mechanism to ensure adequate perfusion to organs & tissues when the heart
begins to fail.
-if heart continues to fail, the compensatory mechanism can get out of control and cause
further harm and cause cardiac remodelling.
**Begins with a myocardial injury causing a LV dysfunction (reduces cardiac output>fall in
BP & reduce organ perfusion) which activates compensatory mechanism to try and
maintain/correct the dysfunction but with time it gets worse**
the mechanism involved
COMPENSATORY MECHANISM IS DIVED INTO TWO
1.extrinsic (changes take place outside heart): neurohormonal system (SNS, RAAS, ADH,
etc)
2.intrinsic (changes take place in heart): cardiac hypertrophy (wall increase in thickness) &
dilation (chambers will increase in volume) > increase stroke volume
Short-term Beneficial effects
-Maintain CO
-Maintain BP
-Maintain organ perfusion
Long-term Harmful effects
-Progressive reduction of cardiac function
-Progressive of reduced cardiac output
-Systemic/pulmonary congestion
1.Sympathetic Nervous System
-Increase adrenaline & noradrenaline increasing HR & heart contraction (increases CO)
beneficial in INITIAL state.
-systemic & pulmonary vasoconstriction (activation of alpha 1 receptors in blood vessels &
smooth muscles)
-SNS activates renin (RAAS)
-continuous Beta receptor and Alpha receptor can be ishaemic which can lead to cardiac
remodelling.
2. Renin-angiotensic-aldosterone system (RAAS)
-Increase angiotensin II causing vasoconstriction and increasing the after-load
-increases aldosterone release causing Na/H20 retention leading to peripheral oedema and
pulmonary congestion
-acts directly on the heart which can promote cardiac remodelling
3. Antidiuretic Hormone (ADH/vasopression)
-Increases ADH causing water retention & vasoconstriction
Explain Natriuretic peptides patho
major role in kidney (increase salt excretion therefore increase water excretion; has
natriuresis & diuresis effects)
-vasodilator effects and prevents remodelling of the heart causes by SNS, RAAS, ADH
-major ones is BNP (ventricular produce small amount of BNP) & ANP (Aterial produced a
small amount of ANP)
-during HF, due to volume and pressure overload you get release of BNP
-offsets neurohormonal system (SNS, RAAS, ADH)
Clinical features of HF (left VF vs right VF) & diagnosis of HF,
LEFT ventricle failure: can lead to FORWARD hypoperfusion (reduce CO) = reduced exercise
tolerance & fatigue& BACKWARD pulmonary congestion (pulmonary oedema) & central
cyanosis (reduce CO=reduce oxygen supply)
RIGHT ventricular failure: FOWARD (reduce CO hypoperfusion) & BACKWARD systemic
congestion (Elevated jugular vein pressure, hepatic/ankle oedema, peripheral cyanosis)
Describe Diagnosis of Heart failure
-Clinical presentation, medical Hx & physical examination
-blood test (rule out other possible condition)
-diagnostic test
-Chest x-ray (check enlargement of heart or water in lungs)
-ECG (check underlying ECG abnormalities
-Natriuretic peptides BNP & NT-proBNP (has longer plasma half life than BNP)
-Echocardiogram (checks wall motion)

HF Part 2: Medication
-Chronic Heart failure with reserved ejection fraction
-Aim: reduce CO (forward failure) & reduce A/V filling pressure (backward failure) & reverse
myocardial remodelling

Give an account of the non-pharmacological &

pharmacological management of ACS
Increase myocardial contractility
 -Inotropic agents: Increase force of contraction of the heart to increase CO to help with
hypo-perfusion
-not encouraged to add more work to a failing heart.
Reduce cardiac workload (afterload/preload)
-increase afte-rload causes vasoconstriction causing LV to work heart
-too much volume overload interns of venous return preload causes increase of workload on
the heart
-Diuretics reduces plasma volume therefore reduce VR
-Vasodilators reduces preload and relax veins
Inhibit chronic neurohormonal activation
- ACE, BB, ARBS, ARNI & aldosterone antagonist

Give an account of mechanisms of action of the major classes of drugs used in the
management of HF
Diuretics
Site of mechanism:
Thiazide diuretics: inhibit active exchange of Na+, Cl in the distal convoluted tubule
K-sparing diuretics: Inhibit the action of aldosterone (aldosterone receptor antagonist) in the
distal convoluted and collecting tubule
Loop diuretics: Inhibit the Na/K/Cl transporter in the thick ascending loop of henle
Mechanism of clinical effects:
-Increase diuresis & natriuresis
-Reduces preload & venous return: reduce systemic & pulmonary congestion
-reduce plasma volume
-relief of SOB & increase exercise tolerance
-Loop diuretic are preferred
-AVOID NSAIDS & COX 2 inhibitor - will antagonise these effects - due to targeting
prostaglandins: the GFR is dependant on the hydrostatic pressure of the renal artery in the
bowman’s capsule. the pre-renal artery are typically dilated and post renal artery are
constricted. prostaglandins help vasodilator to reduce GFR.
when NSAID OR COX 2 is given you cause the prostaglandin to vasoconstrict causing
hypovoluemia and increasing GFPressure.

Angiotensin Converting Enzyme inhibitors (ACEis)

Mode of action
-Inhibits ACE from the conversion of angiotensin I to angiotensin II
-Increase bradykinin activity but inhibiting kininase II enzyme from breaking down
bradykinin
Mechanism of action
Suppression of angiotensin II:
-reduce peripheral vasoconstriction (reduce VR)
-reduce aldosterone release (reduce fluid retention = low plasma volume
-reduce activation of SNS that indirectly causes vasoconstriction reduce preload/afterload -
hypoperfusion & congestive symptoms
-reduce cardiac remodelling
Promotion of bradykinin activity
-Increase peripheral vasodilation = reduced SVR
-increase prostaglandin release = increase vasodilation = reduce SVR

Beta adrenoceptor antagonist

effects two systems:
1.cardiac sympathetic activity
blockers beta activation - reduce myocardial cell death and decrease arrhythmias to prevent
cardiac remodelling
2.sympathetic active to blood vessels & kidney
blocks beta receptor that is in control of activating RAAS in the kidney blocking
vasoconstriction and lowering fluid retention preventing cardiac remodelling
-reduces CO
EXAMPLE OF BB TO USE TO TREAT HF: BISOPROLOL, CARVEDILOL & NEBIVOLOL

Angiotensin II Receptor blockers (ARBS)

-compete with angiotensin II for ACE receptor and block the effect at receptor site
-body finds other ways to convert angiotensin I to II if given ACEi
-harmful effects are from AT1 receptor but AT2 is beneficial on HF - ACE blocks both as they
do not distinguish between the two receptor
-ARBs are SELECTIVE AT1 receptor blockers
-AT1 Target: aldosterone release, vasoconstriction, proliferative actions
-you don’t get a cough as there are no activation on bradykinin
Mechanism of clinical effects
-arterial vasodilation = low afterload = increase CO = low hypoperfusion
-venodilation = reduce preload = lower pulmonary congestion
-lower aldosterone release = low fluid retention = low systemic congestion
-prevent cardiac remodelling = increase survival
EXAMPLE OF DRUGS: candesartan, losartan, valsartan.
adverse effects: 1st dose hypotension, worsening renal function, hyperkalaemia, (no
dry cough and very less likely to get angioedema)

Aldosterone Receptor Antagonists

-competes with aldosterone in binding to aldosterone receptor
-effects blood vessel and heart from cardiac remodelling
-inhibit aldosterone secretion blocking Na/H20 retention = lower plasma volume - blocking
congestive symptoms
-inhibiting aldosterone secretion which prevents hypertrophy & apoptosis, fibrosis = prevent
cardiac remodelling
-NEUROHORMONAL BLOCKER
adjunct to ACEis, BB, DIuretics for symptom control & survival prolongation
EXAMPLE OF DRUGS: Spironlactone, eplerenone
adverse effect: spironolactone blocks other mineral cjjortical steroid.
-Female: menstrual disorders (block oestrogen)
-Male: increase breast (block testosterone effect)
-Hyperkalaemia
Specialised drug:
Angiotensin Receptor-neprilysin inhibitors (ARNI)
Sacubitril/Valsartan (Entresto)
-Inhibits the enzyme neprilysin that metabolises natriuretic peptide (breaks down ANP &
BNP)
-pro-drug: inhibits neprilysin from breaking down ANP
-neprilysin inhibition also increases angiotensin II - BUT due to the effect of valsartan, this
reduces the effect of increases AII
-Combined with inhibition of neprilysin and AT1 angiotensin II receptors
-must be NYHA class II-IV with LVEF <35%
-must have already tried BB with an ACE or ARBs
-should have 36 hours drug free before administering this drug.
-should have no history of angioedema
I-f Channel Inhibitiors - specialised drug
Ivabradine
-block funny current that is responsible for firing SA nodal cells = reduces phase 4
depolarisation & HR
-For high resting heart rate, breathless activation of SNS
-high heart rate can lead to mortality, therefore this drug helps slow down heart rate.
-requirement to be on this medications are:
1.NYHA class II-IV <35% in SINUS RHYTHM & with resting heart rate >75% beats/min
2.must have already tried ACE/ARBs, BB & aldosterone antagonist
3. OR BB contraindicated or not tolerated
adverse effects:
1.bradycardia
2. AV block, headache, dizziness
3.visual disturbance

Miscellaneous - Vasodilators
Hydralazine-Nitrate combination
1.Hydralazine role: reduce arterial BP & afterload = hyperfusion & arterial vasodilation
2.Isosorbide dinitrate: reduce venous return & preload = reduces congestive symptoms
-specifically more effective in AFRICAN AMERICAN

Inotropic Agents
Digitalis = Digoxin
Phosphodiesterase inhibitors = Milrinone, enoximone
-break down cAMP
1. Digoxin (referred to as cardenolide)
pharmacological action =
Cardiac mechanical effect
-increase force of contraction by increasing intracellular levels of calcium thus inhibiting
Na/K pump
Cardiac electrical effects
-Indirect action
-PNS activation in low doses (slow AV node conduction)
 -SNS activation in high doses
-Direct action
-due to increase intracellular Ca you get increase of automaticity = even heart cells that
don’t fire action potential will then fire action potential.

Na out of cell & K into the cell

another exchanged Na/Ca will take Ca out of the cell for exchange of Na into the cell.
-digoxin inhibit potassium ATP which keeps Na into the cell which switch on the Na/Ca
exchanger to remove Na out of the cell for Ca into the cell. this will cause actin and myosin
form cross bridge leading to contractility.

-Increase contraction = increase CO = increase exercise tolerance = reduce hypoperfusion

-Na/K are present in the renal nephrons - Digoxin will inhibit this causing naituresis &
diuresis reducing congestive system
-can produce effect on neurohormonal control by activiating PNS reducing SNS activity
-low plasma noradrenaline
-low PNS
-low RAAS activity
-does not reduce mortality but reduce hospitality visits.
adverse effects:
-cardiac arrhythmias from digoxin overdose
-neurological disturbance from digoxin overdose
-GIT disturbance
-if patient is on a diuretic such as loop and thiazide, be very careful with putting the patient
on digoxin because they all cause hypokalaemia which can be toxic

2.Phosphodiesterase Inhibitors (PDEIs): milrinone, enoximome (not licensed for

maintenance therapy for chronic HF)
mode of action: Inhibit of PDE III = Increase intracellular cAMP
-increase contraction in skeletal muscles
-increase peripheral vasodilation in smooth muscles
-increase contractility = increase CO = increase hyper perfusion symptoms
-increase vasodilation = reduce afterload = reduce congestive symptoms
-used for short-term
-for acute decompensated HF

NICEGUIDLINE
1.Diuretic
2. BB & ACE/ARBS (if intolerant to ACE)
3. MRA
4. sacubitral/valsartan, ivabradine, hydralazine/ISDN,

HYPERTENSION
Hypertension:
general rule: if BP persistantly >140/90mmHg
-start on ABPM or HBPM
Describe the causes, underlying coronary pathology, major clinical features &
diagnosis of hypertension
Target Organ Damage
Cerebrovascular damage:
-TIA
-Ischemic or hemmorrhagic stroke
-Vascular damage
Hypertensive retinopathy
Left ventricular dysfunction
Coronary artery disease
-myocardial infarction
-angina pectoris
-congestive heart failure
peripheral artery disease
chronic kidney disease
-hypertensive nephropathy
-albuminuria
Mechanism of target organ damage
1.increases afterload
-systolic dysfunction
-LVH (diastolic dysfunction) & Increase oxygen demand
-Heart failure & MI
2.arterial damage
-formation of atherosclerosis and weak vessel wall
-organ damage listed.
-myocyte hypertrophy & fibrosis
EXAM!!
Mechanism of target organ damage:
begins with:
1. increase arterial stiffness give you
2. increase systolic BP and pulse pressure causing stroke & chronic kidney disease
3. this pressure leads to increase ventricular afterload, myocyte hypertrophy & fibrosis, and
lowers coronary perfusion.
4. increase ventricular afterload increases systolic and diastolic dysfunction
5. myocyte hypertrophy & fibrosis leads to diastolic dysfunction
6. low coronary perfusion causes systolic dysfunction

3 major factors to control with hypertension

Control Blood pressure
1.Cardiac Output
2.Peripheral vascular resistance
3.Blood volume

Non-modifiable risk factors: AGE, GENDER, FAMILY HX, ETHNICITY

Give an account of the non-pharmacological & Pharmacological management of

Hypertension
Non-pharmacological:
1. lifestyle modification
- Diet - Salt, vegetable, fat intake
- Exercise - increase physical activity, reduce weight, smoking cession and reduction of
excessive alcohol
- BP monitor
- Reduce risk T2D & CVD
Pharmacological:
-ACE
-ARBs
-CCB
-BB
-Miscellaneous
Main mechanism of BP lowering:
-Lower plasma volume
-Lower total peripheral resistance
-Lower cardiac output

Give an account of mechanisms of action of the major classes of drugs used in the
management of hypertension
1. ACE - first line for ALL DIABETICS patients ANDDDD… <55 y.o of non-africana or
caribbean descent
-reduce angiotensin II on AT1 receptor on blood vessel = reduce vasoconstriction and PRV
which will reduce BP
-reducing angiotensin II will release aldosterone from the adrenal gland = reduce fluid
retention = reduce plasma volume
-reducing angiotensin II will reduce SNS = reduce vasoconstriction = PRV = low BP
-increase bradykinin & PGI2 reduces vasocontriction which reduce peripheral vascular
resistant
-shown to reduce MI, stroke & CVD and progression of diabetic nephropathy
-effective combination with CCBs & thiazide like diuretics

2. Angiotensin II Receptor Antagonists (ARBs)

-block AT1 receptors in blood vessel = low vasoconstriction = low PVR = LOW BP
-block ATI in adrenal lower aldosterone secretion = low fluid retention = low PV
-block activation of SNS by angiotensin II = low vasoconstriction = low PVR = LOW BP
-shown to reduce MI, stroke & CVD and progression of diabetic nephropathy
-used as a first line ALSO does NOT have to be intolerant to ACE to use this next. both ACE &
ARBs are used irrespectively

3.Calcium channel antagonist (CCBs)

-had cardiac & vascular action
-reduce BP via block of Ca2+ influx into heart cells and/or blood vessels
- block Ca2+ influx into nodal & conducting cells = low HR & contractility = low CO
- block of Ca2+ influx into arterioles = arteriolar dilatation = low PVR
-dihydropiridines are mostly used but all classes can be used in treatment of hypertension
-shown to reduce MI, stroke & CVD and progression of diabetic nephropathy
-Most beneficial in patients with/of
-elderly
-angina pectoris (they will be on CCB anyways)
-child-bearing age or pregnant
-black ethnic origin
-ELDERLY patients >55 y.o who are NOT diabetic
-black patients of any age
-combination with ACEI, ARBS, BB & THIAZIDE

4. Thiazide & thiazide-like Diuretics

-increase diuresis = reduce PV = reduce CO
-when used in long-term you get the effect of reducing PVR (chronic therapy) IMPORTANT
TO MENTION
-by increases diuresis you reduce sodium stores in blood vessel muscle cells which may
reduce the contractility.
-low dose. thiazide-life diuretics are: indapamide and chlorothalidone
-shown to reduce risk of stroke in clinical trials
-alternaive first-choice for initial therapy in if CCB is contraindicated (worsening peripheral
oedema)
-elderly hypertensive patients (55 & >)
-black patients of any age.
-combination with ACE, ARBS & CCBS

5.B-adrenoceptor antagonist
-block beta receptor
-initial effects: reduces CO (reduce force of contraction of heart and reduce HR) - reduces BP
- PVR may increase slightly (especially non-selective BB)
-chronic effects: CO may or may not return to normal and a generalised reduction in PVR due
to long-term therapy.
postulated BP lowering mechanism
-reduction of CO
-inhibition of renin release - block RAAS that may cause generalise PVR - due to the inhibition
release of renin, recall this is under control of SNS - if you block SNS you cause prevention of
renin to be released.
-resetting of baroreceptors
-NOT FIRST LINE ANYMORE may be less effective in reducing stroke
-Most beneficial in patients with
-tachyarrhythmias
-effort angina
-past MI
-glaucoma
-pregnancy
-ONLY USED when 3 first-line drugs have be tried.
-effective with dihydropyiridine CCB (the others causes cardiac depression)
6.Miscellaneous Agents
Sympatholytic agents (antagonise the effect of a SNS)
1. Alpha-adrenoceptor blocking drugs - fourth line
-blocks alpha 1 in blood vessel = low PVR = low BP
-block alpha 1 receptor preventing noradrinaline/adrenaline = relaxation of arteriole &
venular = LOW PVR
-prazosin, doxazosin, terazosin, indoramin
-Fall in BP with associated low TPR
-little/no change in CO
-postural hypotension (must get up slowly)
-effective in diabetic, all age & racial and with benign prostatic hypertrophy
-reserved for adjunctive (add-on) therapy with drug-resistant hypertension
-additive effects with BB & thiazide diuretics
Side effects: 1st dose hypotension, postural hypotension, dizziness & fatigue
-activation of compensatory mechanism causing fluid retention & tolerance

2. Centrally-acting drugs : produce the BP lowering effect in the brain (enters BBB)
-Clonidine: SELECTIVE alpha2 agonist = presynaptic receptor, BP are in post junctional and
there are present in the medulla as well
-Moxonidine: selective alpha2 & I1 imidazoline receptor
-Alpha-methydopa: converted to alpha-methylnoradrenaline - alpha 2- adrenoceptor
agonist (prodrug)
Mechanism of antihypertensive effects:
-act centrally in the brain stem vasomotor centre
-alpha 2 receptive activation = low sympathetic outflow to heart & blood vessels = Low HR,
CO, PVR = LOW BP
-effective in all ages & race groups
-alpha-methyldopa is safe in pregnancy
Side effects: sedation, drowsiness, dry mouth, clonidine: rebound hypertensive crisis
- activation of compensatory mechanism causing fluid retention = psedotolerance

3. Directly-acting vasodilators : HYPERTENSION CRISIS - not used to treat only for severe
cases
-hydralazine, minoxidil, Na nitroprusside
-direct VSM Relaxation = arteriolar dilatation = low TPR
-relaxation of veins = reduce venous reduce & CO
Mechanism:
-Na nitroprusside: Increase cGMP = relaxation (SIMILAR TO NITRATES)
-Minoxidil: open K+ channels = hyperpolarisation
-combination with diuretics & BB
Side effects: postural hypotension & fluid retention, headache, dizziness
-- activation of compensatory mechanism causing fluid retention = psedotolerance

Describe the consensus care pathways for ACS

Who & When To Treat?
Adults of any age with persistent stage 2 HPT (BP > 160/100 mmHg)
Adults of any age with persistent stage 1 HPT, plus one of more of:
- Target organ damage
- Existing/established CVD
- Renal disease
- Diabetes
- An estimated 10-year CVD risk > 10%
Adults aged under 60 with stage 1 HPT and an estimated 10-year CVD risk >10%
Adults age over 80 with a clinic blood pressure of over 150/90 mmHg

how to treat?
1.lifestlye
2.initiate drug therapy
- one drug “stepped-care” approach
- start with lowest recommended dose
-titrate up - allow >4 weeks
- **recommendation** to use combination therapy (single-pill combination) now - most
effective
-

CARDIAC ARRHTHYMIA
Arrhythmia:

Class I Description RATE CONTROL

-These drug depict their action on the open inactivated Na channel on the upstroke of phase
O of the action potential.
-The type I antiarrthymic act on the his-purkinjie system and not the SA or AV node.
-Their action are on rhythm control by decreasing the slope and slow down the upstroke of
phase 0 action potential of the myocardial hence decrease the conduction velocity of the
action potential
-On the ECG this is seen at a widen QRS complex due to the increase ventricular
depolarisation time.
-Tissue that experience more rapid depolarisation will experience more Na channel blockage.
-QRS widen as heart rate increases due to the strength of various class of type 1 drug.
class IA
-has intermediate dependence on Na channel on the upstroke of depolarisation and a
moderate slow upstroke of the depolarisation.
-also has effects on blocking potassium channel from the plateau and repolarization phase of
the action potential cause a prolongation of the action potential. allowing the myocardium to
be depolarised longer.
-this caues a QT prolongation on ECG
-targets both supraventicular and ventricular tachycardia
Drug: Quinidine, Dysopyrimide
Class IB
-Have low binding affinity for Na channel causing little affect on the phase 0 upstroke
-shortens the action potential of phase 2 and 3 by blocking Na channel, therefore shortening
the effective refractory period
-Due it the rapid binding and unbinding kinetics, highly selective in tissue that act on the
open and inactive Na channel making it more selective for ventricular and His purkinjie
system
-for specific for ischemic myocardial; ischemia induced ventricular arrhythmia
-Therefore only for ventricular arrhythmia and not supra ventricular
Drug: Lidocaine, Phenytoin, Mexiletine
side effect: neurological effects
Class IC
-Strong binding affinity to the open inactive Na channel thats responsible for the upstroke of
action potential
-causes a drastic slowing of phase 0 upstroke and more dramatic effect on the QRS.
-QRS will be prolonged
-do not act on duration of action potential
-can treat both supra ventricular and ventricular arrhythmia such as atrial fibrillation.
-AF gets treated by controll ventricular rate and restore and maintain normal sinus rhythm
through DC cardioversion or by the use of Class IC DRUGS.
-NOT ideal for patient with history of ischemia heart disease due to pro arrhythmic affect.
Drug: flecanide, propafenone

CLASS II - RATE CONTROL

-inhibit/block adrenergic activity in the heart by blocking beta adrenoceptor
-Drug: Metoprolol, atenolol
-prevent the arrhythmia promoting action of B-adrenoceptor stimulation.
-SNS increase peacemaker currents which increases sinus rate
-also increases conduction velocity at the AV node
-BB block the SNS action at the SA and AV nodes
-decrease cAMP levels = closure of membrane ca channel for upstroke of nodal action
potential.
-prolongations phase 4 activity helps prolong of av nodal conduction time and ERP
-good for supra ventricular arrhythmia e.g AF
-side affects: heart block leading to PR prolongation

CLASS III - RHYTHM CONTROL

-block K potassium causes prolongation of action potential
-prolongs phase 2 and 3 of the action potential and hence prolong their ERP
-amiodarone
-qt prolongation

CLASS IV - RATE CONTROL

-block activated and inactivated L type calcium channel - non-dihydropiridine (verapamil,
diltiazem)
-exerte on SA and AV node supress activity at the node - phase 4 and phase 0 of upstroke
depend on calcium current - prolong phase 4 - decrease slope of phase 4 pacemaker activity
decreases sinus rate
-prolong AV nodal decrease conduction time and prolong ERP
-used for supra ventricular
-cause PR prolongation due to delay av nodal conduction

CHOLESTERAL
Cholesterol:
Why do humans need cholesterol?
-cell membranes: stabilising & transport function
-steroid hormones: e.g adrenal & sex hormones
-bile acids: facilitate GIT absorption of dietary fat
Major sources:
1. Exogenous: dietary supply; eggs, shell fish
2. Endogenous: synthesis in organs & tissue; e.g liver, intestines, ovaries, adrenal
liver controls the synthesis and degradation of cholesterol. controls balance
Cholesterole tranport
Cholesterol are hydrophiobic, therefore in order to get transported to the bloodstream, it
gets coated with hydrophilic coat:
-apolipoprotein, phospholipid, cholesterol
“transported at water-soluble lipoprotein particle”
elevated LDL-cholesterol = risk of CHD

Describe the causes and underlying cholesterol pathology of High colesterol

Three major pathways
1. Exogenous (intestinal) Pathway
2. Endogenous (hepatic) Pathway
3. Reverse cholesterol transport
Exogenous (intestinal) Pathway
-comes from dietary & biliary cholesterol absorbed into enterocytes via a transporter
(NPC1L1) from lumen into the surrounding cells
-the cholesterol gets esterifies (ACAT)
-these esterfied cholesterol gets packaged with triglyceride into apoB-48 to become a
chylomicrons (CMs)
-the CM gets through the lympathic system to the blood stream
-as they pass through adipose tissue and muscle , the LPL that are present on the endothelial
of the capillaries will get activated by ApoC-II that is on the surface of the chylomicrons.
-the active LPL will hydrolyse the triglycerides into free fatty acid which gets released into
the muscle and adipose tissue for storage.
-the remaining chylomicrons are now known as remnant particles (with cholesterol only
present) and as they pass through the liver, they will express receptor (via apoE binding to
the remnant receptor [LRP]) that will pick the remnant chylomicrons for further metabolism.

Endogenous (hepatic) pathway

-once inside the liver cells the CM remnant are packaged with more cholesterol, cholesteryl
esters & ApoB100 to form triglyceride-rich VLDL
-VLDL released into the bloodstream and as they pass they through muscles and adipose
tissue, LPL gets activated by ApoC-II.
-active LPL will hydrolyse triglyceride which will release free fatty acid to muscles and
adipose tissue.
-the VLDL particle size reduces into IDL
-IDL gets taken up directly into liver or further metabolism into LDL-C by hepatic lipase (HL)
-LDL-C gets taken up by organs & tissues via LDLR to meet cholesterol needs
-left over LDL-C particles are finally removed by the liver via LDLR

Reverse cholesterol transport

-Where free excess LDL-C from peripheral cells get returned back to the liver by HDL
-HDL start off as pre-BETA-HDL (rich in apoA-I)
-gets secreted by the intestinal cells or the liver or generated from VLDL and LDL
chylomicrons
-once generated, they will enter the blood stream and pick up free cholesterol
-they pick these free cholesterol via the ATP-binding cassette Ai (ABCA1)
-LCAT converts free cholesterol into pre-BETA-HDL to cholesteryl ester (CE) resulting in
mature alphaHDL
-alphaHDL cholesterol is transported to the liver by a direct or indirect pathway.
NOTE*
-direct pathway: cholesteryl ester from alpha HDL gets taken up by the liver by SR-B1
receptor
-indirect pathway: alphaHDL cholesteryl ester is exchanged for triglyceride in apoB-rich
VLDL & LDL via the CETP.
-which gets taken up by the liver through the LDL receptor

Give an account of the non-pharmacological & pharmacological manage of high cholesterol

Bile acid seqestrants:
-prevents bile acid of cholesterol from being reabsorbed into the liver;
-this forces the cholesterol in the liver to be used up to compensate for the blocked
reabsorptions.
-reducing hepatic cholesterol levels.
-this increases LDL receptor expression to increase more cholesterol to be reabsorbed from
the blood stream.
- drugs: colestyramine
Fibric acid derivates
interact with receptors (PPAR-alpha) that control transcription in the nucleus.
-synthesis protein that control lipid metabolism
-increase uptake of beta-oxidation of FFA in liver & muscle
-increase LPL = increase TG hydrolysis in VLDL & CM = increase elimination of TG-rich
particles
-increase synthesis of apoA-I & apoA-II = increase HDL activity
drug: fenofibrate
adverse effect:
-warfarin = increase anticoagulant effect (monitor INR)
-statins = increase risk of muscle aches (myositis)
-GIT disturbance
-CNS effects

Nicotinic acid group

-decrease movement of FFA from peripheral tissue (muscle & adipose)
-less delivery of FFA to the liver = reduces TG synthesis & VLDL secretion = lowers plasma
LDL
-inhibit the uptake of apoA-I to spend more time in the blood stream to pick up free
cholesterol from tissue and organs = increase HDL & reverse cholesterol transport
Adverse effects:
-vasodilators = increase risk of hypotension
-statins = increase risk of myositis

Statins
HMG-CoA synthesis cholesterol because it catalyses the rate limiting step
-inhibits the synthesis cholesterol in the liver and organ & tissue, this reduced the cholesterol
levels in the liver, the liver responds by expressing more LDL receptors increasing more LDL
to be absorbed from the blood stream
Second generation action:
selective cholesterol absorptio\\

STROKE
Stroke:
Blood supply: brain
-Brain receives 20% of cardiac output 800 to 1000mL/minute
-CO2 is the primary regulatory for CNS blood flow

oxygen and nutrients travel in your blood and are delivered to brain cells via two pairs of
major arteries called carotid & vertebral arteries.

definition:
stroke: clinical syndrome with signs and symptoms of focal or global disturbance leading to
death cells of cerebral functioning lasting more than 24 hours or leading to death
transient ischaemic attack (TIA): acute loss of focal cerebral or ocular function due to
injury with symptoms lasting less than 24 hours.
Subarachnoid haemorrhage (SAH): haemorrhage from a cerebral blood vessel, aneurysm
or vascular malformation into the subarachnoid space surrounding the brain b/w the
arachnoid and pia mater. due to the extremely high pressure evolving.
sign and symptoms of sabarachnoid haemorrhage
-sudden onset of severe headache & vomiting
-loss of consciousness & neck stiffness.

divided into 3: brain stem, cerebellum, cerebrum

cerebrum is the largest part of the brain divided into two halves or hemispheres, which are
further divided into four lobes:
1.frontal: movement, judgement, memories
2.parietal: process what we see, hear, smell, touch
3.temporal: controls hearing & memory & recognition, stores long-term memory
4.occipital: lobe processes the signals from our eyes. primarily for sight.

Two types of stroke:

Ischemic stroke:
1.thrombotic - occurs when blood blot has formed in one of the major arteries leading to the
brain
2.embolic - when a blood clot forms in a different site somewhere else in the body and travels
up in the bloodstream and lodges in the brain.
-lack of circulating blood deprives the neuron
Loose blood clots are linked to atheroscleorsis; build up plaque on the inside walls of
arteries, narrowing them and interfere with blood flow.
blood clot forms when plaque ruptures.
Hemorrhagic stroke:
uncontrolled bleeding can cause localised pressure and swelling that damages or kills the
brain cells.
-cause shortage of oxygen & nutrients
-high blood pressure and/or defects in your arteries are the usual cause; the common defects
include aneurysm; weak areas in the blood vessel wall that filled with blood that comes
out like a balloons that can burst.
-3 sites of possible bleeding
1.at the surface of the brain (subarachnoid)
2.under the skull
3.a burst artery deep with n the brain (intracerebral)

foundation:
4 major vessels
right & left internal carotid artery (ICA)
right & left vertebral artery
the two vertebral artery come together to make the basilar artery.

Cerebrum
-from ICA you get MCA = middle cerebrum artery
-ACA = anterior cerebral artery
-PCA = posterior cerebral artery
ACA is connected by a artery called an anterior communicating artery
PCA & MCA are joined by a posterior communicating artery.
this forms a circle known are the circle of willis
-if blockage occurs in an area of the brain, blood supply can be maintained due to the circle of
willis which can assist in suppling blood in areas that the blocked artery is suppose to reach.
Cerebellum
-Superior cerebellar artery
-Anterior inferior cerebellar artery
-Posterior inferior cerebellar artery

Cause of Ischemic stroke

1.Embolism
when a blood clot gets travelled to the cerebral artery (internal carotid to MCA e.g), get
lodged in a particular artery that serves blood supply to a particular area of the brain, that
part will start to die off.
-these usually come from the heart
-cholesteral build up (atherosclerosis) that comes off and travels upwards.
2.Thrombotic
Arisesis within the blood vessel of the brain. such as a atheroscleorsis that breaks off which
causes blood to form a clot

Common arterial & cardiac abnormalities:

-intracaranial atherosclerosis
-aortic arch plaque
-AF
-Left ventricular thrombi
-penetrating artery disease
Etiology (cause of disease)
-atherosclerosis
-hypertension
-heart disease: AF
-others: trauma (fat embolism), tumour, infection
6 minutes is when cell death occurs. neurons and glia remain alive but functionless for as
long as 30 minutes before cellular death occurs.
programmed cell death triggered by ischemia, evolves over 2 hours.

21 steps of stroke: ischemic cascade

progression
Perfusion pressure: gradually goes down when a person is in a state of stroke
Cerebral blood volume: M02 is needed and therefore increases to maintain level. If MO2
increases, CO2 also increases causing vasodilation. – this then gets saturated.
Blood flow: Starts of steady and saturated but gradually gets depleted.
Cerebral oxygen extraction: low and steady, increases (as mentioned) to maintain level
from getting low, but this eventually gets overcome by loss of oxygen therefore gets depleted.
Cerebral oxygen metabolism: high/normal and saturated but slowly depleted as there isn’t
enough oxygen to metabolize.

Investigation
-CT
-Electrocardiogram
-Chest x-ray
-Complete blood count, platelet count.
-PT, aPTT - coagulation
-Serum electrolytes
-Blood glucose - DM
-renal and hepatic chemical analyses - status

Treatment
suspected TIA: Aspirin 300mg immediately then asses
confirmed TIA: CLOPIDIGRAL 300mg loading dose & 75mg daily thereafter. & high intensity
statin therapy; atorvastatin 20-80mg daily (to reduce non-HDL cholesterol by more than
40%)
statin treatment should be avoided in people with primary intracerebral haemorrhage or
with acute stroke.
emergency treatment:
clot busting drugs must start within 3 hrs (limited time window 4.5hours).

Secondary prevention:
used CHA2DS2VASc stroke risk score to access patients along with HAS-BLED score to assess
risk of bleeding. start on anticoagulant ONLY FOR AF
-DOAC: dabigatron; thrombin inhibitor
-NOAC: edoxaban, apixaban; highly selective reversible factor Xa inhibitor
if anticoagulation is contraindicated, consider offering a combination of aspiring and
clopidogrel. or MR dipyridamole 200mg
-STATINS (again, avoid in acute stoke or primary intracerebral hemorrhage) or
continue statin with acute stroke who are already receiving statin
Anti-hypertensive drugs – For stroke or TIA consider rapid blood pressure lowering for
people with acute intracerebral hemorrhage who:
-Present beyond 6 hours of symptom onset or have a systolic blood pressure greater than
220 mmHg.
-Aim for a systolic blood pressure target of 130 to 140mmHg within 1 hour of starting
treatment and maintain this blood pressure for at least 7 days.
-Blood pressure reduction to 185/110 mmHg or lower should be considered in people who
are candidates for intravenous thrombolysis.
-LMW Heparin inhbits the active Xa factor from converting prothrombin (II) to active
thrombin (IIa) preventing the conversion of fibrinogen to fibrin forming cloths.

M.O.A of warfarin
Inhibits vitamin K epoxide reductase (VKORC1) inhibition of formation of reduced vitamin K
(vitamin K hydroquinone) inhibition of posttranslational carboxylation of clotting factors II,
VII, IX & X reduced synthesis of functional coagulation factors inhibition of coagulation
cascade
M.O.A of Aspirin Inhibitors of Cyclooxygenase
Aarachidonic acid uses Cyclooxygenase to generate TxA2 binds to its receptor and activates
it Gprotein mediated activation of phosolipase C PLC hydrolyzes PIP2 to yield PIP3 and DAG
increase cytosolic calcium concentration activation of protein kinase C activation of
phospholipase A2 activation of GPIIb/IIIa binding of fibrinogen to GPIIb/IIIa platelet
aggregation.
M.O.A of Clopidogrel ADP inhibitor
irreversibly binds to P2Y(ADP) receptor preventing the binding of ADP to the receptor. this
will prevent the activation of G-Protein from alpha-GDP to alpha GTP which prevent the
activation of adenylyn cyclase from converting ATP to cAMP activating PKA.

BLOOD DISORDER
Blood Disorder:

MCV= HCT/RBC
-HCT: the proportion of blood made up of red blood cells
-RBC: RBC count; the number of red blood cells
-MCV: the average size of RBC which can be affected by different types of anaemia.

MCH=Hb/RBC
-Hb: haemoglobin the concentration of haemoglobin in the blood
-MCH: the average amount of haemoglobin per red blood cell

Hypochromic Microcytic anaemia= iron deficiency

Macrocytic anaemia=Vitamin B12 & Folic acid deficiency

Production of Red blood cells

There are oxygen sensor present in the kidney, they will sense how much of RBC are
passing, if they are mature enough and carrying less oxygen, the low tissue oxygen tension
will trigger oxygen sensor in the kidney to release erythropoietin, (hormone synthesis in the
kidney; juxtatubular cells) erythropoietin will act inside the bone marrow (for one day) on
the proliferation, maturation, release and therefore releasing reticulocytes to synthesis RBC.
Destruction of Red blood cells
Hemoglobin goes into the spleen where it gets broken down into “heme” and “globin”
In the heme iron gets reused by bone marrow or stored in spleen (IRON IS METABOLISED
IN SPLEEN) and liver (LARGE AMOUNT IS STORED IN LIVER – storage of ferritin). Some
heme can also presented as free, unconjugated bilirubin, which gets sent to the liver and gets
conjugated and secreted in bile: excreted in feces or urine (why black stool occurs when
taking iron).
Globin gets broken down to amino acids (reutilized)
Iron cycle – Iron is bound to heme or stored bound

Haemoglobin synthesis
-contains two PAIRS of globins
-& four complexes of iron plus PROTOPORHYRINS * (the hemes)

Mechanism of how Iron incorporated with Haemoglobin

-Once iron gets absorbed by the duodenum it goes through a cascade with the help of a
transferrin and enters the blood stream into a RBC, the Iron either converts & stored as
Ferritin or endocytosis to the mitochondria.
-Iron gets joined with glycine + succinyl CoA joined with B6 that eventually convert
into protophorphyrin
-protophorphyrin combines with iron to form haem
-heam leaves the mitochondria and joins amino acid converted into alpha & beta chains to
form haemoglobin

Ferrous iron (Fe2+) is absorbed better than ferric iron (Fe3+)

Iron-Deficiency Anaemia
causes:
-inadequate iron in diet
-significant amount of blood loss
-loss of significant amount of loss due to mestrual cycle
Laboratory test: LOW Serum ferritin & Serum iron, HIGH serum iron-binding capacity

Iron treatment
-ferrous fumarate
-ferrous gluconate
-ferrous sulfate
-Iron sucrose IV : for patient unable to absorb iron or has chronic renal failure receiving
treatment with erythropoietin.

unwanted effects:
Acute iron toxicity: where children are seen to over take iron supplements (gummy
substance)
OR
chronic iron toxicity: due to chronic haemolytic anaemia where RBC get broken down
 breaking down heme into iron!! (along with other break down)

Absorption of Vitamin B12

Vitamin B12 gets ingested and will bind to a carrier protein known as R-binders and enters
the stomach, when the pH is 8, this will remove the vitamin B12 from the R-binder. The
parietal cell presented in the stomach release an intrinsic factor that will carry the vitamin
B12 to the ileum. In the ileum the epithelial cells take up vitamin B12/intrinsic factor
complex. The absorbed vitamin B12 in the blood and binds to the transcobalamin II
(synthesized in the liver) and gets delivered to the liver and other tissue. The intrinsic factor
will be free and will pass through the portal vein.
What can go wrong?
-If the liver does not function properly then there will be less of transcobalamin
production. This will lead to less vitamin B12 being transferred to the blood to
transfer to organs.
-If there are no intrinsic factors (pernicious anaemia), vitamin B12 will NOT be
absorbed; the storage of vitamin B12 will get depleted, because we only need very
little, it will take a number of years before you get deficiency due to transcobalamin
has an enteroheptaic circulation having a longer life period.

Role of Folate in synthesis of thymidylate synthesis

Once absorbed, it does NOT need an intrinsic factor.
1.Folate gets converted to Dihydrofolate (FH2) by the help of Dihydrofolate reductase
(DHFR)
2.Dihydrofolate (FH2) gets converted to Terahydrofolate (FH4) by the help of
Dihydrofolate reductase (DHFR)
3.Terahydrofolate (FH4) (INACTIVE FORM) will combine with ONE carbon atom (provide
a methyl group for conversion) to form back to dihydrofolate in the presence of
2’deoxyuridylate (DUMP) – essential for DNA synthesis
4.2’deoxyuridylate (DUMP) further converts to 2’deoxythmidylate (DTMP) in the
present of thymidylate synthetase.
Key note* - Terahydrofolate (FH4) in turn is a reductant used by thymidylate synthase (TS)
and is converted stoichiometrically back to dihydrofolate.

Role of Vitamin B12 in synthesis of thymidylate

1.Vitamin b12 converts to methyl b12 in the present of methyl FH4 which convers to FH4
2.Methyl b12 converts to b12 by the present of homocysteine, which gets converted to
methionine
3.Methonine converts FH4 TO formyl FH4 to form folate polyglutamate formation that is
essential for DNA synthesis

Vitamin B12 Deficiency pernicious anaemia

• - Macrocytic anaemia
• - Can cause neurological effects such as dementia
• - Lack of intrinsic factor not secreted because of gastric mucosal atrophy (cell break
down)
• - Atrophy also causes the lack of secretion of acid and digestive enzyme (if pH 8 is not
produced, R-binder will not be released to bind to vitamin b12 to sent to the small intestine)

Causes of vitamin B12 deficiency anaemia

-due to pernicious anaemia
-gastrict cancer
-gastric bypass surgery (victoria beckham lingo)
-poor vitamin b12 in diet
treatment: intramuscular Vitamin B12 1000ug

Causes of Folate deficiency

-patients with severe chronic haemolytic anaemia
-pregnant woman
-sickle cell anaemia
treatment folic acid 5mg

Bone Marrow Suppression, Damage, or infiltration

Causes:
Anaemia of chronic disease
Marrow injured by radiation
anticancer drug
aplastic anaemia
Treatment:
blood & platelet transfusion
immunosuppressive drugs
bone marrow transplant

Polycythemia

RENAL
Renal-Acute Kidney Injury:

Define AKI: 3 Subtypes & causes:

Pre-renal:
1.hypovolemia thereby leading a drop in flow and renal perfusion
2. drop in effective extracellular volume
Intra-renal (intrinsic):
1.renal parenchymal injury
Post renal:
1.Urinary tract obstruction
underlying coronary pathology, major clinical features & diagnosis
Pathophysiology of Acute Kidney Injury
Due to two main changes that cause Decrease in GFR
-drop in GFR
-drop in urine output
-increase nitrogenous waste in the blood (urea & creatinine)
-cell death (necrosis/apoptosis)
-loss of adhesion to intrinsic renal cells = obstruction
1.Vascular changes
-endothelial dysfunction: presence of vasoconstriction specifically in the afferent arterioles
(coming into the nehprons)
-increase in adhesion of inflammatory cells (neutrophiles) aggravating inflammation
2.Tubular changes
-presence of loss of cells due to necrosis or apoptosis forming necrotic body
-leading obstruction in the tube as a result the filtrate will back leak leading to other
complications
Reduced GFR & oliguria

Clinical features:
-Creatinine excreted = urine excreted
-High creatinine build-up = acidosis due to inability to excrete H+
-Hyperkalemia due to impaired excretion of K+ ion = electrical conduction disturbance

Causes of pre-renal failure

-Hypo-perfusion
1.Reduced extracellular volume
-hypovolamia
-reduces cardiac output
-systemic dilatation
2.Altered renal vascular regulation
-afferent arteriolar vasodilation (prostaglandins)
-sepsis, hypercalcaemia, NSAID, amino glycoside
-efferent arteriolar vasoconstriction (angiotensin II)
-ACEIs, ARBs
Causes of intra-renal failure; Intrinsic renal azotemia
-acute tubular necrosis
-acute glomeruarnephritis
Causes of Post-renal failure - Ureter
-Urinary stones
-Prostatic hypertrophy
-Presence of stone/obstruction

Course of Acute Kidney Injury

-Pre-renal cause – lead to drop in GFR and presenting oliguria give aggressive therapy early
reversal – must treat within 24 hours
If not treated, acute tubular nephropathy >24hours
If not treated within 1-2 weeks, oliguric phase causing glomerular + tubular dysfunction
(from mediator
If not treated, within 10-30 days, polyuric phase known as persistent tubular dysfunction
Once treated, recovery phase will take 6 months to recovery with some damage remain.

Give an account of the non-pharmacological &

pharmacological management

refer to notes!!!

Renal-Chronic Kidney Injury: Refer to lecture notes!!!

-Patho and causes

Characteristic:
1. Kidney damage: present of proteinuria, haematuria,
2. Decrease kidney function: GFR less than 60ml/min/1.73m2 which persist more than 3
months

who is at risk? Diabetes (#1 condition), hypertension, CV disease, renal tract disease or
prostatic hypertrophy (only in male), nephrotoxic drugs: aminoglycosides, lithium

-stages & measurement of eGFR

-testing
-mechanism and manifestations**
-early detection & investigation
-intervention & drug therapy
-Obstruction & consequences
-glomerular disease

Chronic Kidney disease: Early intervention

1. Glycaemic control
2. Blood pressure control
3. Reducing proteinuria

Glycaemic control
-glycaemic control has been shown to reduce the development of microalbuminuria and
therefore reduces the progression of diabetic renal disease.
-ACEIs/ARBS (first line) have reno-protective effects in early and late nephropathy causes by
type 2 diabetes by reducing micro-albuminuria

Blood pressure
-Control of blood pressure has been demonstrated to slow progression of CKD
-aim of blood pressure should be below 140/90
if ACR >70mg/mmol aim to keep blood pressure below 130/80mmHg
- 1st line ACE, 2nd line ARBs

Cardiovascular Disease
Prophylaxis
-Offer statins for primary prevention

Hydronephrosis: a
frequent effect of partial
or complete occlusion
leading to swelling of a
kidney due to a build up
of urine.

causes:
benign Prostatic
hyperplasia
kidney stone
cancer surrounding the
urinary tract
pregnancy

Renal Calculi
the formation of calculi is
related to:
-impairment of the
metabolism
(overproduction of
metabolites)
-impairment of renal
filtration
-impairment of renal re-
absorption

Composition:
1. calcium oxalate
2. calcium phosphate
3. uric acid
4. struvite
5. cystine
Consequences urinary tract obstruction
-Reduced glomerular filtration rate (back pressure)
-Reduce renal blood flow (after initial rise)
-Impaired renal concentrating ability
-Impaired distal tubular function
-Nephrogenic diabetes insipidus (dysfunction of vasopressin, antidiuretic hormones ADH)
-Renal salt wasting
-Renal tubular acidosis
-Impaired potassium concentration
-Post-obstructive diuresis
Treatment of Obstruction
Step 1:
Narcotic analgesic (small doses of morphine) for pain relief
Correction of fluid and electrolye balance
Intravenous antibiotics
Relief obstruction
Step 2:
Remove calculus: determine stone analysis
Step 3:
Pathogensis: fluid instake/dietary Hx, family Hx, serume & urinary screening
Step 4:
Prevent further caliculi: increased fluid intake (2-3L/day), modify diet, specific treatment of
metabolic abnormality.
GLAUCOMA
Glaucoma:
Label the Eye:

How does Aqueous humour get drained

-Aqueous humour is formed by the ciliary body which moves from the posterior chamber
through the pupils to anterior chamber.
-Drains into the canal of schleme
-Eventually enters the blood
Aqueous humour drainage = Rate of secretion

Types of glaucoma based on characteristics?

Chronic open - angle glaucoma (COAG)
-Obstructive aqueous outflow through the trabecular meshwork
Normal tension glaucome
-Intraocular pressure not raised on screening although signs of damage are present
Ocular Hypertension (OHT)
-Elevated IOP without visual loss or nerve damage
Primary angle - closure glaucome (PACG)
-Closure of anterior chamber angle leading to aqueous outflow obstruction and raise IOP
Secondary glaucomas
-Arise from a number of reasons
1.inflammation
2.intraocular tumour
3.raise episcleral pressure
4.congenitally due to developmental abnormalities
Pathophysiology & Characteristics
Glaucoma is caused by poor drainage of aqueous humour and can cause blindness
Characterised by:
Increase intraocular pressure to more than 21mmHg
consequences are permanent nerve damage leading to blindness
Drug Treatments
Ocular prostanoids: Ester compounds:
Drugs: Lastanoprost, Travoprost (PGA CLASS: used for COAG)
Drops intraocular pressure by increasing oveoscleral outflow
Lasanoprost: converted to its active free acid on entering the eye
Travosporst: Ester prodrug converted to its active form by corneal hydrolytic enzyme as it is
absorbed from the eye
-potent full agonist of PGF2a-receptor
Beta-adrenoceptor antagonists
-blocked of ciliary beta receptor, inhibit cAMP > reduces aqueous humour formation rather
than increase outflow
Drug: Timolol (COAG, OHPT, NTG)
Sympathomimetic agents:
Drug: Apraclonidine
-alpha-2 selective agonist; in high cone. activates alpha-1 receptor
-activation of alpha-2 targets the ciliary body reducing aqueous humour
-activation of alpha-1 reduces ciliary blood flow, this reduces the formation of aqueous
humour
Miotics
Drug: Pilocarpine
Stimulation of ciliary muscle increases outflow of aqueous humour & opening of channels of
trabecular meshwork
not commonly used in chronic open angle glaucoma
used mainly in primary angle close glaucoma and secondary glaucoma
Carbonic anhydrase inhibitors:
Drugs: Dorzolamide
In ciliary epithelium inhibition of CA-II slows formation of bicarbonate ions and their
secretion into the posterior chamber
-reduces sodium transport into posterior chamber; lowering IOP
Acetazolamide is used as an emergency treatment of PACG
Dorzolamide is used for OHT & OAG resistant to beta-blockers
ADME 1
ADME 1 NOTES:
Bioavailability - fraction of drug that has not been altered and entered the circulatory.
- depends on how well the drug has been absorbed
- depends on how much the drug is metabolised by the liver
- e.g if administer 5mg of a drug orally and 1mg gets into the systemic circulatory,
bioavailability = 20%
-I.V bioavailability guaranteed to be 100%
FIRST PASS METABOLISM IN THE GUT WALL
- main cytochrome P450 & CYP3A4, 50% in duodenum, 30% jejunum, 10% ileum, 2% colon

ADME 2
ADME 2
Paracellular
- where drug can enter b/w tight cell
-require small molecule (<4 amstrung = 100picometer)
-sieving effect
-water & urea are what majority get pass through
Transcellular -
-Most drug pass through cell membrane
-passive diffusion - high conc to low
-facilitated diffusion/active transport

-the pH of tissue (environment) = effect solubility & diffusion rate.

phenytoin - aka 8.3 : forms a resonance to stabilise the negative charge on the nitrogen
therefore making it an acidic drug.
the amide property helps us absorb it at a sodium salt. - for a compound to be absorbed must
be in solution.

Passive diffusion
-anything lipid soluble
Facilitated diffusion/active transport
-movement of drug across a cell membrane via a specialised transport
-few drugs absorbed by carrier diffusion
-proteins that are embedded in the plasma membrane
-must trick proteins to think it’s taking in the natural molecule
-does not require energy or move against gradient. (glucose, Na, Cl, HCO3)
-only non-charged species, lipidphilic to avoid saturation
Requirement for passive diffusion
1.water solubility
2.lipid solubility
3.molecule must be unionised
4.molecular size
5.concentration of site of absorption
6.surface area of site of absorption
7.ion-pair absorption (permanently charged)
-ionised can interaction with endogenous ions resulting in an neutral
species (used positive with negative binding) e.g drug is propranolol.

Lipinski Rule
1. molecule size must be 500mw
2. log p less than 5
3. 5 hydrogen bond donor
4. 10 hydrogen bond acceptor
Fick’s Law: membrane surface and the concentration gradient are proportional and is
inversely (rate area increases as surface increases)

the compartment in which the drug is most ionised will contain greatest drug concentration
-for acidic drug, high concentration will be in high pH
-for basic drug, high concentration will be in low pH

- use fraction of unionised (fu) equation :

Acidic: 1/1+10^pH-pKa
Basic: 1/1+10^pKa-pH

ADME 3
-partition coefficient: behaviour of a drug, to see how lipophilic a drug molecule is and to
detect it’s solubility.
-the higher the partition coefficient implies a high lipophilic drug. (must be 5 or less; lipinski
rule)
-
ADME 4
-alpha 1 acid glycoprotein binds mainly cationic drugs
-beta-globulin & lipoprotein binds some lipophilic drugs
-amount of drug bound to protein depends on 3 characters

plasma protein binding: refers to the degree to which medications attach to protein

ADME 5&6
ADME 5 & 6

Chemotroph - organism that get free energy from oxidising organic compounds from other
organism
Phototroph - organism that get free energy by photosynthesis
Metabolism - parent drug gets in contact with enzymes that break down the drug to allow a
structure which will easily eliminate the drug.
makes the drug more water soluble “polar” which usually loses the pharmacological
activates.

Drug metabolism: Factors

-Enzyme concentration and activity
-if the rate of metabolism decreases:
1.increases intensity & duration of drug action
2.increases accumulation of parent drug in the plasma = increase toxicity risk
-if the rate of metabolism increases
1.decreases intensity & duration of drug action
2. toxicity may increase owing to production of toxic metabolites

site of metabolism:
liver
-primary site
-high perfused organ (organ with the most blood flow)
-rich in enzymes
-acts on both endogenous (natural production of the body) & exogenous compounds (things
we put into the body)
endoplasmic reticulum (microsomes) - membrane bound enzymes
-phase 1 enzymes
-glucuronosyl transferase
cytosol: phase II
-glutathione-S-transferases
-sulfate conjugating enzymes
non-specific enzymes
-metabolise compounds with diverse structure

PHASE I
-introduce function groups that will make the drug more polar.
-oxidative, hydrolytic (hydrolysis), reduction
conversion of one function group:
-C-H > -C-OH: carbon oxidation from a benzene (para position) or alkane molecule and turn it
to C-OH
-CH2-OH > -CH=O > -CO2H: alcohol oxidation to make into alcohol to aldehyde to a carboxylic
acid.
-N(CH3)2 > NHCH3 > -NH2: N-demethylation (oxidation)
-3’N(CH2)2 > NH-CH2: N-dealkylation
OR
-2’NH-CH2-CH3) > NH2
-SCH3 > S(=O)CH3 > S(=O)2CH3: oxidation of sulphur
-CH-NH2 > -C=O: oxidative deamination (not to worry)
-Hydrolysis of esters
-Hydrolysis of amides
-C=O > C-OH: reduction of ketone or aldehyde to alcohol

PHASE II
does not have to follow phase I as the drug may already contain a polar section
-compound gets conjugated to other molecules allowing the molecule to stick and attach stuff
to it

other known enzymes that break down bulky molecules that come from biotechnology drugs
(human insulin, prolactin, growth hormones) are of:
-carboxypeptidases
-aminopeptidases and other proteases hydrolyse these drugs and hormones
-beta-glucuronidases (hydrolyse sugars from cardiac glycoside)
-phosphatases, sulfatases

the size of protein is measures by kilodaltin (kDa)

CYP-450
-17 dominate metabolism of drugs and xenobiotics
-common drug metabolised are CYP3A4
-THESE st proteins contain a prophyrin ring - in the centre contains heme which consist of
iron. all connected by carbon units.

how to create a good drug through ADME:

1.insure there is efficient functional groups that are lipophilic which will readily dissolve
drug to pass plasma membrane.
2.ensure volume of distribution across organs and issue is high and ensure it isn’t protein
bounded. and not lipophilic enough that will cross BBB
3.ensure it can undergo phase I & phase II
4.can be metabolised by more than one enzyme isoforms (CYP3A4, CYP2D6, CYP450)
5.must be well developed in infants and young children (a phase II conjugation enzyme)
inducer: - activity is increases and rate of metabolism increases
inhibitor - activity is decreased and rate of metabolism decreases

P-glycoprotein
PGP - not a metabolic protein - its an efflux transporter - this will help spit the drug out from
getting into area where it should not be
such as the brain - PGP can recognze drugs cause efflux from liver by biliary excretion. can
cause resistance e.g cancer drugs.

ADME 6:

PHASE II
-attaching polar endogenous molecules (except methylation and acetylation) to phase I
metabolites or parent drug using transferase enzymes.
-glucuronide, sulphate, glycine, glutathione
glucuronic acid conjugation:
-OH, -CO2H, -NH2, SH
- MUST HAVE A MOLECULAR WEIGHT <250 and/or bile (MW >350)

Glucuronide conjugation
preformed as SN2 reaction due to the inversion at the electrophilic centre.
-attacking chiral centre (going from alpha to beta)

**Beta-glucuronidase** is an enzyme that can hydrolyse glucuronide back off which will have
an impact on elimination.
- conjugates excreted in the bile, freeing the drug for possible reabsorption’s.
(enterohepatic circulation or recycling)

Sulfate conjugation (sulfation/sulfonation)

-occurs primarily with phenols.
-***SULFATE CONJUGATION PLAYS AN IMPORTANT ROLE IN HEPATOTOXICITY and
carcinogenicity of N-hydroxyarylamides***
-less commonly applies to alcohol, N-hydroxyls, thiols or aromatic amine.
-overall addition of a sulfate group (-SO3-)
-final step catalysed by sulfotransferase enzymes
-sulfate conjugates can by hydrolysed back to the parent by sulfatases
-PAPS is the active form of sulfate that will react with the drug
-

e-nun are alkene directly bonded to a ketone are known to be very good electrophilic.
a double bond c-c=c next to a double oxygen c-c=c=o will make the first carbon a good
electrophile which will make a nucleophile atom
from the body to attack it at this position. and the overall transformation is alkylation of DNA
(alkylation of protein, this is bad which can form hepatotoxicity. - this is known as a
****MICHAEL ADDITION*****

Amino acid conjugation

-drugs containing carboxylic acid (forming a peptide bond) mainly glycine is used.
-requires initial activation of the carboxylic acid by acetyl-coenzyme A conjugation
then mediated by amino acid N-acyl transferase enzymes

-
Glutathione Conjugation
-this is a tripeptide that is of glutamic acid-cysteine-glycine
-abbreviated for GSH - because SH (thiol group) that will react with other electrophilic drug.

Methylation
-not typically used
-involves S-adenosylmethionine (SAM) and a variety of methyl transferases
Acetylation
-seperates drugs that have a primary amino group
-inital step is acetyl group provided by acetyl-coenzyme A and catalysed by n-
acetyltransgerases enzyme

oxidation reaction aromatics prefers at the MOST ELECTRON RICH CARBON WHICH IS AT
THE PARA POSITION.
-make sure there is not present of EWG such as Cl, N+R3, COOH, SO2NHR)

OXIDATION REACTION OF BENZYLIC CARBONS

ADME 7&8
Major routes to excretion
Q = organ blood flow
Ca = incoming drug concentration
Cv = outgoing drug concentration

Q > the amount of blood flow that goes into the liver joined by incoming drug concentration >
enters the liver - undergoes hepatic clearance (CLhepatic) (parent drug is cleared) > after
liver is the outgoing drug concentration (e.g parental dose), enters the systemic circulation >
remainder of body > gets cleared renal or others.

CLtotal = CLrenal + CLhepatic + CLothers.

note*: for some drugs, rate of renal elimination is main factor that determines duration of
action
-3 primary steps involved in the elimination process:
renal clearance is the sum of…
1.glomerular filtration
2.active tubular secretion
3.passive tubular reabsorption

Glomerular filtration
-drugs that are bound to protein will not be filtered through this glomeruli and therefore
remain in the blood supply
-occurs by hydrostatic pressure gradient
-
passive reabsorption:
-urine to the blood supply (systemic circulation) if a drug that is present in the urine that is
lipid soluble it can move back into the blood where as polar bond and ionised remain in the
urine
-must have high logP,
-if urine flow increases, time drug is exposed to reabsorptive surface decreases
-forces diuresis with large volume of fluids

active tubular secretion

carries for organic acids and bases move species from blood to urine
-using a transporter to carry drug into the urine
-phase II conjugation of drug with a biological molecule (such as a sugar; glucoronic acid)
-specific mechanism for many phase II conjugates
-carriers can be saturated dependant on the concentration of drug or drug-drug competition
or interaction. (2 drug can be competing for the same active transport which may increase
one drug than other keeping it in the systemic circulation)
-

clearance
-determine dosage regimen; how much and how often of drug is typically given!
1.steady state concentration within therapeutic range
2.rate of administration = rate of elimination
3.rate of clearance dictates interval of administration
volume of distribution needs to be known
-clearance is determined by hepatic blood flow (how much blood flow goes to the liver that
contains the drug)

blood concentration of drug need to be known

Toxic implications:
-overdose-basic drug; must acidify urine (ammonium chloride)
-largely not used due to risk of metabolic acidosis
-overdose-acidic drug: basify urine (sodium bicarbonate)
-shifts equilibrium to favour ionised form
-less reabsorption, more rapid elimination

Excretion via Bile

-with large pores of molecule during phase II - this will increase MW (above 500) causing
glucoronic molecule get excreted through the bile
Phase II metabolism aids biliary excretion
1.particularly glucuronidation
2.increasing polarity
3.increase water solubility
4.increase molecule size.

Enterohepatic recycling IMPORTANT

-possibility for reabsorption after excretion in bile
-drug conjugates may be cleaved by a beta-glucuronidase enzyme to free the parent
lipid-soluble drug which may be reabsorbed

SPECTROMETRY: UV
Spectrometry: UV
Advantages & Disadvantages (limitation) of UV.
Advantage:
-Quantitation of drug in solution: detects drug purity
-rapid
-affordable
-simple & sensitive
-almost universal
-linear response
Disadvantage:
-Prone to interferences:
-Excipient: if a drug has excipients such as red dye colour. which will absorb
UV.
-Degradation products-may be looking another drug - cannot separate
-Metabolites - pk study and looking at excretion of drug, this is a very small
concentration of drug that may have other substances and therefore may interfere with the
drug
What can we do? Change pH, derivatize the compounds, improve specificity by modifying
analyte.
what types of interaction is the molecule having with UV light and why? (MCQ)
-Its convenient to use absorbance in quantitative analysis that the UV that is detecting
-High electron in a pie orbital - to a pie star is the absorbance a molecule will make.
-This is due to a conjugation system where it will contain chromophore (more stabilised)
-The more conjugation you get the higher the wave # = easier to promote electron AND
increases epsilon.
Effect of solvent or substitution (MCQ)
-Bathochromic shift (red shift)
-shift to longer wavelength/lower energy
-Hyposochromic shift (blue shift)
-shift to shorter wavelength/higher energy
-Hyperchromic shift
-increase in absorbance
-Hypochromic shift
-decrease in absorbance
-Absorbance effected by electron on ring, change of lambat changed how much UV is
absorbed.
-Think of electron donation to the ring, if there is a basic functional group YOU
SHOULD BUFFER THIS!!!. this is because we don’t want to get it ionised and unstable
the molecule. - I
Indicatiors:
Indicators are used to see how the UV interaction with changes in pH and ionisation forms.
Quantitation & their method:
-Absorbance & concentration is proportional up to a certain point due to saturation (no more
light will enter the sample cell)
-**Concentration is key** dilution should be done.
-Beer Lambert law applies only to dilute solution (absorbance <1.5 = <0.01M) MCQ
1.Calibration Curve Method
-Requires a pure standard
-Time consuming
-Reduces Error (line of best fit)
-Must know concentration used to graph
-Slope = molar absorptivity
2. Comparative Method
-if you know Asample/Conc.sample = Astd/ConcStd
-very quick (two sample)
-assumes linearity
-you have to ensure concentration is appropriate
3. Absoute Method
-Uses beer lambert equation to get the absorbance
-instrument must be calibrated (same wavelength)
-Accurate lambat
-Spectral resolution
-Absence of stray light
-See British Pharmacopia checks
-Standard is not needed
you can calculate molar absorptivity if in moles or specific absorbance if in percent

ideal for compounds that have already been made with no steps left
used for quantitative to identify impurities
absorb UV and light to help excite electron to its highest orbital
you receive an absorbance due to the present of chromophore and conjugation
the high conjugation the high the absorbance
EDG help and EWG reduce
3 methods used to help identify concentration
calibration method - must have pure std, line of best fit and must know concentration to plot
graph, also slope = molar absorptivity

comparative method
you require to know concentration of std and sample
only require two sample

absolute method
-beer lamber
for molar = mol/L
for percentage = g/100ml

advantage: sensitive, universal, efficient, inexpensive, linear responsive

disadvantage: interference; excipients, degradation, metabolite, endogenous
how to help with this? change pH or modify analyte to improve specificity

SPECTROMETRY: ATOMIC
Spectrometry: Atomic
Emission
-Emission of photons
-Mainly used for metals (Na + K) - shows a characteristic of coloured flame.
-Measure at ppm levels - works with solution that are soluble.
-the intensity of light is proportion to the amount of electrons being excited.
-selectivity is extremely high > each different elements absorb different wavelength
-detects how much concentration that specific metal is present in a specific solution - we
apply a filter to exclude the wavelength that you want to see
-limitation 1: self-absorption
-Not linear using a calibration graph; slight curve
-atoms present in the exterior flame (where its all cooler) tend to absorb the
emitted light, therefore more the concentration the drug is the more of the number is high.
therefore causing a curve graph
-limitation 2: excitation source
- optimised temp of a flame
-at a give temp there is a certain amount that will populate the higher orbital
than the amount of atom that will populate the lower orbital; boatsman distribution (MCQ)
-high flame gives higher photons emission and therefore high intensity.
Absorption
-Works with cool flame, we want them in the ground state to absorb UV as light pass through
-Long & constant flow of gas, air and flames are preferred.
-Absorption plot against concentration on graph ; only looking at atoms
-Hollow cathode lamp is used for absorption: metal lamp is used due to narrow bandwidth &
energy gap being the same.
-beer lambert law same as UV = use comparative method
Major limitation
-alot of sample is needed to get a good reading
-high detection limits (ppm range) due to:
-cannot get perfect flame due to movement
-short lasting of flame
-rapid dilation in the flame
-cannot use solid sample
interferences in AA
-chemical : binding issues
-phosphate suppress signal of calcium: must add releasing agent
-ionisation: certain atoms ionise too well
-e.g magnesium likes to be ionised (gets excited) and therefore prevents any
absorption; use ionisation suppressor
-spectral: overlap
-wavelength of different atom can overlap
Interfering matrix: standard addition
-everything minus what you are NOT looking at (e.g water) is your matrix
-if standard interact with the matrix, signal obtained will be lower since only the free fraction
will contribute to the signal (signal becomes suppressed)
-add standard to the matrix to know much it’ll be changed
-add more and more concentration of analyte in each matrix sample.

MS & NMR SPECTROSCOPY

MS & NMR Spectroscopy

mass spectrometry
-universal detection (no chromophore required)
-gives structural information via fragment mass
-high sensitivity (as a result of high specificity
-may be coupled to chromatographic systems
-ions are all separated based on their mass to charge ratio (m/z)
-matches it to a database by looking at different features in spectrum
such as mass, pattern

ionisation:
compound must be ionised - electron impact (EI)
-radical molecular ion is generated with a charge of +1
-we only see charge/ionised molecules, we do not see neutral or
radical.
-if you alter the amount of energy you put in, you can get a different
degree of fragmentation/ different amount of charges.
the higher the m/z the more stable its indicated.
-isotopes can also show different masses
-the largest mass is typically the parent ion
-its used with gas chromatography - compounds from the volume are
already in the gas phase.

ESI
-liquid chromatography can be integrated with mass spectrometry
using soft technique known as electrospray ionisation (ESI)
-ESI created charged molecules (ions) while removing the solvent
(mobile phase)
-positive ionisation can be encouraged using acidic mobile phase
-if in the molecule there is more than one function group that becomes
ionised then you take the Mr, then the m/z will be (e.g Mr =151, charge
is 2. (151 + 2)/2 = 78)
-ESI is a soft technique,

Quadrupoles
-common mass resolving method involves a quadrupole - mass
selective

Time of Flight (TOF)

-high resolution techniques include TOF
-ions separated based on their m/z - heavier m/z ions take longer to
reach the detector
- the detector counts how long it take to reach the end, this will give
you an estimated on the mass.

mass spectrometry - resolution

-more powerful instruments have a higher mass resolving power - this
helps with differentiating b/w compounds of similar m/z values

Double bond equivalent

(C+1) - [(H* - N)/2]
C = # of carbon atoms
H = # of hydrogens & halogens
N = # of nitrogens
if more = 4 this means its a benzene ring!!!

Nuclear Magnetic resonance spectroscopy (NMR)

- the instrument will excite the molecule
-measurement of frequency of precession: the resonance bit of NMR
-upon relaxation the radio energy can be measured and a spectrum can
be generated by fourier transform
-high electron density shield nuclei from the magnetic field
-protons which lie close to electronegative atoms (O, Cl, Fl) feel the
magnetic field more strongly - they are de-shielded

-a sheilded proton **IMPORTANT**

-absorbs at a lower frequency energy then a deshielded
proton = upfield
-E=hv; low energy = proportional to lower frequency
-small effective magnetic field = lower energy difference b/w
alpha and beta
-high electron density
-as you go to the right you need a HIGH magnetic field
strength = upfield

-deshielded proton
-absorbs at a high frequency = downfield
-increase effective magnetic field = high energy frequency =
higher energy
-low electron density
-high energy difference b/w alpha & beta
-as you go the left you need a LOW magnetic field strength =
downfield

chemical environment = symmetry

when you have an electronegative atom you will withdraw some
electro density from the carbon attached to the protons. causing de-
shielded from the applied magnetic field = greater difference in energy
which corresponds to frequency = larger frequency
- hybridising of sp2 orbital has more S character than the sp3 therefore
the electron are held closer to the nucleus therefore more
electronegative is withdrawn more than sp3
-induced magnetic field is the opposite direction of the applied
magnetic field

- if both arrows point up you get:

-applied magnetic field
-high effective energy felt by the other proton
 -high energy/frequency = high shift

-if both arrows point down you get:

-low applied magnetic field strength
-low effective energy felt by the other proton is lower
-low frequency = low shift

-if one arrow points up and the other down

-this cancel the magnetic field = external magnetic field
-high probability of correct chemical shift - twice probability
= more intense signal at the correct chemical shift.

INTRODUCTION TO CHROMOTOGRAPHY
Introduction to Chromotography

Why is separation science so important?

-because we want a certain product has the correct content in it.
-helps find out purity of it the product
chromatography
-introduces the concept of mobile phase and stationary phase
-stationary does not move ; this is your plate
-mobile phase moves with the analyte and can either be polar or non polar substance and
whatever the mobile phase is, the stationary is the opposite.
-you can compare two analyse and if they move at the same distance then it should they
have same component but if one has a different separation than the other then you can say
they are different component.
-separation occurs according to their different physiochemical properties.
-the mobile phase consist of mixture of non-polar and slightly polar solvent
-the polarity of the component being analysed determines how far they travel on the TLC
plate
-a very polar compound will interact strongly with the stationary phase but not very
strongly with the mobile phase. therefore won’t travel far on the plate
-YOU MUST KNOW WHAT YOUR MATERIAL IS!! TO TEST ITS PURITY!!!
-what to look at**
1.increasing polarity
2.greater stationary phase interaction
3.longer retention time
DCM = non-polar
MeOH = polar

TLC SUMMARY
-fast way to separate and visualise compound
-inexpensive equipment, little training
-can run multiple samples (spots/plates) in one tank
-good sensitivity (stain development)
-limitation resolution - unsuitable for complex sample
-not a quantitative technique -cannot test measurement not for analytical
-not automated

HPL performance liquid chromatography

-increase speed
-increase surface area
-resolution (separating ability) is greatly improved
-compounds leaving the column can be measured quantitatively

the retention time will determine ur compound that retention time for that compound will
always be the same no matter what instrument you used.
-for HPLC - normally the mobile phase is non-polar and the stationary phase is polar
however if you drug is majority non-polar then it will all move up to the top with no
separation. so it had to be discovered that the stationary phase should contain some non-
polar particles to aid with this situation this is where reverse phase - LC come into place…

Reverse phase - LC (RPLC)

-suitable retention requires interaction with a non-polar stationary phase i.e reversed
phase.
-alkylating the silica, CHn chains are bonded to the silica particles creating a non-polar
environment
-commonly C18 chains are used
-polar solvents like water are weak eluents & more non-polar solvents such as
methanol and acetonitrile are used as the strong eluents
RPLC: Effect of Mobile Phase
-by modifying the composition of the mobile phase we can increase or decrease the
retention time.
-useful for separating mixtures with different polarities
RPLC: Effect of pH
-ionised molecule interact weakly with the stationary phase (we want the molecule to be
99% unionised = high retention time)
-how to improve the resolution of your compound
-for basic drug we want the mobile phase to have water with buffer to increase the
pH to keep it unionised.
-for acid drug we want the mobile phase to have water with buffer to decrease the pH
to keep it unionised
-this allows a better separation.
-Tr = retention time (y-axis) mobile phase pH (x-axis)

Isocratic vs Gradient Elution

Isocratic
-mobile phase is premixed at a ratio
-the mobile phase becomes constant from start -phase
-mobile phase has to be changed all the time
not the best way for separation
-overlaps
-takes longer time
-waste of solvent (constantly changing mobile phase)
Gradient Elution
with gradient you keep the amount of the aqueous buffer initially high to get resolution by
force interaction with column.
-once all eluted/separated you can change the portion/ratio of strong/weak solvent that
reached the column.
-therefore anything that was strongly retained is
now being pushed off the column a lot fast without changing the front end.
-you slowly increase the non-polar solvent

Chromatographic Parameters
Known as the fundamental resolution equation
sharp peak with best retention is what we want.
Efficiency = width
Selectivity = the ability to differentiate b/w two peaks
Retention = the value/retention time of that peak.
-Broadening of peaks reduced resolution **
1.Eddy diffusion - silica packing - where peaks are meant to be narrow, when aren’t packed
evening, it can cause cracks and the peaks become broad.
2.Longitudinal diffusion - concentration gradient in mobile phase = something with high
concentration will want to disperse out (through the mobile phase) causing longitudinal
diffusion
3. Mass Transfer - drugs will interact with the pores, move inside the pores with there is
hydrophilic chains, and will move back out. we don’t want to put too much drug column in
it, we can also increase the temperature to change the rate. some drug will only interact
with the mobile phase and some other molecules will simply move

Summary
-Chromatography separates compounds based on interaction with the mobile phase and
the stationary phase
-seperated components can be quantified - critical for purity determination/QC check
-TLC may be useful for ID/limit test
-HPLC can give precise quantitative data - to achieve this, peaks must be fully
resolved.