Drugs - hypertension onwards Flashcards
Hypertension causes
Primary (essential/idiopathic) - causes unknown, obesity, insulin resistance, high alcohol/sodium + genetic factors all involved.
Secondary - identified cause e.g. polycystic renal disease, renal artery stenosis, phaeochromocytoma
Calcium channel blockers
1st line treatment NICE pathway.
Targets L(1.1-1.4) type Ca2+ channels (heart + vascular smooth muscle)
Smooth muscle controlled by sympathetic NS, noradrenaline determines arteriole resistance.
opening L type channels -> Ca2+ influx -> contraction increasing BP
If blocked then reduced BP as resistance arterioles undergo vasodilation
vascular drugs are dihydropyridines - nifedipine, amlodipine
cardiac drugs - diltiazem, verapamil
Drug name hints
ACEIs - pril
ATII antagonists/ARBs - artan
CCB - dipine
B blockers - olol
a blockers - zosin
RAAS
Provides slow compensatory control of BP - responds to symp NS + decreased blood flow to kidney
Angiotensinogen (+renin) -> Angiotension I (+ACE) -> Angiotensin II
Angiotensin II acts via GPCR, binds AT1R which stimulates aldosterone secretion from adrenal cortex -> vasoconstriction
- Renin secreted by j. aparatus into circulation, has global control -> stimulated by adrenaline, prostacyclins, decreased Na+ in distal tubule + decreased BP in kidney.
- Angiotensinogen produced + secreted by liver.
- ACE found in many tissues, produced locally in angiotensins.
ACE inhibitors
Stop angiotensin I (10mer)-> angiotensin II (8mer) conversion.
Stops aldosterone production + causes vasodilation.
e.g. lisinopril, captopril (from venom of Brazilian pit viper)
Can cause hypotension + cough (bradykinin build up)
Angiotensin II antagonists (ARBs)
Receptors are GPCRs: AT1R for vascular effects, AT2R for growth + development.
Antagonists to AT1R: iosartan, candesartan.
Can cause hypotension but no cough.
Can also be used for heart failure, after heart attack, if centrally active then can be for Alzheimer’s.
Aliskiren
Inhibits renin
But can cause kidney problems, strokes + hypotension.
Not on NICE care pathway.
Diuretics
Diuresis - increased urine output, intravascular salt + water depletion decreasing BP short term.
Increase excretion of Na+, Cl- & water, closer to glomerulus diuretic acts the greater the max effect.
The decreased Na+ -> reduced Ca2+ entry so arterial dilation.
Long term effects against hypertension.
Thiazides
Class of mild/moderate diuretics.
Block cotransport Na+Cl- out distal convoluted tubule, lower osmotic gradient -> less water reabsorbed by tissues in nephron.
e.g. bendroflumethiazide, chlortalidone.
Can be used for oedema from heart failure, hypertension (diuresis then vascular effect long term)
Loops
Most powerful diuretics (10 litres urine per day)
Block NaCl transport in ascending limb -> water cannot move out of descending limb as no osmotic gradient.
e.g. furosemide, bumetanide -> inhibits Na/K/2Cl cotransporter
Used for heart failure, pulmonary oedema, renal failure + hypertension.
Can cause hypokalaemia (as well as thiazides)
Potassium sparing
Class of weak diuretics usually used in combination.
Decrease Na+ movement so decrease -ve lumen potential so less K+ lost.
e.g. spironolactone is aldosterone antagonist at mineralcort. receptors so blocks Na+/K+ ATPase formation
e.g. amiloride blocks ENaC sodium channels in luminal mem.
Spironolactone used for hyperaldosteronism - caused cirrhosis or conn’s syndrome
Alpha blockers
Antagonists on a1 adrenoreceptors -> stop visceral smooth muscle contraction (cause vasodilation)
e.g. doxazosin dilates arterioles + veins
Can cause postural hypotension, relaxation of bladder neck
Beta blockers
Antagonists at B1 adrenoreceptors that control heart rate + force of contraction.
e.g. propranolol non selective comp. antagonist, very lipid soluble so good penetration of CNS
e.g. atenolol + bisoprolol have greater selectivity (bisoprolol most), more water soluble (atenolol most)
Unwanted effects in adrenoreceptor antagonists
- bronchoconstriction
- cold extremities
- precipitation of cardiac failure
- glucose control (mask hypoglycaemia warnings in diabetes)
- CNS effects (vivid dreams), propranolol
drugs w/ high potency at B1 + low potency at a1 are cardio selective beta-blockers
Beta blockers in diabetes
Hypoglycaemia -> sympathetic NS activation (increased HR). Glucose release controlled by B2 adrenoreceptors.
SO if blocked then no warning sign + no glucose release - can cause coma
Phenoxybenzamine is irreversible a-adrenoreceptor antagonist - used for removal of phaeochromocytomas (release dangerous levels of adrenaline if removed by surgery)
1st line treatment for if >55 or of African heritage
CCB
2nd line treatment to add ACEI/ARB or diuretic
4th line treatment is spironolactone or adrenoreceptor antagonist
Terminology of BNF
Indications - what drug used for
Cautions - risk factors associated w/ drug
Contra-indications - conditions that mean drug should not be prescribed
Side effects - unwanted effects
Catecholamines
NTs w/ benzene ring + 2 OH groups, normally involved in fight of flight response
Coronary artery vs coronary heart disease
Artery - how plaque builds up in artery, viewed w/ coronary angiogram
Heart - angina/heart attack, consequences of plaque build up
Heart attack + angina cost £6.7. billion to economy
Jerry Morris
Established link between exercise + CV health
1953 study in bus drivers vs conductors
Lipid transport + metabolism
Lipoproteins transport lipids in plasma: HDL, LDL, VLDL, chylomicrons
Hepatocytes synthesise cholesterol -> bile acids which emulsify fats. Chylomicrons then transport cholesterol + fats to tissues - taken up by lipoprotein lipase.
Liver makes:
VLDL - delivers fats to tissues via conversion to LDL (delivers cholesterol)
HDL - takes up cholesterol from tissues, delivers to VLDL
LDL/VLDL vs HDL
LDL + VLDL - bad cholesterol, involved w/ fatty streak formation, inhibits fibrinolysis, activates platelets
-> increased risk atherosclerosis
HDL - increases fibrinolysis, increases prostacyclin formation (decrease aggregation)
-> high HDL/LDL lowers atherosclerosis risk
Hyperlipidaemia & familial hypercholesterolaemia
Hyperlipidaemia - too much lipid in blood, classified according to disturbance in lipoproteins
FH - mutation in LDL receptor or ApoB protein, autosomal dominant, treated w/ statins + other drugs
-> if homozygous then severe childhood CHD
-> if heterozygous then CVD by 30-40 yrs
Atheroslcerosis
Foam cells from plaque, originally from macrophage cells -> chronic inflammatory condition
- monocytes migrate to intima, converted to macrophages.
- excess LDLs enter intima + oxidised, take up by macrophages forming foam cells
- foam cells release cytokines, recruit smooth muscle cells
- foam cells attach endothelium + form fatty streak stabilised into plaque s. muscle cells
Statins
Aim to reduce LDL/VLDL + increase HDL.
Statins - atorvastatin inhibits HMG-CoA reductase (rate limiting enzyme in cholesterol production, HMG-CoA -> mevalonate)
-> reduces liver cholesterol production
-> lower cholesterol means more LDL receptors, more LDL removal
-> lowers triglycerides, higher HDL
Issues:
- myositis - muscle inflam
- rhabdomyolysis - muscle breakdown can lead to kidney failure (urine dark brown)
- altered liver function tests
QRISK3 calculates risk of having heart attack/stroke
Ezetimibe
Inhibit cholesterol absorption from GI tract, targets transporter
-> reduced LDL + cholesterol
-> used in patients who cant tolerate statins
-> can be co-administered w/ statins so no synthesis or absorption
Anion exchange resins
Binds bile acid in gut + stops reabsorption -> increased usage of cholesterol by liver
Fibrates
Agonists at PPARa (nuc. hormone receptor), used in patients w/ high VLDL
Tendency to produce muscular problems
Nicotinic acid
Vit B3 - mechanism poorly understood, needs to high dose
More problems than statins.
Fish oils
Cold water fish rich in polyunsaturated f. acids (Omega 3 in herring)
Reduces plasma triglycerides, increases cholesterol.
BUT reduces platelet aggregation + reduces fibrinogen
Olestra
Fat substitute, cannot be absorbed by GI tract but behaves same way as saturated cooking fats
- lipid soluble vitamins not absorbed
- diarrhoea
- compensatory eating
anal leakage
Banned in EU + Canada.
Used in paint.
Stable vs unstable angina
Stable - most common, ath. plaque in coronary arteries is stable, triggered by exercise, excitement/stress or cold. Relived by rest
Unstable/ACS - rarer, more serious, atherosclerosis + blood clot, unpredictable triggers, not relieved by rest -> can progress to heart attack
Other angina types caused by vessel constriction/spasm
Treatment for angina
- reduce oxygen demand
- increase oxygen supply
NICE pathway: short acting nitrates relieve attack (SANs)-> beta blockers, CCB -> long acting nitrates (LANs)
Surgery can help w/ revascularisation if drugs ineffective
Organic nitrates
Must be administered via transdermal, buccal, sublingual pathways.
e.g. glycerol trinitrate (GTN) - explosive w/ vasodilatory actions (headaches)
- given in solution so it is stable
- prodrugs that must be metabolised at site of action to NO.
- NO acts on sulfhydryl groups on guanylyl cyclase -> active form.
- GTP -> cGMP, PKG activated
- results in reduced [Ca2+] -< vasodilation
Dilating coronary arteries less important -> nitrates relieve attacks by reducing cardiac work
- preload + afterload reduced
How do organic nitrates reduce cardiac workload?
- peripheral vessels dilated -> heart does not have to push so hard , less blood returned to heart (decreased mycocardium stretch so lower contraction force needed) -> preload reduced
- large nitrate dose causes arteriolar dilation - less peripheral resistance, reduction in cardiac afterload (less work to push blood out)
- improved coronary blood supply by dilating collateral vessels, more blood to myocardium
Long acting nitrates
Isosorbide dinitrate administered orally, buccally, transdermally or via IV - metabolised to mononitrate (1st pass).
Mononitrate form has better bioavailability + longer duration of action (administered via tablets)
Unwanted nitrate effects:
- flushing of skin
- headache
- postural hypotension
- reflex tachycardia
Nicorandil + beta blockers for angina treatment
Activates K+/ATP channels + NO donor, dilates arteries + veins
- similar to nitrates
Can cause headache, flushing, hypotension, nausea + vomiting
Beta blockers reduce cardiac workload, reducing O2 demand by blocking symp NS via bet adrenergic receptors.
CCBs for treating angina
Verapamil - use dependent, blocks Ca2+ channels, more potent in heart muscle
- reduces heart rate + CO
- dilation of arterioles reduces afterload
Cardiac work + O2 demand reduced
Amlodipine - voltage dependent, more potent vascular smooth muscle.
- dilates arterioles so reduces afterload
- dilation of capacitance veins reduces preload
Cardiac work + O2 demand reduced
Surgery to treat stable angina
Coronary artery angioplasty or PCI:
Catheter inserted to large vessel, threaded to blockage in heart, balloon inflated + stent keeps artery open- stent stainless steal or has anti-inflam drugs.
-> minimally invasive but can cause heart attack
Coronary artery bypass graft (CABG):
More invasive, open heart surgery, removes non-essential blood vessel from another body part - inserts it into heart to restore blood flow. Internal mammary artery or great saphenous vein commonly used.
Can make multiple new connections.
-> grafts may need to be replaced, dysrhythmias, blood loss, poor healing, embolisms/debris from surgery can cause heart attack/stroke
Acute coronary syndrome
Disorders characterised by severe pain from left arm + jaw, not relieved by rest:
- Unstable angina, no blood markers
- NSTEMI: non-ST elevated myocardial infarction, blood markers
- STEMI: ST-elevated myocardial infarction (most serious)
-> Can use ECG to classify
Treatments:
- opioids for pain
- reduce cardiac workload (B-blockers, GTN)
- prevent further thrombosis (antiplatelets, atorvastatin)
- reperfusion: PCI, CABG, thrombolysis
Thrombosis + embolism
Clotting necessary for haemostasis -> prevents blood loss.
Thrombosis is pathological -> DVT, embolism, stroke + heart attack.
Fibrin traps platelets + attaches to vessel wall impeding blood flow.
Venous thrombosis - coagulation major role
Arterial thrombosis - platelet aggregation more important
Embolus is whole thrombus detached + travels through vessels until reaches small vessel in pulmonary, cardiac or CNS circulation
Coagulation cascade
Thrombin (proteolytic enzyme) converts soluble fibrinogen -> insoluble form.
- active thrombin formed by cleavage of prothrombin by factor Xa
- factor Xa activated by both factors IXa & VIIa
Heparins
Naturally occurring anticoagulant. Purified from pig intestine/cow lungs.
Family of sulphated mucopolysaccharides, in liver, lungs + mast cells. Repeating group w/ high negative charge.
- inhibits thrombin + factors Xa & IXa
- requires antithrombin III (endogenous protease inhibitor)
- ATIII normally inactivates thrombin so fibrin not formed
LMW heparins shorter + only affects factor Xa. Immediate action + lasts longer e.g. enoxaparin
- reduces aggregation
- reduces platelet numbers
- releases lipoprotein lipase influencing metabolism
Clinical uses + problems w/ heparin
Venous thrombosis/embolism, after heart attack/stroke, reduce risk of DVT.
Fondaparineux is synthetic LMW heparin.
Problems:
- poorly absorbed from oral administration
- allergic reactions
- individualised doses
- haemorrhage risk (can add protamine to prevent this)
Warfarin
From dicoumarol - potent inhibitor of clotting cascade.
- used as rat poison
Antagonist for vit K reductase so reduced vit K not recycled.
- factors II (prothrombin), VII, IX & X not formed
- y-carboxylation of precursors by reduced vit K prevented
- precursors inactive, cant promote coagulation
Used in venous thrombo-embolism, prevention of stoke for those w/ atrial fibrillation, after heart valve replacement.
Warfarin problems
- slow onset
- activity influence by vit K
- S isomer 5x more potent
- risk of haemorrhage
- teratogenic so risk to pregnancy
- interacts heavily w/ other drugs (enzyme induction/inhibition)
Direct acting oral anticoagulants
Dabigatran directly inhibits thrombin.
Rivaroxaban inhibits factor Xa.
Prevents stroke in patients w/ atrial fibrillation.
Don’t require patient monitoring.
Hirudin is 65 a. acid peptide (leeches) attaches thrombin blocking its ability to form fibrin - cant be extracted.
-> bivalirudin (20. a.acid) is synthetic analogue, competitive inhibitor of thrombin, more selective than heparin
Platelet formation
Derived from megakaryocytes (bone marrow), fragments of cytoplasm w/ no nucleus, have glycoprotein receptors.
Receptors bind collagen when vessels damaged -> activation + aggregation.
- structure change to spiky sea urchin state
- TxA2 + ADP mols released & attach nearby platelets
- GpIIb/IIa also activated -> aggregation
ADP binds P2Y (Gi GPCR), decreases cAMP increasing platelet activation
- can also be caused by thrombin
TxA2 (thromboxane) & prostacyclin
TxA2:
Synthesised from arachidonic acid by cyclo-oxygenase.
- binds Gq GPCRs (increase in intracellular Ca2+)
Activates neighbouring platelets by increasing active GpIIb/IIIa.
-> GpIIb/IIIa binds fibrinogen + forms linker between platelets
Prostacyclin:
Inhibits platelet activation + produced by in tact endothelium.
Shares similar formation pathway w/ TxA2.
- binds Gs GPCRs (increase cAMP)
Prostaglandin H2 is branchpoint in pathway: acted on by COX or peroxidases.
Cyclooxygenase (COX)
Many isoforms coded by different genes,
Humans have 3:
1. COX1 - most cells, synthesis of TxA2 + prostacyclin
- COX2 - inflamed tissues, target of non-steroidal anti-inflam drugs (NSAIDs) like ibuprofen.
- COX3 has frameshift mutation so no active enzyme.
NSAIDs side effects: GI tract ulcers due to action on COX1 & 2.
Coxibs selective for COX2 so no GI tract issues but higher risk of CV problems.
Aspirin
Irreversibly blocks COX enzyme, reducing TXa2 synthesis.
Low doses so prostacyclin still produced. Alters PGI2 and TxA2 balance, COX replaced as they have nucleus
Can cause:
- extended bleeding time
- indigestion
- allergy (rare)
- provoke asthma attacks
- Reye’s syndrome (u16s), used during viral illness
Clopidogrel + Ticagrelor
Clopidogrel - inhibits GpIIb/IIa receptor expression in platelets by blocking ADP receptors irreversibly (covalent mod)
Ticagrelor - Allosterically inhibits ADP receptor (reversible)
PLATO trial showed ticagrelor superior: 16% lower mortality rate, did not need CYP2C19 enzyme for activation like clopidogrel
Can cause:
- extended bleeding time
- GI tract issues
- headaches, dizziness
- gout + breathlessness (ticagrelor)
Dipyridamole
Inhibits phosphodiesterase (PDE3) so cAMP hydrolysis in platelets prevented, cAMP levels rise.
cAMP reduces platelet aggregation
Can cause:
* similar to aspirin
- muscle pain
- flushing (vasodilator)
- precipitates/worsens angina
-> collateral vessels not dilated, decreased blood flow to ischaemic tissue
Thrombolytic drugs
‘clot busters’
Sometimes used for heart attack, important in stroke management, administered via IV.
Plasminogen inactive precursor for plasmin, degrades fibrin in thrombus - must be cleaved for activation.
Drugs supplement tissues plasminogen activator (TPA):
- alteplase recombinant version of TPA
- reteplase slightly mutated, improved stability
- streptokinase bacterial enzyme
4.5 hr treatment window for thrombolysis
-> very rapid but also risky, requires no eqipment
Dysrhythmia
Abnormal heart beat rhythm -> too fast, too slow or irregularly.
It impairs CO.
- atrial fibrillation most common EU.
Can be diagnosed w/ ECG (runs at 25mm/sec):
P wave - atrial activation
QRS - ventricular activation
T - recovery (ventricles repolarise)
5 dysrhythmia mechanisms
1) Ectopic pacemakers - tissue elsewhere controls HR reg
2) Delayed after polarisation - Ca2+ build up means train of APs
3) Re-entry circuits - damage/abnormality means AP travels in circles
4) Congenital abnormalities - additional conducting pathways between atria + ventricles
5) Heart block - damage to conducting pathway between atria + ventricles
Re-entry circuits
Electrical signals go round in circles due to damage/abnormalities. Can be local, nodal or global (Wolff Parkinson White)
Local - transmission blocked through damaged area, but can pass opposite direction (unidirectional), retrograde transmission -> circuit
AV node re-entry tachycardia - atria echo reaches secondary pathway after refractory period -> retrograde transmission
After depolarisations
Early (EAD) - when AP is prolonged, Na+ & Ca2+ current reactivated
Delayed (DAD) - occurs when Ca2+ overloaded so spontaneously released, pumped out via Na/Ca electrogenic exchanger (3Na in/1Ca out), slight depolarisation
Atrial fibrillation
Caused by re-entry circuits or ectopic pacemakers - most common in over 80s.
Atrial rate up to 600bpm
Irregular conduction to ventricles, fatigue + palpitations. Increased stroke risk.
Risk factors: heart disease, high BP, congenital heart disorders, genetics
Paroxysmal supraventricular tachycardia (PSVT)
Re-entry circuit through AV node. Starts at young age -> can lead to ventricular fibrillation.
Vent rate is 250bpm.
Palpitations, chest pain, shortness of breath.
Attacks can be halted by Valsalva Manoeuvre.
Ventricular fibrillation
Re-entry circuits or ectopic foci, ventricles cease beating in coordinated way.
No QRS waves on ECG, sawtooth pattern - rapidly fatal.
DC shock may be only way to restore contraction.
Common complication following heart attack.
Heart block
Form of bradycardia.
Damage to AV node impairs conduction atria -> ventricles.
1st degree - slowed conduction, PQ increased, QRS for every P wave
2nd degree - miss QRS complexes
3rd degree - impulses don’t reach ventricles, ventricles/AV node take over as pacemaker
Wolff-Parkinson- White syndrome
Congenital abnormality.
Additional AV conducting pathway (Ken bundle) -> global re-entry circuit, re-entry AV tachycardia
No rate limiter in Ken bundle so v fast ventricular rate -> ventricular fibrillation.
Vaughan Williams classification system
Based on supposed site of action of antidysrhythmic agents.
Problems:
- many have multiple sites of action (amiodarone II, III or IV)
- site of action can change in disease state vs healthy tissue
- useful drugs not inc. (adenosine, digoxin, atropine)
- dysrhythmias can be treated w/ drugs from more than 1 class
Lei et al system more commonly used - 7 classes w/ subclasses
Class I VW (Na+ channel blockers)
disopyramide (1A) - moderate Na+ channel block, increases refractory period (ERP) + AP duration (APD)
-> suppresses re-entry circuits but can increase TPD risk, prevents ventricular dys + WPW.
*blocks K+ efflux
lidocaine (1B) - weak Na+ channel block decreased ERP, shortened APD, preferentially binds inactivated Na+ channels, use-dependent + fast dissociation, suppresses tachycardia
-> given IV for vent dys + after failed defib (alternative for amiodarone)
*promotes K+ efflux
flecainide (1C) - strong Na+ channel block, no change to ERP or APD, no influence on K+
Much lower dissociation rate
Class II VW - B blockers
Reduce slope of pacemaker potential + reduce force of contraction. Block increase in HR through AV node.
Atenolol - reduces automaticity, slows SA node, AV node conduction
Also bisoprolol, metaprolol.
Useful for atrial fibrillation + PSVT, prevents dysrhythmias after heart attack, used for increased catecholamine release (thyrotoxicosis)
Can cause:
- bronchoconstriction
- diabetes
- precipitation heart failure/block
- Reynaud’s phenomenon
Class III VW - K+ channels
Amiodarone acts on K+ channels (tetrameric), lipophilic + has 2 iodine residues.
K+ channel blocker, also has class II, IV + IA actions.
Repolarisation delayed so prolonged AP + refractory period.
-> slows AV node conduction velocity, decreases re-entry
Used for atrial fibrillation, ventricular tachycardias, WPW.
Administered orally or via IV.
BUT many side effects + contra-indications
Class IV VW - L type Ca2+ channels
Verapamil acts on tetrameric Ca2+ channel - CaV 1.1-1.4 (muscle), diltiazem + dihydropyridines (amlodipine only smooth muscle)
-> reduces automaticity , reduced re-entry + reduced AV node conduction velocity
Affects plateau phase of AP.
Given orally or via IV, used for PSVT or ventricular rate in atrial fib.
Side effects/contra-indications:
- WPW, bradycardia, exacerbates heart block
- headache, flushing, hypotension
- partly metabolised by CYP3A4, many drug interactions
Grapefruit drug interactions
Has furanocoumarins (bergamottin), irreversibly inhibit CYP3A4 by cov mod.
CYP3A4 vital for 30% drug metabolism.
-> cause overdose prescriptions
e.g. ritonavir, dizepam, sertraline, verapamil etc
Class III + IV VW.
Also have naringin (flavinoid) - inhibits intestinal drug transport, reducing bioavailability
Adenosine for dysrhythmias
4 GPCRs bind it. A1 is Gi.
- K(Ach) activated by Gi, K+ efflux (hyperpolarisation)
- VG Ca2+ channels inhibited
Short plasma half life, rapid uptake, given as rapid IV bolus.
Used for PSVT, vent tachycardia w/ WPW syndrome supvent tachycardias during surgery - largely replaced verapamil (rapid action)
Caffeine + theophylline are antagonists
Digoxin for dysrhythmias
From foxgloves - inhibits Na+/K+ ATPase, binds K+ binding site + stops pump functioning
Indirectly blocks Na+/Ca+ exchange as no electrochemical gradient.
- stimulates parasymp NS
- increases AV node refractory period
- increases force of contraction, slows ventricles so better filling
BUT mem potential more positive, dysrhythmias at higher doses.
Used for heart failure + atrial fibrillation
Atropine for dysrhythmias
Comp antagonist at M2 -> increases HR.
Acts via By of Gi. Hyperpolarisation stopped so less K+ efflux + Ca2+ not inhibited so can enter.
Used IV in bradycardia + some heart blocks.
Can cause:
- photophobia
- dizziness/drowsiness
- tachycardias/palpitations
Severe interaction w/ phenylephrine (hypertension), + any drug w/ muscarinic actions.
Surgery for dysrhythmias
Ablation used to correct range of dysrhythmias - PSVT + WPW
BUT risk so not 1st line treatment
Electrical methods for dysrhythmias
Cardioversion - ‘jolt’ heart beat out of abnormal rhythm + back into SA node control -> pharmacologically w/ adenosine or via synchronised electrical cardioversion
Defibrillation - non-synchronised pulse of electricity, used to restart heart from flat line ECG, AED (automated) so delivers only if patient rlly needs
Implantable cardioverter-defibrillator (ICD) - inside body if risk of life threatening dysrhythmia, electrode deliver shock if dysrhythmia detected
ERG + complications
‘ether a go go’ related gene found in drosophila
- channel that carries current needed to repolarise mem
Alterations in human ERG -> hERG mutations cause long QT syndrome
long QT can precipitate to serious tachycardia -> torsades de pointes (TDP), sawtooth ECG
can be drug induced, if drugs bind hERG channel
-> discontinuation drug development e.g. terfenadine (antihistamine)
COPD
Progressive chronic condition, narrowing airways.
Mainly inflammatory.
Combination of chronic bronchitis (persistent cough w/ mucus production) & emphysema (destruction of alveolar tissues)
1.2 million in UK
Asthma
Chronic condition where airways narrowed, occurs in attacks, mainly inflammatory.
FEV1 + PEFR used to deficit in function.
5.4 million in UK have asthma
Caused by:
- background tendency factors (genetic or early env)
- specific triggers (pollens, dust mite excretion, cold air, animal fur etc.)
Airways in asthma
Basement membrane thickens. Hypertrophy + hyperplasia in smooth muscle, mucus plugging due to more goblet cells so decrease in lumen size
Immune system allergic asthma
Dendritic APCs present antigen using MHCIIs, migrate to lymph nodes where T cells activated -> clonal expansion.
TH2 cells produce inflammatory cytokine - induce allergic response along w/ interleukins.
Cytokines also induce antibody production (IgE)
Person now sensitised.
Asthma attacks
Biphasic: early phase (bronchoconstriction), later phase (inflammation)
Mast cell activated as receptor recognise IgE antibody, degranulates releasing mediators, also produce signalling mols.
Early mediators: ACh, leukotrienes (C4, D4, E4, histamine, prostaglandin), chemotactic factors
Later mediators: leukotrienes (C4, D4, E4), interleukins, GFs + major basic protein (released from granules in eosinophils)
Anti-asthma drugs
Bronchodilators (relievers) - B2 adrenoceptor agonists, theophylline, mAChR antagonists, leukotriene antagonists
Anti-inflam (preventers) - glucocorticosteroids, monoclonal antibodies
B2 adrenoceptor agonists
B2 only present in smooth muscle, uterus + skeletal muscle. Coupled via Gs to adenylate cyclase - increase cAMP -> activates PKA.
- smooth muscle relaxation
- reduced mast cell degranulation
Adrenaline non-selective between B1 + B2 - so can modify structure so it is a better bronchodilator.
-> more selective + longer duration
1) increase size of substituent on N -> increases B2 selectivity + reduces inactivation
2) replace -OH group w/ -CH2OH, or change ring position on catechol group
Short acting B-agonists (SABAs)
Salbutamol & terbutaline.
Similar but salbutamol has -CH2OH on catechol vs terbutaline only has -OH removed on ring.
Both have extended N substituent.
- low relative lipophilicity
- administered via metered dose inhalers
Long acting B-agonists (LABAs)
Salmeterol & formoterol, last 12hrs.
Usually given in combo w/ glucocorticosteroids.
- high lipophilicity
Have long action due to:
1. terminal bit of alkylamine chain on LABA anchors mol at receptor exosite, can act repeatedly
- v lipophilic so dissolves in bilayer, forms reservoir that leaks out + activates receptor
Routes of administration for anti-asthma drugs
Metred dose inhalers (MDIs) - deliver fixed dose of drug with each press.
-> efficiency improved using spacer (else 90% drug ends up in stomach)
Nebulizers aerosolize drug solutions - patient inhales mist w/ drug. Bulkier + more expensive.
Glucocorticoids in asthma
Hydrocortisone + cortisol identical.
-> decreased expression of pro-inflam cytokines, COX2 (less prostaglandin produced)
-> increased expression anti-inflam mediators (interleukins, annexin1)
Effects are slow, effective as preventers.
Beclomethasone, budesonide + fluticasone - common in inhaler forms.
Prednisolone common in tablet form (recommended by NICE). Dexamethasone also suitable, longer duration.
MART combines fast onset LABA w/ corticosteroid in single inhaler.
Side effects corticoids
Cushing’s syndrome & oral thrush common due to immunosuppression.
- high doses glucocorticoids
- tumour, excess glucocorticoid production by adrenal cortex
Glucocorticoids have metabolic, anti-inflam + immunosuppressive effects (cortisol)
Mineralocorticoids involved in salt/water balance (aldosterone highly selective)
Cushingoid features -> moon face, buffalo hump, increased abdominal fat, poor wound healing, hypertension, osteoporosis (caused by unwanted cortisol effects)
Reducing glucocorticoid side effects
Alter selectivity - dexamethasone does not activate MCRs
Can alter duration of action (hydrocortisone + fludrocortisone short action)
SEGRAMs designed to favour transrepression pathways (fewer unwanted side effects) - occurs via monomeric GCR, not dimer like transactivation does.
-> biased agonism
Adrenal steroid synthesis control + HPA
Hypothalamus releases CRF -> anterior pituitary releases ACTH -> adrenal cortex releases hydrocortisone + corticosterone
External steroids dampen cortisol production so adrenal insufficiency of not taken -> treatment stopped in stepped way.
Steroid treatment card should be carried.
HPA axis: high cortisol levels due to impaired neg feedback common in depressive disorders.
-> glucocorticoids can cause apoptosis in hippocampus + prefrontal cortex
Leukotriene receptor antagonists (LTRAs)
PLA2 converts phospholipids -> arachidonic acid -> leukotrienes or prostanoids.
Leukotrienes produced by mast cells + immune cells, they are agonists at CysLT GPCRs, contract smooth bronchial muscle, stimulate mucus secretion.
LTRAs end in -lukast. Given orally, as add on to SABAs + glucocorticoids. They are bronchodilators.
Effective in exercise + aspirin induced asthma.
Less effect than SABAs
Muscarinic receptor antagonists
Para NS increases ACh release -> bronchoconstriction, increased mucus production.
hyoscine + atropine from thorn apple plant
-> non-selective antagonists, readily passes into systemic circulation as they are tertiary amines –> side effects
1) Ipratropium bromide is short acting antagonist (SAMA), by inhaler, quaternary amine so permanent +ve charge means not easily absorbed
2) Tiotropium bromide is long acting antagonist (LAMA), by inhalation, also quaternary ion.
Both used in asthma + COPD, not 1st line relievers though
Theophylline
Similar to caffeine - alkylxanthine class of drugs
Administered orally or via IV for life threatening acute asthma attack.
2 proposed mechanisms:
1) non-selective inhibitor of phosphodiesterase (more cAMP, bronchodilation)
2) antagonists of adenosine receptors, promote bronchodilation, but cardiac side effects
Very narrow therapeutic window, many interactions w/ other drugs.
NICE omalizumab
Omalizumab is humanised monoclonal antibody against IgE - rapidly removed from circulation once bound, do not activate mast cells.
-> acts as preventer for severe allergic asthma
BUT £26,000 per year, QUALY used + said drug not worth it.
203 allowed to over 6 yr olds due to press + patient access scheme
Max £/QUALY is £30,000.
Stroke
Reduced blood flow + O2 to the brain.
Risk factors identical to heart attack.
Symptoms: severe/sudden headache, unexplained dizziness, facial weakness, speech problems, limb weakness.
Est 2 million brain cells lost each minute.
Ischaemic - vessel becomes blocked
Haemorrhagic - blood vessel bursts, sudden or gradual
Atheroslcerotic plaque filled w/ immune cells so high risk of inflammation.
Tissue plasminogen activator (TPA)
Alleviates heart attack/stroke when administered rapidly (<6 hours after)
- can lead to full recovery as no O2 in brain releases toxins, cause more damage
Needs CT scan, if haemorrhagic stroke then TPA can stop clotting (bad)
PET imaging vital for diagnostics, looks at O2 + glucose in brain.
What happens in brain during stroke?
Cells in immediate area die (lack of O2)
Damaged neurons release toxin that can kill neighbours:
- NTs like glutamate (excitatory)
- ions (Ca2+, Na+)
- free radicals (abnormal O2 mols like superoxide)
Excitotoxicity in strokes
Energy failure as no O2 causes ion influx -> glutamate release which exacerbates effect (+ve feedback loop)
Glutamate targets NMDA + AMPA receptors + is difficult target for drugs as still need a functioning amount.
Glial cell affected: astrocytes involved in glutamate release when damaged, microglia activated when brain damaged.
Reperfusion injury
Restoration of blood flow to area preciously ischaemic by thrombotic blockade of key artery.
Dislodgement of clot -> inflammatory response + free radical formation (oxidative stress)
Disabilities post stroke:
- paralysis/motor control
- sensory disturbance
- language problems
- memory impairment
- depression + anxiety, personality change
Reparative mechanisms inc. plasticity around damaged areas, neurogenesis + angiogenesis.
Current treatments for stroke
TPA for thrombolysis, endovascular thrombectomy.
-> largely focused on brain despite vascular nature
Tackling inflammation key for treating strokes
- microglia synthesise many inflammatory mediators (cytokines, free radicals + prostaglandins)
Cytokines in strokes
Interleukins, interferons, tumour necrosis factors, GFs + chemokines.
- produced by damaged microglia, act locally, communicate between cells.
Interleukin-1 (IL-1) is master cytokine - key inflam mediator, produced rapidly in brain + major disease target.
IL-1Ra
Naturally occurring antagonist of IL-1.
IL-1 expression peripherally induces CNS responses. It targets neurones, glia + endothelial cells.
IL-1Ra studies show it can enter brain safely via blod plasma despite large size:
Small phase II - no increase in infections, reduced inflam markers
Large study - met endpoirnt of reduced inflam markers but no clinical benefit
-> dementia demonstrates raised IL-1 levels
