1. Sympatholytic drugs: α- Adrenergic blockersBy
Nohad A Atrushi
23/11/2014

2. Alpha- Adrenergic Antagonists
I. Non-selective alpha adrenergic receptor antagonists
A. Covalent (haloalkylamines)
Dibenamine
Phenoxybenzamine*
B. Noncovalent
Phentolamine*
Tolazoline
II. a1-selective
Doxazosin
Prazosin*
Terazosin
III. a2-selective
Yohimbine*

3. Structure of several a-receptor-blocking drugs.

4. Adrenergic Antagonists (also called blockers or sympatholytic agents)
α-Adrenergic Blocking Agents
The α-adrenergic blocking agents, phenoxybenzamine and phentolamine, have limited clinical applications, they are nonselective α blockers

5. 1. Beta-haloalkylamine
Phenoxybenzamine, Dibenamine
is used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of the adrenal medulla.
Adverse effects: Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting.

8. Selective a1 blockers cause less reflex tachycardia than Phenoxybenzamine and Phentolamine

9. Phenoxybenzamine
Non specific, long acting irreversible alpha antagonist
MOA: Spontaneously cyclizes in the body to give ethyleniminium intermediate – forms a strong covalent bond with α receptors – blockade of alpha receptor (lasts for 3 – 4 days)
Dibenamine

10. Covalent inactivation of a-receptor by phenoxybenzamine
CH2 N O
CH3 CH
CH2Cl
Phenoxybenzamine
CH2 N O
CH3 CH +
CH2
CH2 N O
CH2 CH
CH2
CH3
Ethylene iminium ion
Alkylated a-receptor

11. Phenoxybenzamine forms a permanent covalent bond with adrenergic receptors. Based on known information about the structures of these receptors, it likely involves attack by the cysteine at position 3.36 in transmembrane helix 3 to form a stable linkage.  Thus, it remains permanently bound to the receptor, preventing adrenaline and noradrenaline from binding. This causes vasodilatation in blood vessels, due to its antagonistic effect at the alpha-1 adrenoceptor found in the walls of blood vessels, resulting in a drop in blood pressure. A side effect of phenoxybenzamine is reflex tachycardia.

12. Phenoxybenzamine can be synthesized by reacting phenol with propylenoxide, which forms 1-phenoxy-2-propanol, the chlorination of which with thionyl chloride gives 1-phenoxy-2-propylchloride. Reacting this with 2-aminoethanol leads to formation of 1-phenoxy-2-(2-hydroxyethyl)aminopropane. Alkylation of the secondary amino group gives N-(2-hydroxyethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine, the hydroxyl group of which is chlorinated using thionyl chloride, giving phenoxybenzamine.

14. 2. Phentolamine
Phentolamine is also used for the short-term management of pheochromocytoma.
Non specific, short acting reversible alpha antagonist
Potent competitive antagonist at both 1 and 2 receptors
Quick acting (in minutes)
Reduction in Peripheral Resistance - blocking both α-1 and α-2 receptors - causes NA release and venodilatation more than arteriolar

15. Phentolamine can be synthesized by alkylation of 3-(4-methylanilino)phenol using 2-chloromethylimidazoline

16. Prazosin, the first known selective α1-blocker, was discovered in the late 1960s , and is now one of a small group of selective α1-antagonists that includes three other quinoxaline antihypertensives terazosin, doxazosin, and alfuzosin and the nonquinazoline benzensulfonamides tamsulosin and silodosin .Prazosin, doxazosin, and terazosin contain a 4-amino-6,7-dimethoxyquinazoline ring system attached to a piperazine ring, whereas alfuzosin has a rotatable propylenediamine group (an open piperazine ring). The other structural differences are the heterocyclic acyl groups attached to the second nitrogen of the piperazine or the propyl chain.

17. The differences in these groups afford dramatic differences in some of the pharmacokinetic properties of these agents .For example, reduction of the furan ring for prazosin to the tetrahydrofuran ring of terazosin increases its duration of action by altering its rate of metabolism. Some of the important clinical parameters of the quinazolines . The long half-lives and durations of action for terazosin, doxazosin, tamsulosin, and silodosin permit once-a-day dosing and generally lead to increased patient compliance.

18. Prazosin Uses: Highly selective alpha-1 blocker (1:1000)
Non-specific blockade of all subtypes - α1A, α1B and α1D
Blockade of sympathetic vasoconstriction - fall in BP
NA is not released as α-2 is not blocked (only mild tachycardia)
Dilates arterioles more than veins – Postural hypotension is less – only 1st dose effect (dizziness and fainting)
Kinetics: effective orally (70%), metabolized in liver and half life is 6-8 Hrs
Uses:
Hypertension
Raynaud`s disease
BHP

19. Disorders of the Autonomic Nervous System: Raynaud’s Disease
Raynaud’s disease – characterized by constriction of blood vessels
Provoked by exposure to cold or by emotional stress

20. 3. Prazosin terazosin, doxazosin, and tamsulosin
are selective competitive blockers of the α1 receptor.
The first three drugs are useful in the treatment of hypertension.
Tamsulosin is indicated for the treatment of benign prostatic hyperplasia.
Doxazosin is the longest acting of these drugs.

21. The first dose of these drugs produces an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action, termed first-dose effect.
Tamsulosin is a more potent inhibitor of the α1A receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin's minimal effect on blood pressure.

23. 4. Yohimbine
Is a selective α2 blocker.
It is found as a component of the bark of the yohimbe tree and is sometimes used as a sexual stimulant (aphrodisiac) or cardiovascular stimulant.

24. Comparison of alpha blockers
Receptor affinity

26. Sympatholytic drugs: beta- adrenergic blockersBy
Nohad A Atrushi
26/11/2014

27. β-Adrenergic Blocking Agents
Nonselective β-blockers act at both β1 and β2 receptors, whereas cardioselective β antagonists block β1 receptors
[Note: There are no clinically useful β2 blockers].
Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension, because the α-adrenoceptors remain functional.

28. myocardial infarction, congestive heart failure, hyperthyroidism,
β-Blockers are also effective in treating
angina,
cardiac arrhythmias,
myocardial infarction,
congestive heart failure,
hyperthyroidism,
glaucoma, as well as serving in the prophylaxis of migraine headaches.

29. Structures of some b-receptor antagonists. 0

31. 1. Propranolol
A nonselective β blocker
Sustained-release preparations for once-a-day dosing are available.
Actions:
Cardiovascular: Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects.
Cardiac output, work, and oxygen consumption are decreased by blockade of β1 receptors; these effects are useful in the treatment of angina.
The reduction in cardiac output leads to decreased blood pressure.

32. Bronchoconstriction: Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle.
Non-selective β-blockers, are contraindicated in patients with COPD or asthma.
β-blockade leads to decreased glycogenolysis and decreased glucagon secretion, thus pronounced hypoglycemia may occur after insulin injection in a patient using propranolol.
β-Blockers also mask the normal physiologic response to hypoglycemia.

33. Mechanisms of action
Propranolol lowers blood pressure in hypertension by:
Decreased cardiac output is the primary mechanism,
inhibition of renin release from the kidney and decreased sympathetic outflow from the CNS also contribute to propranolol's antihypertensive effects .

34. Adverse effects:
Bronchoconstriction
Arrhythmias: Treatment with β-blockers must never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe.
Sexual impairment

35. Drug interactions:
Drugs that interfere with the metabolism of propranolol, such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects.
Conversely, those that stimulate its metabolism, such as barbiturates, phenytoin, and rifampin, can decrease its effects.

36. 2. Timolol and nadolol:
Nonselective β blockers,
are more potent than propranolol.
3. Acebutolol, atenolol, metoprolol, and esmolol:
Selective β1 blockers
Esmolol has a very short lifetime. It is only given intravenously if required during surgery or management of poisoning.
4. Pindolol and acebutolol:
blockers with partial agonist activity

37. 5. Labetalol and carvedilol:
blockers of both α- and β- adrenoceptors
Carvedilol also decreases lipid peroxidation and vascular wall thickening, effects that have benefit in heart failure.
Labetalol may be employed as an alternative to methyldopa in the treatment of pregnancy-induced hypertension.
Intravenous labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure.

38. Drugs Affecting Neurotransmitter Release or Uptake
Some agents act on the adrenergic neuron, either to interfere with neurotransmitter release or to alter the uptake of the neurotransmitter.
1. Reserpine
Reserpine, a plant alkaloid that causes the depletion of biogenic amines.
Sympathetic function, in general, is impaired because of decreased release of norepinephrine.

39. 2. Guanethidine
Guanethidine blocks the release of stored norepinephrine as well as displaces norepinephrine from storage vesicles (thus producing a transient increase in blood pressure).
This leads to gradual depletion of norepinephrine in nerve endings except for those in the CNS.
Guanethidine commonly causes orthostatic hypotension and interferes with male sexual function.

40. 3. Alpha methyl dopa
Antihypertensive
Mechanism: Transformed to alpha methyl noradrenaline in adrenergic neuron,
When released, alpha methyl noradrenaline acts as agonist on presynaptic alpha2 receptors. Thus further release of transmitter is inhibited.

41. beta-adrenergic receptor antagonists (beta-blockers)
β-adrenergic receptor antagonists (beta-blockers/β-blockers) were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias.[1] In1950s,dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.

42. The evolution of non-selective and selective β-blockers
By the time propranolol was launched, ICI was beginning to experience competition from other companies. This potential threat led to ongoing refinements in the pharmacologic structure of β-blockers and subsequent advances in drug delivery. ICI studied analogues further and in 1970 launched practolol, under the trade name Eraldin®. It was withdrawn from the market a few years later because of the severe side effects it caused, nevertheless it played a large role in the fundamental study of β-blockade and β-receptors.

43. The withdrawal of Eraldin® gave ICI the nudge to launch another β-blocker, atenolol, which was launched in 1976 under the trade name Tenormin®. Atenolol is a selective β1-receptor antagonist and was developed for the purpose of obtaining the “ideal β-blocker”. It soon became one of the best-selling heart drug. ICI’s β-blocker project was based on Ahlquist’s dual receptor theory. The drugs that were the outcome of this project, from propranolol to atenolol, helped to establish the receptor theory among scientist and pharmaceutical companies.

44. The progress in β-blocker development led to the introduction of drugs with variety of properties. β-blockers were developed having a relative selectivity for cardiac β1-receptors (for example metoprolol and atenolol), partial adrenergic agonist activity (pindolol), concomitant α-adrenergic blocking activity (for example labetalol and carvedilol) and additional direct vasodilator activity (nebivolol). In addition, long-acting and ultra-short formulations of β-blockers were developed.[7] In 1988, Sir James Black was awarded the Nobel Prize in Medicine for his work on drug development.[3][4][6][7]

45. Binding to β-adrenergic receptors
Figure 3: β-blockers cause a competitive inhibition of the β-receptor, which counters the effects of catecholamines.
Three different types of β-adrenergic receptors have been identified by molecular pharmacology. β1-receptorsare located in the heart and consist of about 75% of all β-receptors. β2-receptors can be found in the smooth muscles of vessels and the bronchies. β3-receptors are presumed to be involved in fatty acid metabolism and are found in the adipocytes.[9] β-blockers cause a competitive inhibition of the β-receptor, which counters the effects of catecholamines.

46. β1 and β2-receptors are G-protein coupled receptors, which couple to Gαs-proteins. When activated, it stimulates an increase in intracellular cAMP via the adenylyl cyclase. cAMP, which is the second messenger, then activates protein kinase A that phosphorylates the membrane's calcium channeland increases the entry of calcium into the cytosol. Protein kinase A also increases the release of calcium from the sarcoplasmic reticulum, which causes a positive inotropic effect. The phosphorylation of troponin I andphospholamban by protein kinase A causes the lusitropic effects of β-blockers. This increases the re-uptake of calcium by the sarcoplasmic reticulum.

47. β-blockers are sympatholytic drugs
β-blockers are sympatholytic drugs. Some β-blockers partially activate the receptor while preventing catecholamines from binding to the receptor, making them partial agonists. They provide a background of sympathetic activity, while preventing normal and enhanced sympathetic activity. These β-blockers possessintrinsic sympathomimetic activity (ISA). Some of them also possess what is called membrane-stabilizing activity(MSA) on myocardial muscle fibers.

49. A few of the non-selective β-blockers
Labetalol
                 
Pindolol
              
Propranolol
Timolol

50. A few of the selective β1-blockers
Atenolol
Acebutolol
Bisoprolol
Nebivolol
Metoprolol

51. Selectivity
β-blockers can be selective for either β1 or β2-receptor or non-selective. By blocking β1-receptor it is possible to reduce heart rate, conduction of velocity and contractility. The blocking of β2-receptor promotes vascular smooth muscle contraction, which results in increase of peripheral resistance.  Blockade of the β2-receptor effectively reduces the sympathetic activity, which results in reduce of the associated platelet and  coagulation activation. This is why a non-selective β-blocker treatment may result in a lower risk of both arterial and venous embolic events.

52. (S)-propranolol[edit]
Propranolol exist in two different enantiomers, (S)- and (R)-enantiomers. The (S)-isomer is 100-fold more potent than the (R)-isomer and that is the general rule for most β-blockers. It is possible to produce the (S)-propranolol enantiomer from α-naphthol and 3-bromopropanol as seen in figure 6.
 α-Naphthol and 3-bromopropanol are refluxed for 6 hours to give alcohol. The alcohol is oxidized by using 2-Iodoxybenzoic acid (IBX) to givealdehyde. The aldehyde is subjected to L-prolinecatalyzed asymmetric α-aminoxylation and a reduction is made with NaBH4 in methanol. A diol is obtained by Pd/C-catalyzed hydrogenolysis. Finally the diol is converted to epoxide using the Mitsunobu reaction and stirred with isopropyl amine in CH2Cl2 to give (S)-propranolol.

53. Figure 6: Synthesis of (S)-propranolol from α-naphthol and 3-bromopropanol.

54. Figure 7: The oxymethylene bridge of propranolol can be seen inside the green ring.

55. Structure activity relationship (SAR)
β-blockers' binding site to the receptor is the same as for  endogenous catecholamines, such as noradrenaline and adrenaline. This binding is based on hydrogen bondsbetween the β-blocker and the receptor, and therefore not based on covalent bonds, which results in the reversibility of the binding. A significant step in the development of β-adrenergic antagonists was the discovery that an oxymethylene bridge (-OCH2) could be inserted into the arylethanolamine structure of pronethalol to produce propranolol.

56. Propranolol is an aryloxypropanolamine, which are more potent β-blockers than arylethanolamines. Today, most of the β-blockers used clinically are aryloxypropanolamines. The length of the side chain is increased when an oxymethylene bridge is introduced. It has been shown that the side chains of aryloxypropanolamine can adopt a conformation that puts the hydroxyl and amine groups in more or less the same position as with beta blocker that do not have this group as a part of the side chain.[2]

57. After the release of propranolol, relative lipophilicity of β-blockers as a significant factor in their varied and complex pharmacology, became an important factor. It was suspected that propranolol’s centrally induced side effects could be due to its high lipophilicity. Thus, it was focused on synthesizing analogues with  hydrophilic  moieties, favourably placed to see if the side effects would decrease.
Selecting para-acylamino groups as the hydrophilic moiety, scientists synthesized a group of para-acylphenoxyethanol-and propanolamines, and selected practolol for clinical trials.

58. Practolol had one property not previously seen with β-blockers, it exhibited cardioselectivity (β1 selectivity). Studies from practolol showed that moving the acylamino group to meta or ortho positions, on the benzene ring, caused a loss of selectivity but not loss of the β-blockade itself. This illustrated the significance ofpara-substitution for β1 selectivity of β-blockers.[5]

59. Figure 8 shows the structural activity relationship (SAR) for β-blockers. For the function of a β-blocker it's essential for the compound to contain an aromatic ring and a β-ethanolamine. The aromatic ring can either be benzoheterocyclic (such as indol) or heterocyclic (such as thiadiazole). This is mandatory.] The side chains can be variable. Figure 8: Structural activity relationship for β-blockers. The X part of the side chain can either be directly linked to the aromatic ring or linked through a -OCH2- group.

60. When X is -CH2CH2-, -CH=CH-, -SCH2- or -NCH2- there is little or no activity. The R group can only be a secondary substitution and branched is the optimal choice. Alkyl (CH3) substituents on the α, β or γ carbon (if X = OCH2) lower beta blockade, especially at the α carbon. The general rule for aromatic substitution is: ortho > meta > para. This gives non-selective β-blockers. Large para-substituents usually decrease activity but large ortho-groups retain some activity. Polysubstitution on carbon 2 and 6 makes the compound inactive but when the substitution is on carbon 3 and 5 there's some activity. For the highest cardioselectivity, the substituents should be as following: para > meta > ortho. All the β-blockade is in one isomer, (S)-aryloxypropylamine and (R)-ethanolamine.[5]