Lecture notes

Medicine year 2 module- clinical pharmacology

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Module
Clinical pharmacology (MS2000)

Institution
University Of Leicester (LE)

These lecture notes follow the Aston and Leicester Medicine program. 75 pages of colourful notes including flow charts, tables, mnemonics, labelled diagrams. It is laid out and explained in a way that is easy to remember and amount of detail in notes of everything you need to know to pass clinical...

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Uploaded on August 25, 2023
Number of pages 75
Written in 2023/2024
Type Lecture notes
Professor(s) Nadia
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1. Lecture notes - Medicine year 2 module- clinical pharmacology
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Hypertension: Primary Hypertension (Essential) is largely
Idiopathic and accounts for approximately
Blood pressure is tightly regulated through multiple regulatory mechanisms (eg. RAAS, 90% of all cases
SNS/PSNS, Nitric Oxide, Prostacyclin) – Though Endothelin, EDRF, NO and ANP have an
effect Secondary Hypertension accounts for
approximately 10% of all cases and have
• Short-term control – Mediated by the Sympathetic Nervous System (when BP KNOWN causes:
is Low) which acts to increase Cardiac Output (binds to Beta 1 receptors to
increase HR), increase Renin production (binds to Beta 1 receptors by • Endocrine (Cushing`s,
Juxtaglomerular Apparatus), increase Venous return and Peripheral Phaeochromocytoma, P.
Resistance (activation of Alpha 1 receptors) Aldosteronism)
• Long-term control – Mediated by the RAAS (when BP is Low), there is a • Renal (Renovascular disease)
reduction in renal blood flow which increases Renin (cleaves Angiotensinogen • Coarctation of Aorta (narrowing of
to Angiotensin I, then ACE (in lungs) converts it to Angiotensin II which acts to the Aorta after the ligamentum
increase Peripheral resistance). Angiotensin II also acts to increase Arteriosus – Particularly in young)
aldosterone secretion (Mineralocorticoid produced by the Zona
Glomerulosa). The reduction in perfusion also causes a slight decrease in GFR Risk Factors:
(Causes reduced plasma flow thus filtration, this causes reduced delivery of
• Non-Modifiable – Age, Gender,
NaCl to the Macula Densa which increase Prostacyclin production causing
Black Carribean/African, Genetics,
Afferent Arteriole dilation and RAAS activation causing the Efferent Arteriole
Diabetes/Kidney disease
to constrict)
• Modifiable – Smoking, Alcohol,
Why Check? Hypertension increases the risk of developing Heart Failure, Stroke, Obesity, Physical Activity, Anxiety
Coronary Artery Disease, CKD, Vascular Dementia and Peripheral Arterial disease. and Salt intake (5-6g per day)

Silent killer? Hypertension is largely Asymptomatic until organ damage is sustained in Can help patients reduce risk by modifying
which case, it is too late to reverse the damage so treatment and symptom their lifestyle (use GRINs model for change
management is the only available thing. to help convey this information)

Diagnosis: Investigations: Classification of Hypertension:

• Measure BP of Patient in clinic using the • Urine dip – Haematuria, • Stage 1 – Greater than 140/90 in
appropriate cuff size, Measure both arms Proteinuria clinic and 135/85 in Home
(if greater than 15mmHg, repeat and if still • ACR and U&E`s for Renal function Monitoring (Ambulatory or Home)
same, repeat BP readings from arm with • Examine Optic Fundi • Stage 2 – Greater than 160/100 in
highest BP). Measure 3 times (If greater • 12-lead ECG – CVS health + have clinic and 150/95 in Home
than 140/90 and take lowest two Lipid profile and Q score to Monitoring
readings) measure risk (LV Hypertrophy • Stage 3 – Greater than 180 in
• If Greater than 140/90, offer ABPM or causes Tall QRS) Systolic or 120 in Diastolic
HBPM and investigate organ damage (if • HbA1c – Diabetic state • Accelerated Hypertension –
so, start treatment) + Access CVS risk Greater than 180/120 and signs of
• If greater than 180/120, Start treatment if retinal Haemorrhage
got organ damage and same day referral if
there are optic symptoms/suspected For stages 3 and above, refer urgently to
malignancy. If no organ damage, repeat Secondary care in order to start treatment
within 7 days
Ambulatory BPM – takes two readings every
N.B. The above may be due to Coarctation of the hr (automated) and from 8am – 10pm
Aorta.
Home BPM – Ask for 2 readings, one in
morning and evening (same time) for 4 days
Choice of Hypertensive Management (<55, not black African/Caribbean or has diabetes):

• Step 1 – ACEi or ARBs – due to a high renin state (start low dose, titrate up)
• Step 2 – Above + Calcium Channel Blocker or Thiazide-like Diuretic
• Step 3 – ACEi or ARB + Calcium channel blocker + Thiazide-like Diuretic
• Step 4 – Diagnose resistant hypertension, consider specialist referral (may add alpha/beta
blocker or spironolactone)

Choice of Hypertensive Management (>55, Black African/Caribbean):
Papillary Oedema is caused by High BP and is
• Step 1 – Calcium Channel Blocker – as defined as a Low Renin State the swollen Optic Nerve, typically presents
• Step 2 – The above + ACEi/ARB or Thiazide-like Diuretic with Retinal Haemorrhage (also known as
• Step 3 and 4 – follow the same management as the above Flame)

, Hypertension Management:
ACE inhibitors (ACEi):

Action – Binds to ACE and prevents the Side-Effects: Examples:
conversion of Angiotensin I to Have the Suffix (-pril)
Angiotensin II • Persistent Dry Cough – due to Bradykinin increasing the cough
reflex • Captopril
Causing – Vasodilation (reducing SVR), • Bradykinin-Mediated Angioedema – swelling of the lips and • Enalapril
Reducing Aldosterone/ADH secretion tongue by increasing vascular permeability (more common in • Lisinopril
(reducing intravascular volume), females, black populations and >65) • Ramipril
Reduced cell growth and proliferation, • Renal Failure – causes dilation of efferent arteriole and
Reduces Bradykinin degradation particularly in Bilateral Renal Artery Stenosis Should avoid in Pregnancy
(causes vasodilation (ACE typically • Hyperkalaemia – Concurrent use of K+ sparring diuretic is due to association with Fetal
increases Bradykinin degradation)) contraindicated Malformation

Angiotensin Receptor Blockers (ARBs):
Action – A Side Effects: Examples: Have the Suffix (-sartan)
competitive
antagonist to the • Renal Failure – blocks • Losartan
Angiotensin I vasoconstriction • Candesartan
receptor (No • Hyperkalaemia – increased • Irbesartan
increase in sodium and water retention
• Angioedema – Mechanism is ARBs should be avoided in Pregnancy due
Bradykinin – No Dry
unclear, incidence lower than ACEi to its association with Fetal Malformation
Cough)

Calcium Channel Blockers (block L-type Voltage-gated Calcium Channels):
Dihydropyridines: Phenylalkylamine:

Used to reduce SVR and Arterial pressure (thus Used to depress SA node and slow AV nodal conduction (Class IV antiarrhythmic – selective for
vascular selectivity – treats Hypertension) myocardium) Less used for Hypertension treatment

Side-Effects: Used for Angina Management by reducing oxygen demand

• Tachycardia – Leads to baroreflex cardiac E.g., Verapamil
stimulation (SNS) + increased inotropy
• Palpitations
Benzothiazepines:
• Oedema – increased capillary pressure
• Drug interaction – Amlodipine is a CYP Has both vascular and myocardial effects, largely used in Angina management and minimally in
3A4 inhibitor so interacts with hypertension.
Simvastatin (increases) and increases risk
of Myopathy (improper muscle function) Side-Effects:

Examples: Have the Suffix (-dipine) • Similar to Verapamil
• Bradycardia + Negative inotropic effect – avoid this medication in pre-exsting
• Amlodipine bradycardia, HFrEF
• Nifedipine • Drug interaction with Beta blockers (as Beta blockers already reduce HR)
• Nicardipine
• Felodipine E.g., Diltiazem

Thiazide-like Diuretics: Alpha-1-Adrenorecptor Blockers:
Action – Inhibits the Sodium-Chloride cotransporter in DCT (proximal aspect), this causes
Used in hypertension as they are the predominant alpha
Diuresis which reduced BP, ECV and SVR (may lead to Hypokalemic Metabolic Alkalosis)
receptor on vascular smooth muscle
Side-Effects:
Side-Effects:
• Hypokalaemia – ENaC cause for Sodium absorption which promotes potassium
• Dizziness and Headache
excretion
• Oedema – especially combined with a
• Hyperuricemia (leads to gout – commonly 1st metatarsal) and Uremia (High urea
Dihydropyridine
levels)
• Postural Hypotension – loss of reflex
• Impaired glucose tolerance (+hypercalcaemia)
vasoconstriction
• Increase in Cholesterol and TAG`s
E.g., Doxazosin
E.g., Bendroflumethiazide, Indapamine

,Beta-Blockers: Side-Effects: Examples:

Action – Inhibits normal sympathetic effects • Bronchoconstriction Have Suffix (-lol)
• Can mask Tachycardia – Particularly
Cardiac effects – Decrease in Contractility (negative inotrope), Heart Rate
in hypoglycaemia/thyrotoxicosis • Bisoprolol
(negative Chronotrope), and Conduction velocity (negative Dromotrope)
• Bradycardia – avoid in 2nd/3rd • Labetalol
degree heart block • Carvedilol
Vascular effects – Smooth muscle constriction (peripheral)
• Cold extremities, Paraesthesia and Labetalol is commonly
Contraindication – Asthmatics and COPD patients or with history of Numbness used in hypertensive
Bronchospams as Beta Blockers cause Bronchoconstriction (beta-2) • Erectile Dysfunction patients who are pregnant

Heart Failure:
Heart Failure is the inability of the heart to provide adequate CO and oxygen delivery to meet metabolic demands of the
body.

• Acute HF – develops rapidly (hrs to days), typically caused by Sepsis, Acute MI, Severe Arrythmia (reduces CO)
and reperfusion injury. This can be immediately life-threatening so is a medical emergency.
• Chronic HF – Associated with adaptive responses of the Heart to precipitating conditions/pathology (typically
months to years to develop)’

Cardiac-related Conditions High Output states Drugs
Coronary Artery Disease (most common) Anaemia (increase HR to compensate) Alcohol
Hypertension Thyrotoxicosis Cocaine
Cardiomyopathy (restrictive, dilated, Septicaemia NSAIDs
hypertrophic)
Valvular heart disease Phaeochromocytoma Beta-blockers
Congenital defects Liver failure Chemotherapy
Arrythmias AV shunts Calcium Channel Blockers
Myocarditis Paget`s disease Thiamine (B1)
deficient

Heart Failure can be further classified by the Left Ventricular Ejection Fraction (LVEF):

• HFrEF – this is when the LVEF is <40% (typically manage the HF at this stage
• HFpEF – This is when the LVEF is >50% (typically manage the underlying condition and associated comorbidities)

Classification of Heart Failure based on Symptom Severity – typically use the New York Heart Association tool:

• Class I – No physical limitation, Ordinary activity doesn’t elicit symptoms
• Class II – Slight physical limitation, comfortable at rest, Ordinary activity elicits Fatigue, Palpitations or Dyspnoea
• Class III – Marked physical limitation, comfortable at rest, less than Ordinary activity elicits symptoms
• Class IV – Unable to do physical activity, Symptomatic at rest, discomfort increased with activity

Pathophysiology of Heart Failure and associated mechanisms:

• Myocardial Insult – decrease in CO +/- arterial pressure
• RAAS and SNS activation – causes positive chronotrope/inotrope (tachycardia thus increased work – may lead to
arrythmia). Also causes myocardial remodelling (hypertrophy/fibrosis/apoptosis), the previous point also
contributes to this. Also causes Sodium-water retention (increases ECV, thus preload/afterload – may also cause
venous congestion)
• Naturitic Peptide System Activation – has a positive feeback on RAAS, Sodium-water retention and Myocardial
remodelling
Symptoms of Heart Failure: Lifestyle Modification:
Treatment Aims:
• Chest pain – especially • Maintain fluid balance – restrict
• Reduce Mortality
exertion fluids to approx. 1.5L-2L
• Relieve Symptoms
• Dyspnoea • Restrict dietary Sodium
• Improve exercise tolerance
• Dizziness (<5g/Day)
• Reduce acute exacerbations (the incidence)
• Peripheral Oedema • Regular low intensity exercise
• Weight gain (sudden) (Stable HF)
• Fatigue or Weakness • Limit/reduce/stop Alcohol
(sudden)

, Heart Failure Management:
ACE inhibitors (ACEi): Beta-adrenoreceptor Blockers:

Action – Inhibits the conversion of Angiotensin I to Angiotensin II Action – Ultimately blunts the Sympathetic Nervous System.
Slows the HR to allow for longer diastolic filling for better filling
Effects: which increases output
• Reduce Afterload – Enhanced SV and improves EF Also, may be used in arrythmia treatment as it displays Class I
• Reduce Preload – decrease pulmonary/systemic congestion thus oedema antiarrhythmic effects
• Reduce Sympathetic activation

Dosage – Start low initially (especially with Diuretic) Angiotensin receptor/Neprilysin inhibitors:
Alternative – If ACEi not tolerated, swap with an ARB Action – combination drug with dual action of RAAS and NP
(Natriuretic Peptide)
Aldosterone Receptor Antagonists (Potassium Sparing Diuretic): • Sacubitril – pro-drug, when activated, acts as a
Neprilysin inhibitor which prevents breakdown of
Action – Block action of aldosterone, this inhibits the reuptake of sodium and water
Natriuretic peptides
Side-Effects: • Valsartan

• Hyperkalaemia – When sodium is reabsorbed, Potassium is excreted and
as this is blocked it increases serum potassium and reduced excretion Management of Heart Failure:
• Gynecomastia – Breast tissue enlargement in males (reversible when drug
• Step 1 – Offer and ACEi and Beta blocker and offer
is discontinued)
personalised cardiac rehabilitation (consider ARB if
Examples: Spironolactone, Eplerenone ACEi not tolerated) If intolerant of both, consider
Hydralazine and Nitrate

Sodium-Glucose cotransporter-2 Inhibitors: If Symptoms persist despite 1st line treatment, seek specialist
advice and consider the following:
Action – Blocks the SGLT2 receptor in PCT which increases sodium and glucose
excretion • Replace ACEi with Angiotensin receptor/Neprilysin
inhibitor (if <35% EF)
Effects: • Add Ivabradine with Sinus Rhythm and HR > 75 (if
<35% EF)
• Increased Haematocrit – relative cortex hypoxia causes reversion of
• Add Hydralazine and Nitrate
Myofibroblasts to EPO producing fibroblasts
• Add Digoxin with Sinus Rhythm to improve symptoms
• Weight Loss – Increase in Glucagon:Insulin which increases lipolysis and
improved glycaemic control
• Improved ventricular loading – A reduction in plasma volume reduces BP Digoxin –
thus afterload and diuresis reduces preload
• Improved CVS health – reduced leptin which reduces epicardial fat and Action – Enhances the Vagal activity to slow AV nodal
autophagic clearance helps to reduced damaged organelles (thus conduction thus HR and blocks 3Na+/2K+ ATPase and Na+/H+
ROS/Inflammation) exchanger causing increased intracellular Na+ which decreases
• Improved Cardiac Efficiency – reduced sodium, restores Na/Ca exchanger Na+/Ca2+ exchanger activity so increased intracellular Ca2+
to improve contraction and relative fasting state leads to ketone leading to increased contraction force of the myocardium
production to increase ATP
Must monitor for potential toxicity
Examples:

Have the Suffix (-gliflozin)

• Dapagliflozin
• Empagliflozin

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