L18 - L25 Flashcards
Beta Blockers Action in Heart
- BB block B1 receptors in heart. meaning NA/A have less effect to increase heart rate.
- slows SA node, slowing heart rate allowing LV to fill completely before contraction. easing workload
- vascular smooth muscle has B2 receptors which increase cAMP in lungs leading to dilation. blocking B2 leads to constriction of airways which is why BB is contra in asthma patients
B1 Adrenergic Receptor as a Target
-interactions between NA and B1
interactions between NA and B1 receptor include:
- charged amine (+) forms ionic bond with aspartic acid at terminal 3
- aromatic ring binds phenylalanine at terminal 6 in pi bond
- hydrogen bonding at catacholhydroxyls & serene amino acids at TM1
- alkyl groups between wedge OH & amine promote alpha selectivity
Beta Blocker Development
- Propranolol (non-selective BB causes dizziness)
- developed by increasing chain link from benzene to amine
- reduced the lipophilicity to reduce CNS side effects
- it forms a hydrogen bond at specific site absent from B2 to increase B1 selectivity
Practolol & Bisoprolol
- most selective beta blocker
Proctolol - serious liver damage
- separated amide from aromatic ring giving increased selectivity
Bisoprolol
very selective yet still binds to B2 sometimes
- ratio of 1/70
- occupies lipophilic pocket in B1 which isnt in B2
Selectivity of Steroid Hormones
- Adrenaline / Noradrenaline / Isoprenaline
All more selective to Beta adrenoreceptors.
- NA more useful at B1 than iso
Catechol Group = aromatic ring with 2 hydroxyls next to each other
- wedged OH R config is more potent than S. amide can also gain charge
IV Injection vs Infusion
Injection
- 1mm or less
- rapid increase in drug plasma concentration
Infusion
- up to a few litres
- generates steady state
Areas for IV Administration
- Central line
- Intra-arterial
Central Line
- for high toxicity drugs (anti-cancer drugs)
- rapid dilution in large volume of drug
Intra-arterial
- much greater risk
Intracardiac
- greatest risk only done in life-threatening situations
Injection types
- Intra-dermal
- Subcutaneous
- Intramuscular
- Intra-articular
ID - skin
- volume up to 0.2ml, slow absorption, long delivery
- typically used for vaccines
SC - injected to fatty tissue
- 1ml volume of aqueous solution/suspension
- faster absorption because well vascularised
IM - buttocks/thighs/shoulders
- up to 4ml
- slower systemic absorption than SC
IA - aqueous solution/suspension
- synovial fluid of joint cavities
- anti-inflammatory drugs to treat arthritic conditions
Injection Types
- Intraspinal
Intrathecal - up to 10ml
- only aqueous solutions
- potential to avoid BBB
Epidural
- injection into epidural space
- requires anaesthesia
Chronotropic Control
Sympathetic & Parasympathetic Fibre Action
- NA
- ACh
Sympathetic
- NA activates B1 in heart, increasing permeability of nodal cell plasma membrane to NA2+ & Ca2+
Parasympathetic
- ACh activates M2 muscarinic receptors , to increase permeability to K+ and decreasing permeability to Na2+ and Ca2+
Vagal Nerve
- stimulates ACh release
- ACh and parasymp innervation stimulates opening of K+ channels
- allowing efflux of potassium to lower membrane potential and slow the upstroke
Mechanisms For Heart Arrythmia
- absolute refractory period - 250ms in myocytes
- abnormal impulse conduction
- abnormal automaticity
- re-entry arrythmia
- Arrythmia is when heart beats irregularly because of abnormal electrical activity
Use for CCB and SCB
CCB Use
- SA and AV node are slow conductors , using calcium channels for action potential upstroke
- blocked by CCB
- CCB in vessels stops calcium entering cells , reducing contraction
SCB Use
- atrium and ventricular cells are fast conductors , using sodium channels for ap upstroke
- blocked by sodium channel blockers SCB
Ventricular Cells Action Potential Phases
- resting at -90mV
Phase 0 Depolarisation
- at -70mV voltage gated sodium channels open, resulting in influx and fast rise
Phase 1 Repolarisation
- Na+ channels close & voltage gated K+ channels open, K+ leaves a little to decrease membrane potential
Phase 2 Plateau
- voltage gated L-type calcium channels open due to depolarisation & balances out K+ efflux (causes contraction )
Phase 3
- Ca2+ channels close & K+ efflux dominates, reducing potential to baseline (large efflux)
Phase 4 Return to Resting
- negatic intracellular (90mV) at rest
Action Potential of Nodal Cells
- phase 4 , phase 0 , phase 3
Phase 4 Slow Depolarisation
- Na+ enters at -60mV. at -50mV, T-type Ca2+ opens causing gradual depolarisation
Phase 0 Depolarisation
- depolarisation of Ca2+ influx through voltage gated L-type channels
Phase 3 Repolarisation
- L-type Ca2+ channels close , voltage gated K+ channels open and efflux of K+ is priorities
Classification Of Anti-Arrhythmic Drugs
- Class I (rhythm control)
affect upstroke of action potential by slowing depolarisation - affects phase 0
- Sodium Channel Blockers
- targets Phase 0 depolarisation in Ventricular cells or Nodal cells
IC - flecainide.
- majorly inhibits membrane responsiveness to electrical impulses, slowing rate
Classification of Anti-Arrhythmic Drugs
- Class II (rate control)
Blocks effects of catecholamines at B1 receptors , reducing Ca2+ influx
- decreasing SA & AV node conduction & contractility
- NA opens sodium + Ca2+ channels, BB block this
- decreases sinus rate
- Beta Blockers (metoprolol, propranolol)
- affects Phase 4
Classification Of Anti-Arrhythmic Drugs
- Class III (Rhythm Control)
Amiodarone & Sotalol
- Potassium Channel Blocker, delaying repolarisation
- has slight Na & Ca channel inhibition effects and blocks beta & alpha receptor selectivity
- blocks potassium channels in phase 3 repolarisation
- very long half life 42days
- works primarily on phase 3 but has effects on phase 0, 1 & 2
Classification of Anti-Arrhythmic Drugs
- Class IV (rate control)
Targets AV/SA node conduction & affects contractility so prolongs upstroke. blocks Ca2+ channels phase 4
- CCBs’ (verapamil, diltiazem)
Verapamil: slows nodal depolarisation at phase 4 (first stage for nodal cells AP)
- decreases contraction force too
Digoxin Treatment
- digoxin increases Ca2+ stimulating K+ channels to shorten action potential and refractory period
- digoxin exerts positive inotropy effect by binding & inhibiting Na/K ATPase in myocyte membrane
- causes increase in intracellular Na+ and Ca2+ due to Na/Ca antiport : stronger contraction
- Na/Ca pump takes sodium out, bringing Ca2+ in
- only used in Heart Failure with Arrhythmia
Atropine
- reduces effect of excessive vagal activation on heart
- negative inotropic effect
- reduces rate of firing
- reduced conduction velocity
Atrial Fibrillation
- Definition
- Risk Factors
AF is supraventricular tachycardia characterised by disorganised electrical activity
- no significant atrial depolarisation - no P-wave
Risk Factors
- HTN, ACS, CAD, hyperthyroidism, lung diseases, viral infections
Symptoms
- dyspnoae, dizziness, palpitations, tiredness, chest discomfort
- need to confirm with ECG (lack of Pwave)
Diagnosing AF
- ECG
- Holter monitor
- Loop recorder (records arrhythmic function
Blood results to rule out underlying conditions
- diabetes, hyperthyroidism, anaemia
Thromboembolic Risk Assessment
- CHADSVAS score
>/= 2 should be offered ac DOAC
- measures need for anticoagulation
C - chronic heart failure 1p
H - hypertension 1p
A - age >65 1p, >75 2p
D - diabetes 1p
S - stroke/TIA 2p
Va - vascular disease 1p
S - gender female 1p
