Flashcards in L46 – Calcium antagonist, α and β adrenergic blocking agents Deck (76):
Explain the action of Ca2+ during membrane doplarization?
membrane depolarization > Ca2+ channel undergo conformational change > Ca2+ influx down electrochemical gradient into cell
Explain the action of CCB?
Block L-type Voltage gated Ca2+ channels > decrease Ca2+ entry (down electrochemical gradient) into cell
Result of CCB on cardiac muscle and blood vessels?
CCB Decreases force of contraction and decreases vasoconstriction > decrease TPR
What specific type of calcium channel is targeted by CCBs?
High voltage activated dihydropyridine sensitive channels
2 roles of cardiac L-type voltage- gated calcium channels in cardiac myocytes?
Regulate HR (pacemaker potential at SA node and AV node conduction)
Regulate force of contraction of heart
Role of cardiac L-type voltage- gated calcium channels in vascular smooth muscle cells?
Regulate force of smooth muscle contraction
increase intracellular Ca2+ > trigger further release in stored Ca2+ > vasoconstriction
CCBs are used in which three pathological conditions?
Name of three structural classes of CCB? dbp
Name 1-2 common CCBs in each structural class?
Dihydropyridine= nifedipine, amlodipine
Which CCB class is cardiac selective?
Which CCB class is vascular selective?
How does the dosage of dihydropyridine affect its function on CVS?
Low dosage = block vascular L-type channel
High dosage = block cardiac L-type channel
How does dosage of cardiaic selective CCBs affect their function on CVS?
Cardiac selective CCB = benzothiazipine, phenylakylamine
At low dosage = cardiac selective
At high dosage = vascular selective
Why is vascular selective CCB used for treatment of angina?
Dilate coronary vessels too > relieve angina
Vascular -selective CCB may alter myocardial contractility. Why?
Not a direct effect
CCB decrease TPR, heart senses drop in resistance and adjusts to lower contractility
Why does Nifedipine cause slight decrease in HR when it is a vascular -selective CCB?
Nifedipine is not very vascular-selective > slight effect on cardiac L-type CC > decrease HR
Why does Amlodipine increase HR when it is vascular selective?
Drop in TPR > sensed by baroreceptors > stimulate sympathetic NS > reflex tachycardia > ensure sufficient blood to brain and kidney
Effect of vascular selective CCB on SA node and AV node conduction?
3 effects of vascular selective CCBs.
increase coronary flow
Increase vascular dilatation
Increase neurohormonal activation
Effect of vascular selective CCB on renal system?
due to increase in renal blood flow and intraglomerular pressure
Compare effects of cardiac selective CCBs with vascular selective CCBs?
Cardiac selective causes similar increase in coronary flow, vascular dilatation and neurohormonal activation
But also decrease in SA node, AV node conduction and HR
Which vascular selective drug causes a similar effect on HR as cardiac selective CCBs?
What are some side effects of vascular-selective CCBs on vascular dilatation?
High dosage = oedema
Mismatch in vasodilation between arteriole and venous (High Ra and normal Rv) > blood volume increase in capillary > Pc increase > increase filtration > oedema
Some side effects of cardiac selective CCBs when given in very high dosage?
Very high dosage> HR and contractility drop too much > trigger reflex tachycardia > heart failure/ arrhythmia
Apart from oedema, what are some common adverse effects of CCB?
Why is nifedipine not favored for clinical use? (think half-life...)
Short half- life (rapidly metabolized in body) > cause surges/ oscillations in BP and sympathetic reflex activity within dosage interval > increase risk of CVS damage and high frequency of admin. = low compliance
Why are sustain-release CCBs used instead of start half life ones?
Reduce adverse effect (flushing, dizziness, peripheral oedema)
Reduce fluctuations in BP
Change in TPR causes what BP change? How about change in stroke volume?
Change in TPR = diastolic increase, systolic unchanged
Change in SV = increase in diastolic + even bigger increase in systolic
Which type of hypertension is CCB best used for?
Isolated systolic hypertension - increase in systolic, normal diastolic
Which patient groups can use CCB best as hypertensive treatment?
Patients with low renin status e.g. elderly
Explain the adverse action of CCB on gastroesophageal reflux
CCBs inhibit contraction of lower esophageal sphincter > lead to gastroesophageal reflux
Which CCBs are used as anti-arrhythmic dugs?
Only cardiac selective CCBs
e.g. verapamil , diltiazem
Decrease HR, SA node and AV node conduction
Which type of arrhythmia is CCB most effective for?
Delayed-afterdepolarization (DAD)- mediated arrhythmia
CCB can reduce calcium overload
(DAD: Ca2+ accumulation exceeds storage capacity > trigger extra heart beat)
What are 2 precautions when using CCB as antiarrhythmic drug?
Caution in patients with hepatic dysfunction (increase plasma conc.)
Avoided in patients with Ventricular tachycardia
(drug can worsen hypotension > cardiac arrest)
What does a1 receptor signal?
Formation of IP3 and DAG > increase intracellular Ca2+
What does a2 receptor signal?
Inhibition of adenylyl cyclase > decrease cAMP
What do b1, b2, b3 receptors signal?
Stimulate adenylyl cyclase > increase cAMP
Name two common a-Adrenergic receptor blockers
How is Prazosin/ Doxazosin used to manage hypertension?
Both a1- Adrenergic receptor blockers > inhibit a1 adrenergic receptors in arterioles and venules > dilate arterioles and veins > decrease peripheral vascular resistance
What is the normal action of a1- adrenergic receptors?
Stimulate = vasoconstriction
General adverse effects of a1-adrenergic receptor blocker ?
dizziness, palpitations, headache
Explain the "first dose phenomenon" caused by a1- adrenergic receptor blocker.
Orthostatic hypotension (huge drop in BP from supine to upright posture)
with initial dose/ after dosage increase
because vasoconstriction from baroreceptor reflex is inhibited
What drug worsens orthostatic hypotension caused by a1 adrenergic receptor blockers?
Diuretics > hypovolemia already causes hypotension
How does the body compensate after first dose of a1 adrenergic receptor blockers?
Sympathetic nervous system compensate > increase systemic vascular resistance
Activate RAAS > Decrease renal sodium excretion > Na+ and water retention
Both compensations oppose drug action
Why is a-blocker used with diuretics and b-adrenergic receptor blockers?
Diuretics : body counteract a - blocker by salt retention > oedema
B-adrenergic receptor blocker: prevent effect of sympathetic NS on heart
Is a - blocker used as long term antihypertensive drug?
Body keeps counteracting drug > reduce efficacy
Name 3 common B-adrenergic receptor blockers
What is the normal action of B1 adrenergic receptor activation on heart?
Stimulate adenylyl cyclase > increase cAMP > enhance activity of L-type channels > increase HR and force of contraction
Which b-receptors are in vascular smooth muscle?
What is the action of B2 receptor activation and why is it different from B1?
Activate B2 > stimulate adeylyl cyclase > increase cAMP > INHIBIT myosin light chain kinase (MLCK) > reduce contraction on vascular SM > vasodilation
B2 REDUCES contraction
B1 INCREASES contraction
Explain action of B-blockers on heart?
Inhibit B- adrenergic receptors in heart > decrease rate and force of contraction > decrease cardiac output
Explain action of B-blockers on kidneys?
b-block in kidneys> decrease activation of renin production > decrease Na+ and water retention
Explain action of B-blockers on peripheral vascular resistance?
Inhibit peripheral presynaptic B-adrenergic receptors > decrease release of noradrenaline > decrease sympathetic vasoconstrictor nerve activity > decrease peripheral vascular resistance
Which 5 conditions is B-blockers used in?
Why is b-blockers not used in patients with asthma or COPD?
Inhibit B-adrenergic (esp. B2) receptors in respiratory tract > BRONCHOSPASM
Why is b-blockers not used in patients with insulin-dependent diabetes?
Inhibit B-receptor in LIVER > affect glucose metabolism > increase risk of HYPOglycaemia
Why is b-blockers not used in patients with vasospastic disorders/ severe peripheral vascular diseases?
Inhibit B- receptor in vascular smooth muscle > decrease vasodilation
Summarize 3 patients groups which B-blockers is not used in?
patients with asthma or COPD
patients with insulin-dependent diabetes
patients with vasospastic disorders/ severe peripheral vascular diseases
Which B-blocker is less likely to have adverse effects?
B1- selective receptor blockers > higher cardiac selectivity
How could B-blocker lead to arrhythmia and HF? Why is pindolol used ?
Inhibit B-adrenergic receptor in heart > decrease HR and contractility > increase risk of arrythmia and HF
Pindolol has intrinsic sympathomimetic activity > partial agonist, slight activating effect on receptor
How can B-blockers cause psychiatric depression? How to manage?
inhibit B1 and B2 receptros in CNS > CNS disturbance > depression
Less likely with B-blockers with low lipid solubility > cannot cross BBB into brain
List 3 mental effects of B-blockers?
Classify the 3 generations of B-blockers and their action.
First generation = non selective = inhibit B1 & B2
Second generation = cardiac selective = inhibit B1
Third gen. = b-blockers with vasodilating effects = inhibit a and b receptors/ B1 + release NO from endothelium
Name some first gen and second gen B blockers
First gen = propranolol
Second gen = metoprolol, bisoprolol
Name some 3rd gen drugs with diff. functions
Inhibit a & b receptors = labetalol, carvedilol
inhibit B1 + release NO = nebivolol
What are partial agonists B-blockers?
B-blockers with intrinsic sympathomimetic activity
Name some partial agonist B-blockers?
Pindolol > acebutolol
Why are partial agonists B-blockers used?
Inhibit + slightly activate B-receptors = lower risk of arrhythmia and HF
What are 3 main precautions with B-blockers?
How does body counteract b-blocker after long term use?
Body upregulate (increase no. of receptors) and super-sensitize B-receptors > increase sensitivity to sympathetic activation by endogenous noradrenaline
What happens when B-blocker is suddenly withdrawn after long term usage?
Body compensate by increase sensitivity of B-receptors
Withdrawal = rebound hypertension, tachycardia, nervousness
How to discontinue patient from B-blocker?
Gradual dosage reduction
Which drugs can interact with B-blockers?
Adrenaline and Cocaine
Both can activate a&b receptors
Cocaine DEcrease uptake of noradrenaline > activate a&b
Also nonsteroidal anti-inflammatory drugs (NSAID)
How can B-blocker cause severe hypertension when taken with adrenaline or cocaine?
B- receptor blocked > shift the endogenous noradrenaline to a-receptors > severe hypertension
Why does B-blocker mask insulin-induced hypoglycemia in diabetics?
insulin-induced hypoglycemia > result in tachycardia (warning sign)
B-blocker slow HR > mask the warning sign