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Yr 1 Sem 2 > Drugs - hypertension onwards > Flashcards

Drugs - hypertension onwards Flashcards

1
Q

Hypertension causes

A

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

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2
Q

Calcium channel blockers

A

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

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3
Q

Drug name hints

A

ACEIs - pril
ATII antagonists/ARBs - artan
CCB - dipine
B blockers - olol
a blockers - zosin

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4
Q

RAAS

A

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.
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5
Q

ACE inhibitors

A

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)

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6
Q

Angiotensin II antagonists (ARBs)

A

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.

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7
Q

Aliskiren

A

Inhibits renin

But can cause kidney problems, strokes + hypotension.
Not on NICE care pathway.

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8
Q

Diuretics

A

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.

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9
Q

Thiazides

A

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)

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10
Q

Loops

A

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)

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11
Q

Potassium sparing

A

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

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12
Q

Alpha blockers

A

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

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13
Q

Beta blockers

A

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)

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14
Q

Unwanted effects in adrenoreceptor antagonists

A
  • 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

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15
Q

Beta blockers in diabetes

A

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)

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16
Q

1st line treatment for if >55 or of African heritage

A

CCB

2nd line treatment to add ACEI/ARB or diuretic

4th line treatment is spironolactone or adrenoreceptor antagonist

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17
Q

Terminology of BNF

A

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

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18
Q

Catecholamines

A

NTs w/ benzene ring + 2 OH groups, normally involved in fight of flight response

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19
Q

Coronary artery vs coronary heart disease

A

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

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20
Q

Jerry Morris

A

Established link between exercise + CV health

1953 study in bus drivers vs conductors

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21
Q

Lipid transport + metabolism

A

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

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22
Q

LDL/VLDL vs HDL

A

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

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23
Q

Hyperlipidaemia & familial hypercholesterolaemia

A

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

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24
Q

Atheroslcerosis

A

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
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25
Q

Statins

A

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

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26
Q

Ezetimibe

A

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

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27
Q

Anion exchange resins

A

Binds bile acid in gut + stops reabsorption -> increased usage of cholesterol by liver

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28
Q

Fibrates

A

Agonists at PPARa (nuc. hormone receptor), used in patients w/ high VLDL

Tendency to produce muscular problems

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29
Q

Nicotinic acid

A

Vit B3 - mechanism poorly understood, needs to high dose

More problems than statins.

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30
Q

Fish oils

A

Cold water fish rich in polyunsaturated f. acids (Omega 3 in herring)

Reduces plasma triglycerides, increases cholesterol.
BUT reduces platelet aggregation + reduces fibrinogen

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31
Q

Olestra

A

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.

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32
Q

Stable vs unstable angina

A

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

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33
Q

Treatment for angina

A
  • 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

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34
Q

Organic nitrates

A

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

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35
Q

How do organic nitrates reduce cardiac workload?

A
  1. 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
  2. large nitrate dose causes arteriolar dilation - less peripheral resistance, reduction in cardiac afterload (less work to push blood out)
  3. improved coronary blood supply by dilating collateral vessels, more blood to myocardium
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36
Q

Long acting nitrates

A

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

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37
Q

Nicorandil + beta blockers for angina treatment

A

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.

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38
Q

CCBs for treating angina

A

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

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39
Q

Surgery to treat stable angina

A

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

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40
Q

Acute coronary syndrome

A

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

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41
Q

Thrombosis + embolism

A

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

42
Q

Coagulation cascade

A

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
43
Q

Heparins

A

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
44
Q

Clinical uses + problems w/ heparin

A

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)

45
Q

Warfarin

A

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.

46
Q

Warfarin problems

A
  • 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)
47
Q

Direct acting oral anticoagulants

A

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

48
Q

Platelet formation

A

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
49
Q

TxA2 (thromboxane) & prostacyclin

A

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.

50
Q

Cyclooxygenase (COX)

A

Many isoforms coded by different genes,
Humans have 3:
1. COX1 - most cells, synthesis of TxA2 + prostacyclin

  1. COX2 - inflamed tissues, target of non-steroidal anti-inflam drugs (NSAIDs) like ibuprofen.
  2. 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.

51
Q

Aspirin

A

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

52
Q

Clopidogrel + Ticagrelor

A

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)

53
Q

Dipyridamole

A

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

54
Q

Thrombolytic drugs

A

‘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

55
Q

Dysrhythmia

A

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)

56
Q

5 dysrhythmia mechanisms

A

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

57
Q

Re-entry circuits

A

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

58
Q

After depolarisations

A

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

59
Q

Atrial fibrillation

A

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

60
Q

Paroxysmal supraventricular tachycardia (PSVT)

A

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.

61
Q

Ventricular fibrillation

A

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.

62
Q

Heart block

A

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

63
Q

Wolff-Parkinson- White syndrome

A

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.

64
Q

Vaughan Williams classification system

A

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

65
Q

Class I VW (Na+ channel blockers)

A

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

66
Q

Class II VW - B blockers

A

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

67
Q

Class III VW - K+ channels

A

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

68
Q

Class IV VW - L type Ca2+ channels

A

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

69
Q

Grapefruit drug interactions

A

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

70
Q

Adenosine for dysrhythmias

A

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

71
Q

Digoxin for dysrhythmias

A

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

72
Q

Atropine for dysrhythmias

A

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.

73
Q

Surgery for dysrhythmias

A

Ablation used to correct range of dysrhythmias - PSVT + WPW
BUT risk so not 1st line treatment

74
Q

Electrical methods for dysrhythmias

A

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

75
Q

ERG + complications

A

‘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)

76
Q

COPD

A

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

77
Q

Asthma

A

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.)

78
Q

Airways in asthma

A

Basement membrane thickens. Hypertrophy + hyperplasia in smooth muscle, mucus plugging due to more goblet cells so decrease in lumen size

79
Q

Immune system allergic asthma

A

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.

80
Q

Asthma attacks

A

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)

81
Q

Anti-asthma drugs

A

Bronchodilators (relievers) - B2 adrenoceptor agonists, theophylline, mAChR antagonists, leukotriene antagonists

Anti-inflam (preventers) - glucocorticosteroids, monoclonal antibodies

82
Q

B2 adrenoceptor agonists

A

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

83
Q

Short acting B-agonists (SABAs)

A

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
84
Q

Long acting B-agonists (LABAs)

A

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

  1. v lipophilic so dissolves in bilayer, forms reservoir that leaks out + activates receptor
85
Q

Routes of administration for anti-asthma drugs

A

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.

86
Q

Glucocorticoids in asthma

A

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.

87
Q

Side effects corticoids

A

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)

88
Q

Reducing glucocorticoid side effects

A

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

89
Q

Adrenal steroid synthesis control + HPA

A

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

90
Q

Leukotriene receptor antagonists (LTRAs)

A

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

91
Q

Muscarinic receptor antagonists

A

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

92
Q

Theophylline

A

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.

93
Q

NICE omalizumab

A

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.

94
Q

Stroke

A

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.

95
Q

Tissue plasminogen activator (TPA)

A

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.

96
Q

What happens in brain during stroke?

A

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)

97
Q

Excitotoxicity in strokes

A

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.

98
Q

Reperfusion injury

A

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.

99
Q

Current treatments for stroke

A

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)

100
Q

Cytokines in strokes

A

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.

101
Q

IL-1Ra

A

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

Yr 1 Sem 2 (5 decks)

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