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MADD > Beta blockers > Flashcards

Beta blockers Flashcards

1
Q

How many GPCRs are approved drug targets by the FDA?EMA?

A

134

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2
Q

How many GPCR-targeting drugs are there, and what proportion of all drugs in clinical use do these represent?

A

~700 drugs, ~35% of all drugs in clinical use

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3
Q

Who gave the first recorded clinical description of angina pectoris (and when)?

A

William Heberden in 1768: activity-dependent pain/disagreeable sensation in the breast

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4
Q

What did Sir Richard Quain record and what did he propose (and when)?

A

The deposition of fatty material in blood vessels (1852). Proposed that angina could occur in conditions of (a) ossified coronary arteries, (b) in blood vessels with fatty accumulation or (c) in the absence of any disease

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5
Q

Who showed that cholesterol alone caused the atheromatous changes in the vascular wall (and when)?

A

Nikolai Anitschkow in 1913, using the cholesterol-fed rabbit model

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6
Q

What did the comprehensive explanation of angina, published in 1928 by Keefer & Resnik confirm?

A

That anoxemia was the underlying cause of angina, but could itself be caused by coronary heart disease, vasospasm and decreased oxygen saturation of the blood

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7
Q

What does the chronic formation of an atherosclerotic plaque depend on? (x3)

A
  1. Endothelial Integrity
  2. Inflammatory response (e.g. cytokines and chemokines attract monocytes to site and cause proliferation and morphology changes to macrophages)
  3. Plasma lipid levels (high LDL:HDL ratio increases risk of LDL infiltration and formation of foam cells
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8
Q

How does the atherosclerotic plaque increase the risk of clot formation?

A

It protrudes into the artery and narrows its lumen, impeding blood flow

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9
Q

How does angina arise?

A

When an artery supplying oxygen and substrates for energy production is blocked, this leads to dysfunction of myocardial cells resulting in angina

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10
Q

What therapies were available for coronary heart disease at the time of James Black’s research?

A
  1. Vasodilators (i.e. nitrates)
  2. Calcium channel blockers (e.g. nicardipine)
  3. Ganglion-blocking drugs (e.g. pempidine)
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11
Q

How are organic nitrates reduced to NO?

A

Metabolized to 1,2-glyceryl dinitrate and nitrate via the mitochondrial aldehyde dehydrogenase 2 enzyme (mtALDH), and then nitric oxide and S-nitrosothiols

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12
Q

How does NO produce vasodilation?

A

Activates smooth muscle guanylyl cyclase to form cGMP, which inhibits calcium entry (and thus lowers intracellular calcium levels) to promote muscle relaxation.

cGMP also stimulates a cGMP-dependent protein kinase that activates myosin light chain phosphatase

NO can also directly activate K+ channels causing hyperpolarization and thus relaxation

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13
Q

What was ICI’s solution prior to beta blockers?

A

Quaternary ammonium derivatives that acted as ganglion-blocking drugs, e.g. pempidine

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14
Q

Why were the ganglion-blocking drugs not successful?

A
  1. Poorly absorbed

2. Caused postural hypotension and constipation

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15
Q

Who developed pempidine and when?

A

Spink, 1958

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16
Q

How did black intend to revolutionise the approach to treating coronary heart disease?

A
  1. He was not interested in increasing myocardial oxygen supply, but rather he was trying to reduce the myocardial demand for oxygen
  2. Black (and the ICI) had shifted their focus from peripherally- to centrally-acting agents
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17
Q

Since when has adrenaline been known?

A

Late 1800s (1894)

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18
Q

What was Dale able to demonstrate about adrenaline after its isolation in 1913? (x2)

A

(a) In the peripheral circulation, smooth muscles around blood vessels (arterioles) contract, diverting blood from the peripheral circulation to essential internal organs
(b) In the lungs, smooth muscles around the tubes carrying air (bronchi) relax, so lungs can expand more for deeper breathing

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19
Q

What was Raymond Alhquist’s theory?

A

The Dual Receptor Theory (1948): receptors could be classified as either excitatory or inhibitory, and there are two distinct types of adrenergic receptor, alpha and beta

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20
Q

What did Black understand from Alhquist’s theory?

A

The potential of beta-blocking drugs in the treatment of coronary heart disease and angina

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21
Q

What did Black know he needed to accomplish to reduce chronotropic and inotropic effects of the heart?

A

He needed to block the action of adrenaline on myocardial cells

22
Q

What was Eli Lilly’s intention in the synthesis of dichloroisoprenaline?

A

To produce a long-acting vasodilator, with actions resembling isoprenaline

23
Q

What was found about DCI, by who, and when?

A

In 1958, Powell and Slater published a report, describing that instead of acting like isoprenaline, DCI acted as an antagonist

24
Q

What was concluded after Stephenson’s synthesis of DCI and subsequent testing in assays by Black?

A

DCI inhibited smooth muscle relaxation as well as cardiac stimulation, but demonstrated partial agonist activity

25
Q

What was the first beta blocker synthesised by Black?

A

Pronethalol

26
Q

How effective was pronethalol?

A

In vitro, it antagonised the myocardial beta receptors but not the peripheral alpha receptors, and clinical investigation in humans produced the same results (reduced heart rate and increased exercise tolerance in people with angina)

27
Q

Why was pronethalol withdrawn?

A

It was found to produce thymic tumours in mice

28
Q

Between June 1961 and January 1962, how many analogues were synthesised and what 3 features was James Black looking for?

A

136 analogues were synthesised and tested for SARs, looking for compounds that were longer acting, had greater resistance to catecholamine breakdown, and showed less CNS penetration than pronethalol

29
Q

What was later found to be a critical feature that led to the synthesis of another 269 compounds?

A

Pronethalol’s beta blocking activity was confined to the S-isomer only

30
Q

What derivatives of pronethalol were tested, and which eventually led to the discovery of propranolol?

A

Napthalene, phenyl or heterocyclic derivates; Napthalene

31
Q

By how much was propranolol more potent than pronethalol and DCI?

A

10-20 times

32
Q

What produces beta-specificity and resistance to MAO?

A

Increased bulkiness of alkyl substituents on the Nitrogen atom in the ethanolamide side chain; must be present

33
Q

What does an alpha-methyl group produce?

A

Specificity for alpha receptors and resistance to MAO; should therefore not be present in beta-blockers

34
Q

What does the removal/substitution of the beta-OH group lead to?

A

Reduced interaction with adrenergic receptors and destruction of beta-blocking activity; must be present

35
Q

What could make beta blocking drugs susceptible to COMT catabolism? What does their removal lead to?

A

-OH groups on the catechol ring; however, their removal abolishes affinity for adrenergic receptors

36
Q

What can catecholamine ring -OH groups be substituted with to render resistance to COMT while retaining affinity? At what positions is potency greatest?

A

Similar electron-withdrawing groups such as Cl or benzene ring; ortho > meta > para

37
Q

What do methoxy linkages between the aryl ring and ethanolamide side chain lead to?

A

Increased potency of beta blockers

38
Q

List the essential features for beta blockers (x5)

A
  1. Increased BULKINESS of alkyl substituents at N atom
  2. Absence of ALPHA methyl group
  3. Presence of BETA -OH group
  4. CATECHOLAMINE -OH group substitution for Cl/benzene
  5. METHOXY linkage

Hint: Benzoes And Booze Cause Mania

39
Q

Which beta blocker came after propranolol and why?

A

ICI studied analogues further and in 1970 launched practolol with the intention of reducing adverse effects

40
Q

How was practolol different from propranolol?

A

Had an acetoamido subsitution in the para position of the catecholamine ring, that increased its polarity

41
Q

What did the increased polarity of practolol mean? What was the drawback?

A

Less membrane stabilising activity (MSA) and inability to cross the BBB; not as potent as propranolol

42
Q

What did the market withdrawal of practolol lead to?

A

The development of atenolol

43
Q

What chemical features made atenolol the “ideal beta blocker”?

A
  1. Isopropyl group on the N atom (beta selectivity and MAO resistance)
  2. Beta -OH group (adrenergic receptor interaction)
  3. Methoxy linkage (potency)
  4. Para amide substitution (COMT resistance, receptor activity and selectivity)
  5. Methyl group between amide and catechole ring (no ISA)
  6. Hydrophilic molecule (no MSA)
44
Q

Outline 4 therapeutic uses of beta-blockers

A
  1. Hypertension
  2. Angina
  3. Arrhythmias (sympathetic nerve inhibition)
  4. Chronic Heart Failure
45
Q

How are beta blockers useful for the treatment of hypertension?

A

They reduce cardiac output + inhibit renin release (resulting in a decrease in angiotensin II and aldosterone, and therefore promoting the renal loss of Na+ and water, leading to a reduction in arterial pressure)

46
Q

How do beta blockers help in angina?

A

They reduce heart rate, contractility and arterial pressure = reduce work rate and oxygen demand that relieves anginal pain

47
Q

How are beta blockers beneficial in chronic heart failure?

A

Reduce cardiac remodelling (enlargement of the [usually] left ventricle), thus improving cardiac function (who’s contractility is diminished) and reducing mortality

48
Q

Name 2 beta1-selective antagonists

A

Bisoprolol, Metoprolol

49
Q

Name 2 beta-blockers with concomitant alpha receptor activity

A

Carvedilol, Labetolol

50
Q

Name 1 beta blocker with vasodilator activity (+ explain how this activity arises)

A

Nebivolol - has an NO-potentiating effect promoting vasodilation via beta3R stimulation

51
Q

Why was labetolol created?

A

To account for the compensatory effects of beta blockers (i.e. vasoconstriction after blocking beta receptors is inhibited by a1 antagonist properties)

52
Q

What determines the cardioselectivity of nebivolol?

A

The patient profile and the drug dose - at 5 mg it is highly cardioselective but at 10 mg it blocks beta2 as well.

MADD (5 decks)

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