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Pharmacology 4
Cardiovascular
Anti-hypertensives
- central
- reserpine
- Vesicular Monoamine Transporter (VMAT) inhibitor - lowers levels of catecholamines
- rarely used antihypertensive and antipsychotic
- methydopa
- indirect alpha 2 agonist: metabolised to alpha-methyl-noradrenaline
- nasal congestion!
- clonidine
- via alpha 2 agonism
- also inhibits ADH release
- trimetaphan
- non-depolarising competitive antagonist at nicotinic receptors
- T 1/2: 2 mins
- ‘rrrrrrr CMT is bad!’
- heart
- renal
- diuretics
- osmotic
- mannitol
- also reduces CSF production
- glucose
- urea
- carbonic anhydrase inhibitors
- acetazolamide
- reduce HCO3- reabsorption
- metabolic acidosis
- weak diuresis
- loop
- inhibit Na/K/2Cl co-transporter in thick ascending limb
- furosemide
- cause hypokalaemic, hypochloraemic metabolic alkalosis
- actively secreted into the PCT
- thiazide
- inhibit Na/Cl co-transporter in early DCT
- bendroflumethiazide
- metolazone (thiazide-like)
- (also cause K loss due to increased aldosterone production in response to hypovolaemia)
- K sparing
- spironolactone
- amiloride, triamterene
- Na channel blocker in DCT
- xanthines
- caffeine
- aminophylline
- Non-selective phosphodiesterase inhibitor
- Non-selective adenosine receptor blocker
- vasopressin inhibitors
- others
- renin inhibitors
- vasculature
- alpha blockers
- Ca channel blockers
- ACE inhibitors
- SE’s
- renal failure
- reduce efferent arteriole tone, so can reduce GFR
- BUT also slow progression of HTN or diabetic CKD
- build up of bradykinin
- hyperkalaemia
- CI's
- renal artery stenosis
- pregnancy
- ARB’s
- K channel activators
- diazoxide
- increases renin and aldosterone —> reduces UO
- vasodilation
- opens K channels on beta cells —> reduced insulin secretion
- minoxidil
- direct
- hydralzine
- reflex sympathetic stimulation
- used in pregnancy
- mainly causes arteriolar vasodilation
- Nitrates
- GTN
- converted to NO, which activates cytoplasmic guanylate cyclase in vascular smooth muscle cells, causing vasodilation
- BA: 3%, due to extensive 1st pass metabolism (avoided w. S/L administration)
- Sodium nitroprusside
- Inorganic complex
- uses
- hypertensive crisis
- aortic dissection
- LVH
- intra-operative hypotension
- MOA
- reacts with sulphydryl groups in smooth muscle, (MAINLY VENOUS) membranes to inhibit Ca influx
- Effects
- Increased intracranial pressure
- Widespread vaso and venodilation
- Impaired HPV
- Impaired GI motility
- Metabolism
- Enter rbc's and are hydrolysed to form NO, metHb and 5 CN-
- one CN- combines with met Hb to form cyanometHb (non-toxic)
- other 4 enter plasma
- 80% react w. the sulphydryl groups on thiosulphate (catalysed by hepatic rhodanase) to form thiocyanate (100x less toxic) —> excreted in urine (T1/2 2 days)
- 20% react with hydroxycobalamin (B12) to form cyanocobalamin (non-toxic) —> excreted in urine
- Thiocyanate can be converted back to CN- by thiocyanate oxidase in rbc's
- toxicity
- CN- combines with cytochrome C oxidase and impairs aerobic metabolism
- Tx
- dicobalt edetate
- sodium thiosulphate
- provides sulphydyrl groups for formation of thiocyanate
- amyl nitrates
- promotes metHb formation to help form cyanometHb
Cardiovascular Contd…
anti-arrythmics
- Vaughan-Williams
- I: Sodium channel blockers
- prolong phase 0 in myocytes
- A
- middle Na channel blockade
- also lengthens AP and ERP (effective refractory period) (likely due to K channel activity)
- also anticholinergic
- procainamide, disopyramide, quinidine
- B
- weakest Na channel blockade
- also shortens AP and ERP (likely due to K channel activity)
- lidocaine, phenytoin, mexiletine
- C
- strongest Na blockade
- no effect on AP or ERP
- flecainide, propafenone
- II: Beta-blockers
- prolong phase 4 in pacemaker cells
- III: Potassium channel blockers
- prolong phase 3 in myocytes
- IV: Calcium channel blockers
- prolong phase 0 in pacemaker cells
- classes
- I (phenyl alkyl amines)
- potent negative inotropy and chronotrophy (more cardioselective)
- verapamil
- racemic
- synthetic papaverine derivative
- fully absorbed but extensive 1st pass metabolism: BA = 15%, PB 90%
- do not use with beta blockers
- additive bradycardia, risk of AV block, reduced inotropy
- II (dihydro pyridines)
- reduces vascular smooth muscle tone, may cause reflex tachycardia (more vascularly selective)
- nifedipine
- reduces coronary and peripheral artery tone
- nimodipine
- more lipid soluble, so crosses BBB and used for vasospasm
- amlodipine
- longer acting than nifedipine
- III (benzo thiazepines)
- negative inotropy without reflex tachycardia (more cardioselective)
- diltiazem
- ‘PV-DAB’D’
- others
- digoxin
- cardiac glycoside
- actions
- DIRECT: reduces activity of Na/K ATPase pump, increasing intracellular Na, therefore reducing Na/Ca exchange and increasing intracellular Ca
- competes w. K for binding site, so more SE’s w. hypokalaemia
- INDIRECT: increases vagal activity
- ECG (LSDSU)
- long PR
- ‘Salvador Dali’ sagging ST
- dipping/biphasic/flat T wave + depression of J point
- short QT
- U waves
- don’t indicate toxicity, just that pt is on digoxin
- PK
- T1/2: 35 hours
- exc. mainly unchanged
- antidote
- amiodarone
- REDUCES RENAL CLEARANCE OF DIGOXIN
- C: benzofuran derivative
- U: SVT’s, VT’s, WPW
- P: tablet or solution for mixture w. 5% dextrose
- A: mainly class III, but also I, II and IV
- D: IV - 5mg/kg over an hour then 15mg/kg over 24 hrs, 200mg TDS —> 200mg OD
- Side effects (BITCHP)
- Bradycardia + blue man syndrome
- Interstitial lung disease
- Thyroid problems
- Corneal microdeposits
- Hepatic problems + hypotension
- Peripheral neuropathy + photosensitivity
- kinetics
- adenosine
- natural purine nucleoside
- acts on A1 adenosine receptors in the SA and AV nodes
- open K channels, hyper polarising myocardium, reducing opening of voltage gated Ca channels
- PK
- contraindicated
- asthma
- sick sinus syndrome
- 2nd and 3rd degree HB