Pharmacology S9 Flashcards
1 st Line Pharmacological Therapy of hypertension
Angiotensin Converting Enzyme (ACE)
inhibitors/ Angiotensin Receptor Blockers (ARB)
§ Calcium channel blockers
§ Diuretics
ACE Inhibitors give examples
E.g. lisinopril, ramipril,captopril
ACE Inhibitors
Main side effects
Important side effects
Main side effect – dry cough (10-15%)
- Important side effects
- Angio-oedema (rare, but more common in black pop.)
- Renal failure (incl. renal artery stenosis)
- Hyperkalaemia
Angiotensin Receptor Blockers give examples
Eg. Losartan, Valsartan
Angiotensin Receptor Blockers Important side effects
Well tolerated few side effects
• Important side effects
- Renal failure
- Hyperkalaemia
Calcium Channel Blockers
Three main groups:
Dihydropyridines (Nifedipine, Amlodipine)
- Benzothiazepines (Diltiazem)
- Phenylalkylamines (Verapamil)
Dihydropyridine Calcium Channel Blockers
Properties
Good oral absorption
- Protein bound > 90%
- Metabolised by the liver
- Few have active metabolite
Dihydropyridine Calcium Channel Blockers
Adverse effects:
Sympathetic nervous system activation – tachycardia and palpitations
- Flushing, sweating, throbbing headache
- Oedema
- Gingival hyperplasia (rare)
Phenylalkylamines - Verapamil
Properties
Impedes calcium transport across the myocardial and vascular smooth muscle cell membrane
- Class IV anti-arrhythmic agent/prolongs the action potential/effective refractory period
- Peripheral vasodilatation and a reduction in cardiac preload and myocardial contractility
Phenylalkylamines - Verapamil
Side effects
Constipation
- Risk of bradycardia
- Reduce myocardial contractility (negative inotrope) can worsen heart failure
Benzothiazepines - Diltiazem
Properties
Impedes calcium transport across the myocardial and vascular smooth muscle cell membrane
- Prolongs the action potential/effective refractory period
- Peripheral vasodilatation and a reduction in cardiac preload and myocardial contractility
Benzothiazepines - Diltiazem
Adverse effects:
Risk of bradycardia
• Less negative inotropic effect than verapamil – can worsen heart failure
Thiazide/Thiazide Like Diuretics
Give examples of
Bendroflumethiazide
Bendroflumethiazide: Adverse Effects
- Hypokalaemia
- Increased urea and uric acid levels
- Impaired glucose tolerance (especially with beta-blockers)
- Cholesterol and triglyceride levels increased
- Actives renin angiotensin system
So we use ACE inhibitors
Alpha Blockers
Give examples
Doxazosin
Alpha Blockers
Properties
Selective antagonism at post-synaptic a-1 adrenoceptors and antagonise the contractile effects of noradrenaline on vascular smooth muscle
- Reduce peripheral vascular resistance
- More effect in upright position
- Benign effect on plasma lipids / glucose
- Safe in renal disease
Alpha Blockers (Doxazosin)
Adverse effects:
Postural hypotension
- Dizziness
- Headache and fatigue
- Oedema (especially if combined with dihydropyridines)
Beta Blockers
Give examples
E.g. Atenolol, bisoprolol, nebivolol
b
-Blockers Adverse Effects
- Lethargy, impaired concentration
- Reduced exercise tolerance
- Bradycardia
- Cold hands – Raynaud’s
- Impaired glucose tolerance
- Contraindication - asthma
b
-Blockers
CI
Contraindication - asthma
Direct Renin Inhibitor
Give examples
Aliskiren
Aliskiren Pharmacokinetics
Main elimination route:
Mainly eliminated as unchanged compound in faeces (78%) o Less than 1% is renal excreted o NOT metabolised via cytochrome P450 o Caution in patients at risk of hyperkalaemia, sodium and volumedepleted patients, patients with HF, severe renal impairment and renal stenosis
Aliskiren cautions
Contra indication
significant drug interaction
Caution in patients at risk of hyperkalaemia, sodium and volumedepleted patients, patients with HF, severe renal impairment and renal stenosis
Aliskiren Pharmacokinetics
Bioavailability ~2.6%
- t 1/2 ~ 40 hours (range 25-45) - supports once-daily dosing
- Steady state takes 5-8 days
Centrally acting Agents
Give examples
Methydopa
Clonidine
Moxonidine
Classification of Hypertension
Isolated Systolic Hypertension
Grade 1
Grade 2
Systolic BP (mmHg)
140-159/ diastolic blood pressure <90 Grade 2 Systolic >160 Diastolic <90
Classification of Hypertension
Optimal
Normal
High normal
Systolic <120 Diastolic <80 Normal Systolic <130 Diastolic <85 High normal Systolic 130-139 Diastolic 85-89
Classification of Hypertension
Hypertension
Grade one mild
Grade 2 moderate
Grade 3 severe
Grade 1 (mild)
Systolic 140-159
Diastolic 90-99
Grade 2 (moderate)
Systolic 160-179
Diastolic 100-109
Grade 3 (severe)
Systolic >180
Diastolic >110
Methydopa mechanism of action
converted to a-methyl-noradrenaline a potent a2-adrenoceptor agonist
Clonidine mechanism of action
direct pre-synaptic a2-adrenoceptor agonist
Centrally acting Agents
can be used to treat hypertension in pregnancy
a-Methyldopa
Moxonidine mechanism of action
imidazoline I 1receptor agonist and some a2 agonist effect
Centrally acting Agents
Centrally acting Agents
Side effects restrict use:
Tiredness/lethargy
– Depression
Prognosis may be improved HF
RAS antagonism:
- ACE I / ARB
- Aldosterone blockade
- Beta-blocker
b-blockers: Physiological effects in HF
- Reduce heart rate (cardiac beta receptor)
- Reduce BP (Reduced CO)
1+2 Þ Reduced myocardial oxygen demand
- Reduce mobilisation of glycogen
- Negate unwanted effects of catecholamines
Minoxidil mechanism of action
Direct Acting Vasodilators
Minoxidil – Open ATP-modulated potassium channels thus inhibits influx of Ca++
- Usually needs to be accompanied by a diuretic and bblocker to reduce effects of tachycardia and fluid retention
- Other main side-effect is hirsutism
Direct Acting Vasodilators
Give examples
Minoxidil
Hydralazine
Minoxidil side effects
tachycardia and fluid retention
• Other main side-effect is hirsutism
Hydralazine – mechanism?
Hydralazine – mechanism unclear (?similar to minoxidil)
- Oral or IV
- Main ADRs: flushing, tachycardia and mild fluid retention
- A lupus-like syndrome may occur
Hydralazine side effects
Main ADRs: flushing, tachycardia and mild fluid retention
• A lupus-like syndrome may occur
Which drug may lead to lupus like symptoms
Hydralazine direct acting vasodilators
What is Phaeochromoctyoma
Adrenal catecholamine-secreting tumour
- Adrenaline / Noradrenaline / (dopamine)
- Paroxysmal symptoms v. sustained high BP
- Diagnosed: urinary catecholamines / Imaging
- 10% Rule
How to treat Phaeochromoctyoma
Treat with non-selective alpha blockers: Direct effect on a1 and a-2 adrenoceptors preventing the action of released noradrenaline
Phenoxybenzamine – oral non competitive Phentolamine – IV competitive for use in hypertensive crisis b-blockers are given AFTER a-blockade
non-selective alpha blockers give examples
Phenoxybenzamine – oral non competitive Phentolamine – IV competitive for use in hypertensive crisis b-blockers are given AFTER a-blockade
Primary Hyperaldosteronism
Causes
Causes hypertension
• Includes:
o Conn’s syndrome o Bilateral adrenal hyperplasia
- Excess secretion of aldosterone
- Plasma renin suppressed
Primary Hyperaldosteronism how to treat
Treat with aldosterone antagonists
- Spironolactone
- Eplerenone
- Alternative: high dose amiloride
aldosterone antagonists give examples
Spironolactone
• Eplerenone
Sodium Nitroprusside: mechanism of action when it use
Mimics the action of endogenous
nitric oxide on vascular smooth muscle, acting as a potent vasodilator
• Intravenous use with powerful rapid onset and offset
• Breakdown to cyanide – caution in liver disease, but renal excretion. Avoid prolonged use (>72 hours).
Used in Hypertensive Emergencies
Hypertensive Emergencies define
Very high BP (often over 220/120 mmHg)
- Associated with acute complications – pulmonary oedema, renal failure, aortic dissection etc
- Need to reduce BP by ~20% or to 100 mmHg diastolic within 1-2 hours
Warfarin: Action
Vit K reductase enzyme inhibitors
PKs of warfarin
Good GI Absorption: Give PO
Preferred choice for long term AC
Slow onset of action:
Heparin cover
Slow offset: t1/2 48 hrs but variable!
Need to stop 3 days before surger
Time to synthesize new clotting factors
Heavily Protein Bound
Caution with drugs that displace it
Hepatic Metabolism: MFO p450 System
Caution with Liver Disease
Caution if used with drugs that affect p450 system
Crosses Placenta:
Do not give in 1 st Trimester: Teratogenic
Do not give in 3 rd Trimester: Brain Haem
If Female patient on warfarin advise re pregnancy
Monitoring Warfarin
Extrinsic Pathway Factors Prothrombin Time
I.N.R=International Normalised Ratio
Drugs potentiating Warfarin
3 Ways are Clinically Significant 1. Inhibit Hepatic Metabolism
• Amiodarone, Quinolone, Metronidazole, Cimetidine, ingesting alcohol
- Inhibit Platelet function
• Aspirin
- Reduce Vitamin K from gut bacteria
• Cephalosporin Antibiotics Albumin Displacement (NSAIDS) & drugs that
decrease GI absorption of Vit K have lesser effect
INR will increase
if you start one de novo
Drugs inhibiting Warfarin
Antiepileptics (except Na valproate) Rifampicin St Johns Wort
Most work by inducing hepatic enzymes thereby increasing metabolism of warfarin
INR decreased
Main Uses of Warfarin
DVT (3-6 months) PE (6 Months) Atrial fibrillation (Until Risk > Benefit)
2.0–3.0
Mechanical prosthetic valves (high risk) 2.5–4.5 Patients with recurrent thromboses on Warfarin Thrombosis associated with inherited thrombophilia conditions
Other Uses: Cardiac Thrombus, CVA esp with AF, cardiomyopathy
Adverse Effects of warfarin
Bleeding / bruising at sites : intracranial epistaksis injection GI loss
Teratogenic at first T
Brain Haem an second T
Heparin Molecules
Unfractionated Heparin (intravenous, continuous, occasionally, subcutaneous for prophylaxis) 20 kDa
Low Molecular Weight Heparins (subcutaneous) 3-4 kDa
Unfractionated Heparin
Mechanism of action
Unique pentasaccharide sequence which binds to ANTI-THROMBIN III n This causes conformational change and increased AT III activity n AT III inactivates thrombin (IIa) and factor Xa: but also V,VII,IX,XI
Selective factor Xa inhibitors
Fondaparinux, idaparinux, rivaroxaban, apixaban, edoxaban
Direct thrombin inhibitors
Bivalirudin, desirudin, lepirudin, argatroban, dabigatran
No effect on Xa
Low Molecular Weight Heparins (LMWH)
Mechanism of action
Like UH, have unique sequence to bind to ANTI-THROMBIN III Unlike UH, they do not inactivate thrombin (IIa) Affects Factor Xa specifically. No monitoring required usually. Cleared by Kidneys, care in Renal Failure Less likely to cause thrombocytopenia
Pharmacokinetics of UFH & LMWH
Must be given parenterally as poor GI absorption
•Rapid onset and offset of action
UFH
LMWH
Dose-response
Non-linearity
Predictable
Bio-availability
Variable
(unpredictable binding to cells and proteins)
Predictable (less
binding to macrophages and endothelium)
Action
Variable
Monitor with APTT test
No monitoring
Little affect on APTT
Administration
IV
SC (Not IM!)
Initiation
Bolus then IVI
OD/BD
Uses of UFH & LMWH
Prevention of Thrombo-embolism
Peri-operative: LMWH low dose
Immobility: CCF, frail or unwell patient
Used to cover for risk of thrombosis around times of operation in those normally on warfarin but who have stopped it for the surgery, as quick offset time allows its cessation if bleeding
Treatment
n
DVT/PE and AF
n
n
Administered prior to warfarin-quick onset to cover patient whilst warfarin loading is achieved LMWH often used unless fine control required
Acute Coronary Syndromes
Reduces recurrence/extension of coronary artery thrombosis MI, unstable angina
Pregnancy
Can be used cautiously in pregnancy in place of warfarin
Adverse Effects of heparin ttt
Bruising/bleeding Sites
Intracranial
Injection sites Gastrointestinal loss Epistaxis
Thrombocytopenia (HIT)
Autoimmune phenomenon (usually 1-2 weeks of Rx) May bleed or get serious thromboses Heparin and PF4 on platelet surface are immunogenic – immune complexes activate more platelets, release more PF4, forms more IgG and complexes, leads to depletion of platelets, thrombosis Platelets <100 (or a 50% reduction) Lab assay for these antibodies Stop heparin, add hirudin
Osteoporosis
Mechanism of action of hirudin
Inhibit factor 2 ( thrombin )
Reversal of Therapy of heparin
Protamine sulphate
Dissociates heparin from anti-thrombin III Irreversible binding to heparin Allergy/Anaphylaxis
Stop Heparin If actively bleeding, give Protamine Monitor APTT if unfractionated
Anti-platelet Drugs
Give examples
Aspirin n COX-1 inhibition
Dipyridamole
Phosphodiesterase Inhibitors
Clopidogrel n ADP antagonists
Glycoprotein IIb / IIIa Inhibitors
Phosphodiesterase Inhibitors give examples
Dipyridamole
ADP antagonists antagonist
Clopidogrel
G IIb / IIIa Inhibitors
Give examples & mechanism of action
Abciximab, tirofiban, eptifibatide
Decreases platelet crosslinking by fibrinogen
P2Y12 antagonist
Give examples
Clopidogrel, prasugrel, ticagrelor blocks P2Y12
P2Y12 receptor decreases cAMP via Gi
What is the effect of PGI 2 increases
PGI 2 increases cAMP reduces aggregation
Glycoprotein IIb/IIIa Receptor Antagonists
Uses
High risk ACS
Post PCI (Increases bleeding complications but decreases acute thrombosis and restenosis
