1. ADRENERGICS

2. 1. Nerve transmission Peripheral nervous system CNS Brain
Peripheral nerves
Muscle
Heart
Gastro-
intestinal
tract
(GIT)
Spinal cord

3. 1. Nerve transmission Peripheral nervous system Skeletal muscle CNS
(Somatic)
(Autonomic)
Ach
(N)
Synapse
AUTONOMIC
Smooth muscle
Cardiac muscle
Ach (N) NA
Adrenal
medulla
Sympathetic
Parasympathetic
Adrenaline
Ach
(N)
Synapse
Ach
(M)
Ach
(N)

4. 1. Nerve transmission Synapses 100-500A Receptors New signal
Nerve impulse
Nerve
Vesicles containing
neurotransmitters
Release of
neurotransmitters
Receptor binding
and new signal

5. 2. Adrenergic receptors (adrenoceptors)
Notes
Two types of adrenoceptor (a and b)
Subtypes (a1 and a2; b1, b2 and b3)
Subtypes of subtypes (a1A a1B a1D a2A a2B a2C)
G-protein coupled receptors
Signal transduction
a1-adrenoceptor
Generates inositol triphosphate and diacylglycerol
a2-adrenoceptor
Inhibits generation of cyclic AMP
b1, b2 and b3-adrenoceptors
Generate cyclic AMP

6. 2. Adrenergic receptors (adrenoceptors)
Distribution and effects

8. 2. Adrenergic receptors (adrenoceptors)
Distribution and effects
Activating a-adrenoreceptors generally contracts smooth muscle (except gut)
Activating b2-adrenoreceptors relaxes smooth muscle
Activating b1-adrenoceptor contracts cardiac muscle
b2-Adrenoceptors predominate in the airways
b1- Adrenoceptors predominate in the heart
Receptors are distributed differently in different organs and tissues
Receptor selective drugs act selectively at different organs and tissues

9. 3. Chemical messengers General structure -catecholamines
Alkylamine
Catechol
General structure -catecholamines
Catechol
General structure -catecholamines
General structure -catecholamines
Noradrenaline - neurotransmitter
Adrenaline - hormone

10. 4. Biosynthesis
Notes
Pathway controlled by regulation of tyrosine hydroxylase
Inhibited by noradrenaline - feedback control

11. 5. Metabolism of noradrenaline
MAO = Monoamine oxidase
COMT = Catechol O-methyltransferase

12. Catechol-O-methyl transferase
The enzyme introduces a methyl group to the catecholamine which is donated by S-adenosyl methionine (SAM).
COMT inhibitors, like entacapone saves L-dopa from COMT and prolongs the action of L-dopa. Entacapone is a widely used adjunct drug of L-dopa therapy. When given with an inhibitor of dopa decarboxylase (carbidopa or benserazide), L-dopa is optimally saved. This "triple therapy" is becoming a standard in the treatment of Parkinson's disease.

13. Monoamine oxidases /Diary product interaction
They are found bound to the outer membrane of mitochondria in most cell types in the body.
In humans there are two types of MAO: MAO-A and MAO-B. Both are found in neurons. MAO-A is also found in the liver, gastrointestinal tract and placenta. Outside the central nervous system, MAO-B is mostly found in blood platelets.
Monoamine oxidase inhibitors are one of the major classes of drugs prescribed for the treatment of depression.

14. . 6. Transmission process . . . . . . Target cell
nerve signal .
Target
cell
Vesicles fuse and release transmitter
nerve signal
Target
cell .
Receptor binding and new signal
Target
cell .
signal . .
Neurotransmitter departs receptor
Target
cell
Neurotransmitter reabsorbed
by active transport
Target
cell
Neurotransmitter repackaged or
metabolized
Target
cell .
Receptor
Vesicle containing
noradrenaline .
Transport protein

15. 6. Transmission process Presynaptic Control
Presynaptic receptors control release of noradrenaline
Prostaglandins, acetylcholine and noradrenaline affect release
Active cholinergic nervous system inhibits adrenergic activity NA
Smooth muscle
Prostaglandins
Ach
Cholinergic receptor
Presynaptic adrenergic receptor
Activation of receptor
reduces noradrenaline release
Prostaglandin receptor
Postsynaptic adrenergic receptor
NA Noradrenaline NA

16. 7. Drug targets . 5 .
5. Transport protein for noradrenaline
1. Enzymes in the biosynthesis of noradrenaline .
Tyr 1 2 .
2. Vesicles carrying noradrenaline 4 .
4. Adrenergic receptor 3 .
3. Exocytosis of vesicles with cell membrane 6
Metabolites
6. Metabolic enzymes 7
7. Presynaptic receptors
Noradrenaline
Adrenergic receptor
Transport protein
Presynaptic receptor

17. 8. Adrenergic binding siteO H
Ser-207
Ser-204
TM5
Phe-290 C 2
TM6
Asp-113
TM3 .
Asn-293
NH2 + O H N C 3
here

18. 9. Structure-Activity Relationships
Alcohol
Alkylammonium ion
Phenol
Notes
Phenol groups form H-bonds to binding site (especially b-adrenoceptors)
meta-Phenol can be replaced with other hydrogen bonding groups
Alcohol forms a hydrogen bond to the binding site
Alkylammonium ion forms an ionic bond to the binding site
N-Alkyl groups affect target selectivity
Larger N-alkyl groups lead to selectivity for b-adrenoceptors
Aromatic ring forms van der Waals interactions with the binding site

19. Dopamine
Mechanism of action: α, β, D1 and D2 agonist.(vasodilatation )
for anaphylactic shock.
Side effects: rare because of rapid metabolism
used IV not orally, since it is substrate for both MAO and COMT.

20. Norepinephrine (when used as drug, called Levarterenol)
Mechanism of action: resembles epinephrine but with weaker effect on β2 (CH3).
anaphylactic shock (vasoconstriction).
Side effects: skin sloughing
Since it is a substrate for both MAO and COMT, it is used IV .
Less than 10% secreted from adrenal gland.

21. Epinephrine
Mechanism of action: β effect (vasodilator) at low doses and α effect (vasoconstriction) at high doses, Hyper- glycemia by glycogenolysis (β2 effect) and reduction of insulin (α2 effect). Lipolysis (β effect).
Structure-based explanation of Therapeutic uses: Acute asthma , anaphylactic shock. cardiac arrest. Used with local anaesthetics

22. Ephedrine
Mechanism of action: α ,β agonist and NE reuptake inhibitor (mixed mech.)
Structure-based explanation of Therapeutic uses: asthma, nasal decongestant (CNS side effects).
Orally active?
Chiral centers?
Not Catechol, long duration of action.

23. Pseudoephedrine ((s,s) diastereomeric of ephedrine)
Mechanism of action: NE reuptake inhibitor
Structure-based explanation of Therapeutic uses: asthma, nasal decongestant .
Structure-based explanation of Side effects: It has less CNS side effect than ephedrine (Stereoselective).

24. Amphetamine (drug with abuse)
Mechanism of action: NE reuptake inhibitor.
Therapeutic uses: Child hyperactivity, appetite control.
Side effects: Increases the blood pressure.
Talk about Fenethylline (Captagon(R))
Orally active?
Duration? MAO ?

25. Cocaine
Mechanism of action: local anaesthetic by blocking Na/K ATPase which is used also for NE reuptake.
Therapeutic uses: historically used as local anaesthetic.
Side effects: Increases the blood pressure.
Weak AntiChol. Effect, why?

26. Phenylephrine Mechanism of action: α1> α2 agonist
Therapeutic uses: nasal decongestant.
Similar to adrenaline, less potent?

27. Clonidine (Catapress)
Mechanism of action: α2 agonist by feed back inhibition .
Therapeutic uses: centrally acting hypotensive agent.
Guanido gp, pka?

28. Methyldopa (Aldomet)
Mechanism of action: α2 agonist after conversion to methylnorepinephrine. Prodrug?
Decarboxylase inhibitor
Therapeutic uses: centrally acting hypotensive agent.

29. Dobutamine
Mechanism of action: β1 agonist, positive inotropic with little chronotriopic effect, so less demand on oxygen by the heart.
Therapeutic uses: congestive heart failure
Side effects: CNS disturbances (rare), stroke (hemorrhage), arrythemia

30. Metaproterenol or Orciprenaline
Mechanism of action: β2 >β1agonist.
Therapeutic uses: asthma.
Catechol, Resorcinol, hydroquinone.
here

31. Terbutaline (Brethine (R))
Mechanism of action: short acting β2 agonist

32. ADRENERGIC AGONISTS
β2-Agonists

33. 1. b2-Adrenoceptor Notes G-Protein-coupled receptor
Activates the generation of cyclic AMP
Predominant receptor in bronchial smooth muscle
Activation results in smooth muscle relaxation
Dilates or opens airways
Agonists for the b2-adrenoceptor are potential anti-asthmatic agents

34. 2. Natural messengers Noradrenaline - neurotransmitter
Adrenaline - hormone
Notes
Activates all adrenergic receptors
No selectivity
Adrenaline used for severe anaphylactic shock
- fast acting, but short acting
- cardiovascular side effects
- unsuitable for long term medication

35. 3. Isoprenaline Notes Shows some selectivity for b-adrenoceptors
Bulky isopropyl group introduces b-selectivity
No selectivity between b-subtypes
Cardiovascular side effects

36. 4. Isoetharine Notes Shows selectivity for b2-adrenoceptors
Ethyl group introduces b2-selectivity
Short lasting due to drug metabolism
Metabolised by catechol-O-methyltransferase
Ether
COMT
Isoetharine
Inactive metabolite

37. 5. Variation of the meta-phenol group
Notes
Phenol is an important binding group (HBD or HBA)
Susceptible to metabolism
Replace with a different hydrogen bonding group
Carboxylic acid
Ester
Amide
Inactive
b2-Antagonist
b2-Antagonist

38. 6. R-Soterenol Sulfonamide group retains b2-agonist activity
Long lasting selective b2-agonist
Not used clinically

39. 7. Salbutamol (Albuterol)
Hydroxymethylene
t-Butyl group
Notes
Hydroxymethylene group retains b2-agonist activity
OH shifted from aromatic ring by one bond length
Forms a hydrogen bond to the target receptor
Not recognised by COMT
Same potency as isoprenaline
2000 times less active on the heart
4 hours duration of action
Market leader for the treatment of asthma
Administered as a racemate by inhalation

40. 8. Levalbuterol Notes R-Enantiomer of salbutamol
R-Enantiomer is 68 times more active than the S-enantiomer
Example of chiral switching

41. 9. Salmefamol Notes N-Arylalkyl group added
Extension
Notes
N-Arylalkyl group added
Methoxy group interacts with a polar region of the binding site
Extra binding interaction
1.5 times more active than sulbutamol
Longer duration of action (6 hours)

42. 10. Salmeterol Notes Longer lasting agent Used for nocturnal asthma
Polar group
Hydrophobic
Hydrophobic
Notes
Longer lasting agent
Used for nocturnal asthma
Increased lipophilicity
Binds more strongly to tissue in vicinity of the receptor
N-Substituent is lengthened
2x more active than salbutamol
Longer duration of action (12 hours)