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adrenergicdrugs-181220100636 (1).pptx
- 1. ADRENERGIC DRUGS DEPARTMENT OF PHARMACEUTICAL CHEMISTRY ISF College of Pharmacy, Moga Presented by- Shalini jaswal M.Pharm 1st sem Presented to : Dr. Vikram Deep Monga
- 2. What are adrenergic drugs? • Adrenergic drugs are medications that stimulate certain nerves in your body. They do this either by mimicking the action of the chemical messengers epinephrine and nor epinephrine or by stimulating their release. These drugs are used in many life-threatening conditions, including cardiac arrest, shock, asthma attack, or allergic reaction. Catecholamines The neurotransmitters of adrenergic system noradrenaline(norepinephrine) and of substance known as adrenaline(epinephrine) belongs to a class catecholamines. They called catecholamines because they have an alkylamine chain linked to catechol ring.
- 3. • Biosynthesis of catecholamines The biosynthesis of NE and adrenaline starts from the amino acid l-tyrosine. Adrenergic Neurotransmitters Biosynthesis of noradrenaline and adrenaline
- 6. The adrenergic binding site • The adrenergic receptors are G-protine couple receptors . • The knowledge of binding site is based on the mutagensis studies and molecular modelling. • From these studies it has been proposed that the three of the trans membrane helices (TM3, TM5, TM6) are involved in the binding site, • These studies also indicate the importance of an aspartic acid residue (Asp- 113), a phenylalanine residue(phe-290) and two serine residue(ser-207, ser- 204). • Modelling studies indicates that these groups can bind to adrenaline or noradrenaline
- 9. Classifications of adrenergics receptor agonist
- 10. Classification of direct acting alpha adrenergic agonist MOA: Adrenergic alpha-agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α₁ and α₂. Alpha 2 receptors are associated with sympatholytic properties. α Adrenergic agonists have the opposite function of alpha blockers Selective agonist alpha-1 adrenergic receptor agonist • Phenylephrine • Methoxamine • Midodrine • Metaraminol alpha-2 adrenergic receptor agonist Clonidine Xylazine Guanfacine Guanabenz Apraclonidine Lofexidine
- 11. Metaraminol methoxamine Midodrine Clonidine Xylazine Guanfacin guanabenz Apraclonidine Phenylepherine Lofexidine NEWER DRUG alpha-1 adrenergic receptor agonist alpha-2 adrenergic receptor agonist
- 13. Classification of direct acting beta adrenergic agonist MOA: β adrenergic receptors are coupled to a stimulatory G protein of adenylyl cyclase. This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes, inactivate myosin light-chain kinase and activate myosin light-chain phosphatase. In addition, β2 agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells. The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation.
- 14. Beta-1 receptor agonist • Dobutamine • Denopamine • Xamoterol • Prenalterol Dobutamine Denopamine Xamoterol prenalterol
- 16. synthesis of clenbuterol synthesis of Orciprinaline
- 17. Non selective adrenergic agonist MOA: They can stimulate either of the receptor i.e alpha as well as beta or both. Drugs Available •Adrenaline •Norepinephrine •Isoprenaline •Dopamine Adrenaline Norepinephrine Isoprenaline Dopamine
- 18. Mixed acting agonist Mixed-acting adrenergic agonists are compounds that cause activation of adrenergic receptors by both direct binding as well as release of endogenously-stored norepinephrine from presynaptic terminal. • Ephedrine • pseudoephedrine Ephedrine Pseudoephedrine
- 19. Indirect acting adrenergic agonist • Indirect-acting adrenergic agonists are compounds that cause activation of adrenergic receptors by mechanisms other than their direct binding. MOA for indirect acting •Indirectly acting adrenergic agonists affect the uptake and storage mechanisms involved in adrenergic signalling. •Two uptake mechanisms exist for terminating the action of adrenergic catecholamines - uptake 1 and uptake 2. Uptake 1 occurs at the presynaptic nerve terminal to remove the neurotransmitter from the synapse. Uptake 2 occurs at postsynaptic and peripheral cells to prevent the neurotransmitter from diffusing laterally. •There is also enzymatic degradation of the catecholamines by two main enzymes - monoamine oxidase and catechol-o-methyl transferase. Respectively, these enzymes oxidise monoamines (including catecholamines) and methylate the hydroxal groups of the phenyl moiety of catecholamines. These enzymes can be targeted pharmacologically. • Inhibitors of these enzymes act as indirect agonists of adrenergic receptors as they prolong the action of catecholamines at the receptors.
- 20. cocain Selegiline entacapone amphetamine tyramine The indirect acting adrenergic drugs may be classified as. 1. Releasing agents- amphetamines, 2. Uptake inhibitors- cocain 3. MAO inhibitors- selegiline 4. COMT inhibitors- entacapone
- 21. SAR of alpha and beta receptor agonist
- 22. SeparationofAromaticRingandAminoGroup the greatestadrenergicactivity occurswhen two carbonatoms separatethe aromatic ring from the aminogroup SubstitutionontheAminoNitrogenDetermines-or-Receptor Selectivity
- 23. Substitution on either carbon-1or carbon-2yieldsopticalisomers. (1R,2S)isomersseemcorrect configurationfor direct-acting activity. The more potent enantiomer has the (1R) configuration.This enantiomer is typically several 100-fold more potent than the enantiomer with the (1S) configuration R2,Substitutionon the-Carbon(Carbon-2). Methylorethylsubstitutiononthe a-carbonof the ethylamine side chainreducesdirect agonistactivity at both α-andβ-receptors. a-Substitution alsosignificantly affects receptorselectivity. a-methylnorepinephrine,it isthe erythro (1R,2S)isomer that possessessignificant activity atα2-receptors.
- 24. Substitution on theAromaticRing becausetheresorcinolringis nota substrateforCOMT,B-agoniststhat contain this ring structure tend to havebetter absorption characteristicsanda longer DOAthan their catechol-containingcounterparts. replacementofthemeta-OHof the catecholstructure witha hydroxymethyl groupgivesagentsareselectivebeta-2agonist. Modificationof thecatecholringcanalsobring about selectivity at α- receptorsasit appearsthat the catecholmoiety ismoreimportant for α2- activity than forα1-activity.
- 27. Adrenergic antagonist • An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors.
- 28. Properties of all generations
- 29. General pharmacology of adrenergic antagonist
- 30. • Alpha receptor antagonist • MOA: Alpha-blockers, also known as α-blockers or α- adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors. Alpha-1 selective quinalzoline derivatives Prazosin Terazosin Doxazosin Silodosin Alfuzosin Tamsulosin Prazosin Terazosin Doxazosin Tamsulosin Alfuzosin Silodosin NEWER DRUGS
- 34. Non-selective Haloalkylamine derivatives Phenoxybenzamine Phentolamine Imidazoline derivative Tolazoline Ergot alkaloids ergotamine Phenoxybenzamine Phentolamine Urapidil Ergotamine
- 35. Classification of Beta receptor antagonist MOA:- Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions β1-selective agents :- Selectively act on beta 1 receptor and antagonise the action. •Sotalol •Timolol •Acebutolol •Atenolol •Betaxolol •Bisoprolol •Celiprolol •Metoprolol Sotalol NEWE TR imolo D l Acebutolol Atenolol RUG
- 38. Beta receptor antagonist •β2-selective agent: Selectively act on beta-2 receptor and antagonise the action. •Butaxamine •ICI-118,551 Butaxamine ICI-118,551 NEWER DRUGS
- 40. Non Selective: antagonise action of both beta 1 and beta-2 generally used as beta 2 blockers •Propanolol •Bucindolol •Carteolol •Carvedilol •Labetalol •Nadolol •Oxprenolol •Penbutolol •Pindolol Beta receptor antagonist Propranolol Bucindolol Carteolol Carvedilol
- 42. Synthesis of Penbutolol Synthesis of Oxeprenolol
- 43. SAR of Beta receptor antagonist i.e R isomer is active