ADRENERGICS ▪ Adrenergic nerves forms the postganglionic sympathetic system whose neurotransmitter at the synapse is noradrenaline also called norepinephrine. ▪ There are two types of adrenergic receptors i.e.; α and β receptors ▪ α receptors is subdivided into α1 and α2 while β receptors are β1, β2 and β3. ▪ Various organs in the body have various ratios of α & β and the pharmacological effect of the excitation or inhibition of the receptor will depend on the dominancy of the receptor type i.e. α or β Site Receptor type Effectα Arterioles α1, α2 constriction β2 relaxation Eye α1 pupil dilation GIT α1 β2 decreased motility Heart β1 ↑ force & rate of contraction Lungs β2 bronchodilation Liver α1, β2 ↑ gluconeogenesis & glycogenolysis Uterus β2 muscle relaxation CLASSIFICATION OF ADRENERGIC DRUGS Agonists β -phenylethylamines - Others - Aliphatic amines - Imidazolines -Adrenaline Analogs -Ephedrine analogs Antagonists (antiadrenergic) β blockers α blockers those inhibing release isoprenaline analogs of catecholamines e.g. xylocholine, guanethidine competitive -Ergot alkaloids -Yohimbine ADRENERGIC AGONISTS β - PHENYLETHYL AMINES General structure 1 non competive - β halo alkylamines - Dibenzazepines They are divided into the adrenaline series and the ephedrine series The adrenaline series: Have a 10 or 20 amine group i.e. they have a H or an alky group on the R position, they have no substituents on the α carbon (just hydrogens), have hydroxyl group (-OH) on the β carbon and at least one or two OH group at the phenyl ring The ephedrine series : Are similar to adrenaline series at posn 1 & 3 and different at posn 2 and 4 i.e. they have 10 or 20 amine group, have an alkyl group mainly a methyl on the α carbon, have the OH group on the β carbon and may or may not have the phenolic hydroxyl group. a. Adrenaline series ▪ ▪ ▪ Consists of catecholamines which include: - The hormone adrenaline - The adrenergic NTs ie noradrenaline & dopamine These three are endogenous sympathomimetic catecholamines. Adrenaline is produced in preganglionic nerve endings in the adrenal medulla, noradrenaline is synthesized and stored in adrenergic nerve endings where it is released on physiological or pharmacological stimulation by drugs. Dopamine is synthesized in nerve endings in the CNS where it is a neurotransmitter. Isoprenaline is an exogenous catecholamine Catecholamines are amine derivatives of catechol (2-hydroxyphenol or o-hydroxyphenol) ▪ Endogenous catecholamines are synthesized from phenylalanine and Tyrosine as follows ▪ TH- Tyrosine hydroxylase, DD- Dopa decarboxylase , DH- Dopamine β- hydroxylase, PEANMT- phenylethanolamineN- methyl transferase. The biosynthesis produces levo isomers which are the active isomers. 2 The catecholamines can also be synthetically be produced in the lab through a series of rxns. Lab synthesis produces racemic mixtures which are then purified by fractional precipitation or by reaction with tartaric acid Physical chemical properties and Stability of catecholamines ▪ Catecholamines are basic at physiological PH, and are unstable in neutral or alkaline medium esp. in the presence of air, heavy metals and high temp. ▪ Catecholamines have excess electrons arising from the lone pair of electrons of the OH groups and they π electrons hence the cpds are highly unstable in 02 & light esp. in their basic form than salt form. Thus they undergo auto – oxidation producing pigmented polymers e.g adrenochrome ▪ When adrenaline in soln is exposed to light in the presence of air it undergoes auto-oxidation producing pink pigments. ▪ Auto-oxidation is accelerated in the presence of light O2 & heavy metal in soln. To prevent this, the soln is formulated with antioxidant e.g. sodium metasulphate or nitrogen containing cpds. They are also formulated with metal scavengers or chelating agents or ensuring metal free water. ▪ The soln is also stored in amber coloured bottle to prevent auto oxidation by light Metabolism Catecholamines are metabolized to inactive metabolites by methylation by catechol O-methyl transferase (COMT) and N-oxidation by mono-amine oxidases (MOA).catecholamines used as drugs are only given as injection since COMT enzyme is widely distributed in the body and MOA are available in the liver and intestine b. Ephedrine series ▪ It differs from the adrenaline series by presence of CH3 at psn 2 (or β position) and absence of OH at the phenyl group ▪ Ephedrine has two asymmetric centres (2 chiral carbons) resulting in 4 optical isomers: 2 of them dextro and the other two levo. Only one is active i.e. D- erythro ▪ ▪ ▪ ▪ Only isomer is active hence during chemical synthesis of ephedrine only 25% of the material obtained is active. The threo isomers are also called pseudoephedrine Adrenaline has one chiral centre hence has only two optical isomers i.e. levo & dextro. No geometric isomerism 3 Stability of ephedrine series Ephedrine series are more stable than the adrenaline series becoz they lack the phenolic OH which is responsible for instability for the adrenaline series. Those with OH have equal stability to those of adrenaline series Chemical structures of some β - phenylethyl amine adrenergic drugs : Adrenaline series Adrenaline Noradrenaline Isoprenaline Salbutamol (ventolin®) Terbutaline Phenylephrine Ephedrine series Relative ao at receptors β2 > α1,α2,β1 α>β β2 > β1 β2 > β1 X 3 ׳-OH, 4׳-OH 3׳-OH, 4 ׳-OH 3׳-OH, 4׳-OH 3 ׳-CH2OH, 4׳-OH R OH OH OH OH R1 H H H H R2 CH3 H C(CH3)2 C(CH3)3 3 ׳OH, 5׳-OH 3׳-OH OH OH H H C(CH3)3 β2 > β1 CH3 α1 X R R1 R2 Receptor Ephedrine H OH CH3 CH3 α and β Amphetamine H H CH3 H α and β Methamphetamine H H CH3 CH3 α and β Metaraminol 3׳-OH OH CH3 H α1 MOA of adrenergic agonist ▪ Sympathomimetics or adrenergic agonists, also called pressor drugs are classified on their basis of mode of action into: o Direct acting bind to and activate receptors (α or β) to elicit activity e.g. catecholamines o Indirect acting act by displacing catecholamines (mainly Noradrenaline) from the nerve ending storage sites e.g. Amphetamine o Dual acting act by both mechanisms e.g. ephedrine Note: The presence of the OH group on the β carbon has marked influence on the mode of action of these drugs. Those with OH on the β carbon have a direct action while those without are indirect acting. S.A.R of β - phenylethyl amines 4 1. The alkyl side chain ▪ For max. Ao there must be an ethyl chain separating the amine and aromatic group ▪ Increasing or reducing the chain length reduces or leads to loss of Ao 2. The amino group ▪ The classification of adrenergic receptors into α & β depends on the response obtained from the catecholamines administered. α receptors are sensitive to catecholamines as follows in decreasing order: noradrenaline˃ adrenaline˃ isoprenaline while β receptors,sensitivity decreases as follows: isoprenaline˃adrenaline˃ noradrenaline ▪ α or β Ao is depended on the substituent on the amine group. Primary amines e.g. noradrenaline have higher and better activity ▪ Primary amines, where R is a hydrogen e.g. noradrenaline, have higher affinity & better A o at α receptors. ▪ As the R substituents on the amine is changed from H to alkyl, Ao shifts from α to β depending on the length/size of the chain i.e when R is a small group like methyl, there is mixed α & β Ao e.g. adrenaline. Phenylephrine has exclusive α activity despite N-methyl substituent. ▪ Longer and branched alkyl chains(e.g. isopropyl in isoprenaline) shifts activity/affinity to β receptors. ▪ When the R group is a large alkyl or aromatic group the cpd becomes a β blocker ▪ Dialkylation producing 30 amines destroy Ao or has little Ao & increased toxicity & it can only be active if it undergoes metabolic dealkylation to produce 20 & 10 amines. 3. The alpha carbon ▪ Alkyl group at α carbon makes the cpd stable towards metabolic oxidation by MAO hence imparting oral activity as seen in ephedrine series which are orally active. ▪ However presence of the methyl group reduces CVS Ao ▪ α methyl cpds persists in nerve terminals and are more likely to displace noradrenaline from storage site i.e they have indirect acting Ao ▪ The alkyl group reduces adrenergic Ao & increases CNS stimulation i.e. ephedrine series have CNS stimulation ▪ The alkyl group also introduces optical isomerism. 4 isomers result; In the ephedrine series d isomer is more active . D-erythro is more active than L-erythro. Threo isomers, known as pseudoephedrine, have little adrenergic activity. ▪ Di alkylation on the α carbon produce inactive cpds 4. Beta carbon ▪ A β OH increases adrenergic Ao ▪ The β OH introduces optical isomerism in which the levo isomer is more active ▪ The OH increases polarity which affects CNS Ao i.e cpds with a β OH have limited CNS effects becoz they are unable to cross the BBB ▪ Cpds without OH have marked CNS stimulation i.e amphetamine, methampheramine. ▪ Cpds with β OH are normally solids & those without OH are liquids at room temp & pressure (normal conditions). This explains why this cpds are used in aerosols. The OH facilitates H. bonding which in turn affects viscosity 5 5. The phenyl ring ▪ It cannot be replaced by other bioisosteric rings or groups because the resulting cpds cannot fit on the receptors ▪ Presence of OH on the phenyl increases adrenergic agonist Ao . Non- phenolics have lower affinity for α receptor & lower intrinsic Ao for β receptors, hence less potent than the phenolics ▪ The posn of OH determine potency. For monohydroxylated cpds activity is ▪ ▪ A para hydroxy confers better Ao on β than α- receptors. Dihydroxylated cpds are more active than mono hydroxylated cpds & max. Ao is obtained when the OH are at meta & para (3׳, 4)׳ ▪ The meta –OH is easily metabolized by COMT hence cpds with this group are not orally active unless the grp is protected, hence conversion of the meta OH to a methyl alcohol e.g. in salbutamol confers oral Ao ▪ Dihydroxylated cpds at both meta posn i.e 3 & ׳5 ׳are orally active becoz they are resistant to e.g. are orally active becoz they are resistant to COMT e.g. terbutaline ▪ The dihydroxylated are also more selective for β receptors if they have large amine substituents e.g. terbutaline, salbutamol which are used as bronchodilators ▪ Cpds without OH are not acted upon by COMT Phenolic and the alcohol OH groups ▪ The OH grps on the β carbon on the phenyl ring determines whether the cpd is direct acting, indirect acting or dual acting. Direct acting have a β OH & at least one phenolic OH. ▪ Indirect acting do not have a β OH but have a phenolic OH ▪ Dual acting acting have β OH & no phenolic e.g. ephedrine ▪ Both phenolic & β OH affect CNS Uses of β phenylethylamines 1. α agonists ▪ Adrenaline is used in mngtof emergency tx of anaphylaxis rxn ▪ Adrenaline is also used in mngt of shock ▪ Is used in cardiopulmonary resuscitation ▪ Used to increase duration of action of local anesthetics due to its vasoconstriction effects Noradrenaline ▪ Used in acute hypotension & cardiac arrest / cardiopulmonary resuscitation Isoprenaline – Was previously used as a cardiac stimulant & an antiasthmatic drug Ephedrine – Is used to counter hypotension which arises due to anaesthesia / to reverse hypotension ▪ Is used as a nasal decongestant in cold & flue remedies Phenylephrine – Used as a nasal decongestant ▪ Used in acute hypotension which may arise from general anaesthesia ▪ Mngt of priapism Amphetamines 6 ▪ As CNS stimulants with several clinical uses(CNS stimulants) 2. β agonists Salbutamol & terbutaline ● Used as bronchodilators in obstructive respiratory airway diseases e.g. asthma & COPD ● Salbutamol – used to inhibit uncomplicated immature labour Metabolism ▪ N – dealkylation which affects the side chain ▪ Deamination ▪ O- methylation where the OH is converted to a methoxy. Where there are both meta & para OH, the meta is preferably methylated. ▪ Ring hydroxylation ▪ Mono amine oxidation IMIDAZOLINES They have the general structure below, in which an imidazoline ring is attached to an aromatic group (Ar) through a methylene bridge. They include: 1. Naphazoline (Albalon®) 2. Oxymetazoline (nasivion®) 3. Tetrahydrozoline (visine®) 4. Xylometazoline (otrivin®) - They are alpha receptor agonists - Used in nasal decongestion & vasoconstriction in the eye - Are formulated as liquids i.e. as drops & aerosols becoz they have no OH 2-AMINOIMIDAZOLINES They cause vasoconstriction by stimulating peripheral α1 receptors but this is only a transient effect since their more prominent effect is CNS mediated vasodilation through action at α2 receptors. E.g. clonidine – used in hypertension, recurrent migraine and menopausal flashing Brimonidine – used in glaucoma A halogen substituent on the aromatic ring increases activity Clonidine Others adrenergic agonists - Are open chain analogs of imidazolines e.g guanabenz 7 - They are aliphatic amines with central α2 Ao similar to clonidine. Methyldopa – A centrally acting agent. It is a prodrug converted to α- methyl noradrenaline in the CNS. The metabolite acts at CNS α2 receptors to reduce sympathetic output. Used in hypertension with the advantage of being safe in pregnancy. Dopamine & dobutamine Dopamine – Is a CNS transmitter involved in regulation of movt. - Is not a true adrenergic drug, but selectively stimulators β1 receptors in the cardiac muscle hence increasing contractility/inotropic effects. - Used as a cardiac stimulant - Has the advantage of renal vasodilation unlike the other inotropic agents - It does not cause renal vasoconstriction - It is a substrate/ metabolite of MAO & COMT hence not given orally & has a very short duration of action when given parenterally Dobutamine - Is an analog of dopamine with long duration of action but without oral Ao - Also used for inotropic support e.g during cardiac surgery, shock etc Dopexamine - Used for inotropic support & vasodilation in chronic heart failure NB: Like all other catecholamines these cpds are incompatible with alkaline solution. ADRENERGIC ANTAGONIST - Counter action of sympathomimetic or limit sympathetic flow i.e. interfere with action of catecholamines at the receptors or block the action of catecholamines. - Basing on their mode of action they are classified into: a. Those that antagonize agonists at α receptors(α blockers) b. Those that antagonize agonists at β receptors(β blockers) c. Those that prevent the release of catecholamines mainly noradrenaline from storage sites a. Those that interfere with release of catecholamines They include ▪ Xylocholine ▪ Bretylium ▪ Guanethidine ▪ Debriboquine - They displace noradrenaline / catecholamines from storage site leading to a great depletion of the same - Were used to treat mild to moderate hypertension but have been replaced by better drugs b. β blockers & α blockers - To be discussed in hypertension (CVS) 8 9
