L46 – Calcium antagonist, α and β adrenergic blocking agents

Question 1

Explain the action of Ca2+ during membrane doplarization?

Answer 1

membrane depolarization > Ca2+ channel undergo conformational change > Ca2+ influx down electrochemical gradient into cell

Question 2

Explain the action of CCB?

Answer 2

Block L-type Voltage gated Ca2+ channels > decrease Ca2+ entry (down electrochemical gradient) into cell

Question 3

Result of CCB on cardiac muscle and blood vessels?

Answer 3

CCB Decreases force of contraction and decreases vasoconstriction > decrease TPR

Question 4

What specific type of calcium channel is targeted by CCBs?

Answer 4

Ca v1.2
L-type
High voltage activated dihydropyridine sensitive channels

Question 5

2 roles of cardiac L-type voltage- gated calcium channels in cardiac myocytes?

Answer 5

Regulate HR (pacemaker potential at SA node and AV node conduction)

Regulate force of contraction of heart

Question 6

Role of cardiac L-type voltage- gated calcium channels in vascular smooth muscle cells?

Answer 6

Regulate force of smooth muscle contraction

increase intracellular Ca2+ > trigger further release in stored Ca2+ > vasoconstriction

Question 7

CCBs are used in which three pathological conditions?

Answer 7

Angina
Arrhythmia
Hypertension

Question 8

Name of three structural classes of CCB? dbp

Answer 8

dihydropyridines

Benzothiazepine

Phenylalkylamine

Question 9

Name 1-2 common CCBs in each structural class?

Answer 9

Dihydropyridine= nifedipine, amlodipine

Benzothiazipine= diltiazem

Phenylalkylamine= verapamil

Question 10

Which CCB class is cardiac selective?

Answer 10

Benozothiazipine

Phenylalkylamine

Question 11

Which CCB class is vascular selective?

Answer 11

Dihydropyridine

Question 12

How does the dosage of dihydropyridine affect its function on CVS?

Answer 12

Low dosage = block vascular L-type channel

High dosage = block cardiac L-type channel

Question 13

How does dosage of cardiaic selective CCBs affect their function on CVS?

Answer 13

Cardiac selective CCB = benzothiazipine, phenylakylamine

At low dosage = cardiac selective

At high dosage = vascular selective

Question 14

Why is vascular selective CCB used for treatment of angina?

Answer 14

Dilate coronary vessels too > relieve angina

Question 15

Vascular -selective CCB may alter myocardial contractility. Why?

Answer 15

Not a direct effect

CCB decrease TPR, heart senses drop in resistance and adjusts to lower contractility

Question 16

Why does Nifedipine cause slight decrease in HR when it is a vascular -selective CCB?

Answer 16

Nifedipine is not very vascular-selective > slight effect on cardiac L-type CC > decrease HR

Question 17

Why does Amlodipine increase HR when it is vascular selective?

Answer 17

Drop in TPR > sensed by baroreceptors > stimulate sympathetic NS > reflex tachycardia > ensure sufficient blood to brain and kidney

Question 18

Effect of vascular selective CCB on SA node and AV node conduction?

Answer 18

Zero

Question 19

3 effects of vascular selective CCBs.

Answer 19

increase coronary flow
Increase vascular dilatation
Increase neurohormonal activation

Question 20

Effect of vascular selective CCB on renal system?

Answer 20

mild natriuresis

due to increase in renal blood flow and intraglomerular pressure

Question 21

Compare effects of cardiac selective CCBs with vascular selective CCBs?

Answer 21

Cardiac selective causes similar increase in coronary flow, vascular dilatation and neurohormonal activation

But also decrease in SA node, AV node conduction and HR

Question 22

Which vascular selective drug causes a similar effect on HR as cardiac selective CCBs?

Answer 22

Nifedipine

Question 23

What are some side effects of vascular-selective CCBs on vascular dilatation?

Answer 23

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

Question 24

Some side effects of cardiac selective CCBs when given in very high dosage?

Answer 24

Very high dosage> HR and contractility drop too much > trigger reflex tachycardia > heart failure/ arrhythmia

Question 25

Apart from oedema, what are some common adverse effects of CCB?

Answer 25

Flushing | Dizziness

Question 26

Why is nifedipine not favored for clinical use? (think half-life...)

Answer 26

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

Question 27

Why are sustain-release CCBs used instead of start half life ones?

Answer 27

Reduce adverse effect (flushing, dizziness, peripheral oedema) Reduce fluctuations in BP

Question 28

Change in TPR causes what BP change? How about change in stroke volume?

Answer 28

Change in TPR = diastolic increase, systolic unchanged Change in SV = increase in diastolic + even bigger increase in systolic

Question 29

Which type of hypertension is CCB best used for?

Answer 29

Isolated systolic hypertension - increase in systolic, normal diastolic

Question 30

Which patient groups can use CCB best as hypertensive treatment?

Answer 30

Patients with low renin status e.g. elderly

Question 31

Explain the adverse action of CCB on gastroesophageal reflux

Answer 31

CCBs inhibit contraction of lower esophageal sphincter > lead to gastroesophageal reflux

Question 32

Which CCBs are used as anti-arrhythmic dugs?

Answer 32

Only cardiac selective CCBs e.g. verapamil , diltiazem Decrease HR, SA node and AV node conduction

Question 33

Which type of arrhythmia is CCB most effective for?

Answer 33

Delayed-afterdepolarization (DAD)- mediated arrhythmia | CCB can reduce calcium overload DAD: Ca2+ accumulation exceeds storage capacity > trigger extra heart beat

Question 34

What are 2 precautions when using CCB as antiarrhythmic drug?

Answer 34

Caution in patients with hepatic dysfunction (increase plasma conc.) Avoided in patients with Ventricular tachycardia (drug can worsen hypotension > cardiac arrest)

Question 35

What does a1 receptor signal?

Answer 35

Formation of IP3 and DAG > increase intracellular Ca2+

Question 36

What does a2 receptor signal?

Answer 36

Inhibition of adenylyl cyclase > decrease cAMP

Question 37

What do b1, b2, b3 receptors signal?

Answer 37

Stimulate adenylyl cyclase > increase cAMP

Question 38

Name two common a-Adrenergic receptor blockers

Answer 38

Prazosin | Doxazosin

Question 39

How is Prazosin/ Doxazosin used to manage hypertension?

Answer 39

Both a1- Adrenergic receptor blockers > inhibit a1 adrenergic receptors in arterioles and venules > dilate arterioles and veins > decrease peripheral vascular resistance

Question 40

What is the normal action of a1- adrenergic receptors?

Answer 40

Stimulate = vasoconstriction

Question 41

General adverse effects of a1-adrenergic receptor blocker ?

Answer 41

dizziness, palpitations, headache

Question 42

Explain the "first dose phenomenon" caused by a1- adrenergic receptor blocker.

Answer 42

``` Orthostatic hypotension (huge drop in BP from supine to upright posture) with initial dose/ after dosage increase ``` because vasoconstriction from baroreceptor reflex is inhibited

Question 43

What drug worsens orthostatic hypotension caused by a1 adrenergic receptor blockers?

Answer 43

Diuretics > hypovolemia already causes hypotension

Question 44

How does the body compensate after first dose of a1 adrenergic receptor blockers?

Answer 44

Sympathetic nervous system compensate > increase systemic vascular resistance Activate RAAS > Decrease renal sodium excretion > Na+ and water retention Both compensations oppose drug action

Question 45

Why is a-blocker used with diuretics and b-adrenergic receptor blockers?

Answer 45

Diuretics : body counteract a - blocker by salt retention > oedema B-adrenergic receptor blocker: prevent effect of sympathetic NS on heart

Question 46

Is a - blocker used as long term antihypertensive drug?

Answer 46

No Body keeps counteracting drug > reduce efficacy

Question 47

Name 3 common B-adrenergic receptor blockers

Answer 47

Propranolol Metoprolol Pindolol

Question 48

What is the normal action of B1 adrenergic receptor activation on heart?

Answer 48

Stimulate adenylyl cyclase > increase cAMP > enhance activity of L-type channels > increase HR and force of contraction

Question 49

Which b-receptors are in vascular smooth muscle?

Answer 49

B2

Question 50

What is the action of B2 receptor activation and why is it different from B1?

Answer 50

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

Question 51

Explain action of B-blockers on heart?

Answer 51

Inhibit B- adrenergic receptors in heart > decrease rate and force of contraction > decrease cardiac output

Question 52

Explain action of B-blockers on kidneys?

Answer 52

b-block in kidneys> decrease activation of renin production > decrease Na+ and water retention

Question 53

Explain action of B-blockers on peripheral vascular resistance?

Answer 53

Inhibit peripheral presynaptic B-adrenergic receptors > decrease release of noradrenaline > decrease sympathetic vasoconstrictor nerve activity > decrease peripheral vascular resistance

Question 54

Which 5 conditions is B-blockers used in?

Answer 54

``` Angina, Arrythmia Heart failure Hypertension Myocardial infarction ```

Question 55

Why is b-blockers not used in patients with asthma or COPD?

Answer 55

Inhibit B-adrenergic (esp. B2) receptors in respiratory tract > BRONCHOSPASM

Question 56

Why is b-blockers not used in patients with insulin-dependent diabetes?

Answer 56

Inhibit B-receptor in LIVER > affect glucose metabolism > increase risk of HYPOglycaemia

Question 57

Why is b-blockers not used in patients with vasospastic disorders/ severe peripheral vascular diseases?

Answer 57

Inhibit B- receptor in vascular smooth muscle > decrease vasodilation

Question 58

Summarize 3 patients groups which B-blockers is not used in?

Answer 58

patients with asthma or COPD patients with insulin-dependent diabetes patients with vasospastic disorders/ severe peripheral vascular diseases

Question 59

Which B-blocker is less likely to have adverse effects?

Answer 59

B1- selective receptor blockers > higher cardiac selectivity

Question 60

How could B-blocker lead to arrhythmia and HF? Why is pindolol used ?

Answer 60

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

Question 61

How can B-blockers cause psychiatric depression? How to manage?

Answer 61

inhibit B1 and B2 receptros in CNS > CNS disturbance > depression Less likely with B-blockers with low lipid solubility > cannot cross BBB into brain

Question 62

List 3 mental effects of B-blockers?

Answer 62

mild sedaiton vivid dreams depression

Question 63

Classify the 3 generations of B-blockers and their action.

Answer 63

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

Question 64

Name some first gen and second gen B blockers

Answer 64

First gen = propranolol Second gen = metoprolol, bisoprolol

Question 65

Name some 3rd gen drugs with diff. functions

Answer 65

Inhibit a & b receptors = labetalol, carvedilol OR inhibit B1 + release NO = nebivolol

Question 66

What are partial agonists B-blockers?

Answer 66

B-blockers with intrinsic sympathomimetic activity

Question 67

Name some partial agonist B-blockers?

Answer 67

Pindolol > acebutolol

Question 68

Why are partial agonists B-blockers used?

Answer 68

Inhibit + slightly activate B-receptors = lower risk of arrhythmia and HF

Question 69

What are 3 main precautions with B-blockers?

Answer 69

Withdrawl syndrome Drug interaction Concurrent condition

Question 70

How does body counteract b-blocker after long term use?

Answer 70

Body upregulate (increase no. of receptors) and super-sensitize B-receptors > increase sensitivity to sympathetic activation by endogenous noradrenaline

Question 71

What happens when B-blocker is suddenly withdrawn after long term usage?

Answer 71

Body compensate by increase sensitivity of B-receptors Withdrawal = rebound hypertension, tachycardia, nervousness

Question 72

How to discontinue patient from B-blocker?

Answer 72

Gradual dosage reduction

Question 73

Which drugs can interact with B-blockers?

Answer 73

Adrenaline and Cocaine Both can activate a&b receptors Cocaine DEcrease uptake of noradrenaline > activate a&b Also nonsteroidal anti-inflammatory drugs (NSAID)

Question 74

How can B-blocker cause severe hypertension when taken with adrenaline or cocaine?

Answer 74

B- receptor blocked > shift the endogenous noradrenaline to a-receptors > severe hypertension

Question 75

Why does B-blocker mask insulin-induced hypoglycemia in diabetics?

Answer 75

insulin-induced hypoglycemia > result in tachycardia (warning sign) B-blocker slow HR > mask the warning sign

Question 76

What concurrent conditions result in severe hypertension with non-selective B-blockers?

Answer 76

Pheochromocytoma Clonidine withdrawal (antihypertensive drug)