Adrenergic Agonists PDF

**IV. ADRENERGIC AGONISTS** ***[Learning objectives]*** 1. ***Outline the effects of sympathomimetic agents on peripheral organ systems*** 2. ***List the major sympathomimetic agonists and their routes of administration*** 3. ***Describe the therapeutic and adverse effects of the majo...

**IV. ADRENERGIC AGONISTS** ***[Learning objectives]*** 1. ***Outline the effects of sympathomimetic agents on peripheral organ systems*** 2. ***List the major sympathomimetic agonists and their routes of administration*** 3. ***Describe the therapeutic and adverse effects of the major sympathomimetic drugs*** ***[Reading material]*** **Drugs that mimic the actions of A or NA are referred to as sympathomimetic drugs**. **They have a wide range of effects, such as regulating activities of the heart & peripheral vasculature, especially in response to stress.** **Sympathetic stimulations are mediated by release of NA, A or DA from the nerve terminals that serve to activate the adrenoceptors on postsynaptic sites.** **Adrenaline, noradrenaline and dopamine are called *catecholamines*.** ***[a) The Adrenergic Neuron]*** **Adrenergic neurons release [NA] as the neurotransmitter**. Adrenergic neurons are **mostly found in the CNS and also in the sympathetic nervous system. They form the link between ganglia and the effector organs.** NA is **released from the nerve terminals of the postganglionic neuron.** **The adrenergic neurons and receptors are located either [presynaptically] on the neuron (autoreceptors), or [postsynaptically] on the effector organ.** ***[b) Neurotransmission at adrenergic neurons]*** **It closely resembles that of the cholinergic neurons, except that NA is the neurotransmitter instead of Ach. The process involves 5 steps: (1) the synthesis, (2) storage, (3) release, (4) receptor binding of the NA, (5) followed by removal of the neurotransmitter from the synaptic gap.** **1) Synthesis of NA:** **Tyrosine is transported by a Na^+^-linked carrier into the axoplasm of the adrenergic neuron** **where it is 3-hydroxylated to dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase. This is the rate-limiting step in the formation of NA.** **L-DOPA is then decarboxylated to form dopamine (DA).** **2) Storage of NA in vesicles:** **DA is transported into synaptic vesicles by an amine transporter system that is also involved in the re-uptake of preformed NA. This carrier system is blocked by reserpine (anti-hypertensive drug)** **DA is hydroxylated to form NA by the enzyme, DA β-hydroxylase.** **3) Release of NA:** **An action potential arriving at the nerve junction triggers an influx of Ca^2+^ ions into the axoplasm. The increase in Ca^2+^ ions causes vesicles inside the neuron to fuse with the cell membrane & release their contents into the synapse. This release is blocked by drugs such as guanethidine[.]** **Tyramine can enter the nerve terminal and displace stored NA.** **4) Binding to a receptor: [ ]** **NA released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors, or to presynaptic receptors.** **The recognition of NA by the membrane receptors triggers a cellular response via formation of intracellular second messengers. Adrenergic receptors use both the cAMP & IP~3~ 2^nd^ messenger system.** **5) Removal of norepinephrine:** **NA may** - **(i) diffuse out of the synaptic space & enter the general circulation** - **(ii) be metabolized by postsynaptic cell membrane-associated catechol O-methyltransferase (COMT) in the synaptic space, or** - **(iii) be recaptured by an uptake system that pumps the NA back into the neuron** **The uptake by the neuronal membrane involves a Na^+^/K^+^-activated ATPase and can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine.** **6) Potential fate of recaptured NA:** **Once NA re-enters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system & be ready for release by another action potential, or** a**lternatively, NA can be oxidized by monoamine oxidase (MAO), present in neuronal mitochondria.** **The inactive products of [NA] metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine.** ***[c) Adrenergic receptors (adrenoceptors; ARs)]*** **Several classes of ARs have been distinguished pharmacologically**. **Two families of receptors, designated** - **α-ARs, and** - **β-ARs** **Currently there is a number of AR-subtypes identified.** ***[i) Alpha adrenoceptors]*** **The α-ARs are subdivided into two subgroups, α~1~ & α~2~ receptors based on their affinities for agonists and blocking drugs.** **The α~1~-ARs are postsynaptic and "excitatory", while the α~2~-ARs are presynaptic and has "feed-back inhibitory effect".** ***1) α~1~-ARs*** are **found on the postsynaptic membrane of the effector organs. There are three pharmacologically defined α~1~-ARs (α~1A~-; α~1B~-; α~1D~-ARs) with distinct sequences and tissue distribution.** **Activation of the α~1~-ARs initiates a series of reactions through a G~q~ protein activation of phospholipase C, resulting in the generation of inositol-1 ,4,5-trisphosphate (IP~3~) causing the release of Ca^2+^ from the endoplasmic reticulum into the cytosol.** **Ca^2+^ can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion, or contraction.** ***2) α~2~-ARs*** are **located primarily on presynaptic nerve possessing feedback-inhibitory effect***.* **There are also three subtypes of α~2~-ARs i.e α~2A~-; α~2B~-; & α~2D~-ARs.** **They act by inhibiting the ongoing release of NA from the stimulated adrenergic neuron**. **They are also found on other cells, such as the b cell of the pancreas regulating insulin output**. **They also play a vital role in the CNS, where its inhibitors are useful as anti-depressants (mianserine, mirtazepine).** **The effects of binding at α~2~-ARs are *mediated by inhibition of Gi-adenylyl cyclase & a fall in the levels of intracellular cAMP.*** *ii[**) Beta** **adrenoceptors**]* **The bβ-ARs are subdivided into three subgroups, β~1~-; β~2~-; & β~3~-ARs -- but β~1~-; & β~2~-ARs are the major receptors. Their division is based on their affinities for adrenergic agonists and antagonists.** **β~1~-ARs have approximately equal affinities for A & NA, whereas β~2~-ARs have a higher affinity for A than for NA**. **The β~3~-ARs are about tenfold more sensitive to NA than A** **Thus, tissues with a predominance of β~2~-ARs (bronchial smooth muscles; blood vessels of skeletal muscle) are particularly responsive to the hormonal effects of circulating A released by the adrenal medulla.** **Activation of all the β-ARs results in activation of Gs-adenylyl cyclase complex &, therefore, increased concentrations of cAMP within the cell.** ***[iii) Dopamine receptors]*** **Endogenous catecholamine dopamine (DA) produces a variety of biologic effects that are mediated by interactions with specific DA receptors**. **These receptors are distinct from α and β receptors and are of particularly importance in the brain. They are also located in the splanchnic (innervating the visceral organs) & renal vasculature.** **There is now considerable evidence for the existence of at least 5 subtypes of DA receptors - i.e. D~1-5~. D~1~ receptor -- associated with the stimulation of adenylyl cyclase. D~2~ receptors - inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.** *[iv) **Distribution of receptors**]* **Organs and tissues innervated by the adrenergic neurons tend to have a predominance of one type of receptor e.g. vasculature to skeletal muscle have both α~1~-& α~2~-ARs, but the α~2~-ARs predominate. Other tissues may have 1 type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors e.g. the heart contains predominantly β~1~-ARs**. ***[d) Characteristic responses mediated by ARs]*** **In general, stimulation of α~1~-ARs characteristically produces vasoconstriction (particularly in skin and abdominal viscera) & an increase in total peripheral resistance & blood pressure.** ***Stimulation of β~1~-ARs characteristically causes cardiac stimulation whereas β~2~-ARs produces vasodilatation in skeletal vascular beds (decreasing peripheral resistance) & bronchiolar relaxation (bronchodilation)***  *[e**) Desensitisation of receptors**]* **Prolonged exposure to the catecholamines reduces the responsiveness of ARs - a phenomenon known as desensitization.** **3 mechanisms have been suggested to explain this phenomenon:** - **1) sequestration of the receptors so that they are unavailable for interaction with the ligand;** - **2) down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis; and** - **3) an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase A or b-AR kinase** ***[f) Characteristics of Adrenergic Agonists]*** **Most of the adrenergic agonists are derivatives of phenylethylamine. Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds with varying abilities*.*** A chemical structure with text Description automatically generated *[i) **Catecholamines** ]* **Catecholamines are sympathomimetic amines that contain the 3,4-dihydroxybenzene group e.g. A, NA, & DA. These compounds share the following properties:** - **High potency:** - **Catecholamines with -OH groups in the 3 and 4 positions of the benzene ring show the highest potency in activating both a or β-ARs** - **Rapid inactivation by COMT & MAO:** - **Catechol-O-methyltransferase (COMT) is also found in the gut wall, and monoamine oxidase (MAO) is in the liver and gut wall** - **Thus, catecholamines have only a brief period of action when given parenterally,** - **and are ineffective when administered orally because of inactivation** - **Poor penetration into the CNS:** - **Catecholamines are polar and, therefore, do not readily penetrate into the CNS.** ***[ii) Non-catecholamines ]*** **Compounds lacking the catechol -OH groups have longer t~1/2~ -- since they are not inactivated by COMT.** **These include phenylephrine, ephedrine, & amphetamine.** **Phenylephrine, an analog of epinephrine, has only a single -OH at position 3 (on the benzene ring)**. **Ephedrine lacks both the -OH on the ring but has a methyl substitution at the a-carbon.** **They are poor substrates for MAO and, thus, show a prolonged duration of action**. **Increased lipid solubility of many of the non-catecholamines permits greater access to the CNS.**  ***[c) Substitutions on the amine nitrogen]*** **The nature and bulk of the substituent on the amine nitrogen is important in determining the β selectivity of the adrenergic agonist. A, with a -CH~3~ substituent on the amine nitrogen, is more potent at β-ARs than NA (unsubstituted amine)**. **Similarly, isoprenaline, with an isopropyl substituent -CH(CH~3~)~2~ on the amine nitrogen is a strong β agonist with little α activity** **In general, the smaller the substitution on the amino group, the greater the selectivity for the α activity. A notable exception in phenylephrine -- it has an N-methyl subsistent but is an α-selective agonist** ***[g) Mechanism of action of the adrenergic agonists]*** **Direct-acting adrenergic agonists: These drugs act directly on α- or β-ARs and mimic the effects of A. Direct-acting agonists include A, NA, isoprenaline, & phenylephrine and many others** **Indirect-acting adrenergic agonists: These agents, which include amphetamine & tyramine, are taken up into the presynaptic neuron and cause the release of NA from the cytoplasmic pools or vesicles of the adrenergic neuron. NA then traverses the synapse and binds to the α - or β-ARS** **Mixed-action adrenergic agonists: Some agonists, such as ephedrine & metaraminol, have the capacity both to stimulate adrenoceptors directly & to release NA from the adrenergic neuron**  ***[i) Adrenaline]*** **A interacts with both α- & β-ARs.** **At low doses, β effects (vasodilation) on the vascular system predominate, *whereas at high doses,* *α effects (vasoconstriction) are strongest*.** **[Actions]** **a) Cardiovascular** **The major actions of A are on the cardiovascular system -- it is one of the most potent vasopressor drugs known.** - **Heart**: **A strengthens the contractility of the myocardium -- positive inotropic effect (mediated by the β~1~-AR actions)**. **It also increases its rate of contraction - positive chronotropic (mediated by β~1~ action)**. **Cardiac output therefore increases** - **Vasculature:** **A constricts arterioles in the skin, mucous membranes, & viscera -- mediated by α~1~ actions**. It **dilates vessels going to the liver & skeletal muscle -- mediated by β~2~ action, decreasing the peripheral resistance. Renal blood flow is decreased while coronary blood flow is enhanced**. **At therapeutic doses A has very little constrictor action on the cerebral arterioles**. **Arterial & venous pulmonary pressures are raised & there is redistribution of blood from the systemic to the pulmonary system** **The resultant effect is an increase in systolic blood pressure (positive inotropic & chronotropic effects) coupled with a slight decrease in diastolic pressure (due to dilatation of the skeletal muscle vasculature).** **b) Respiratory:** **A affects respiration primarily by relaxing bronchial smooth muscles (β~2~-AR effect). The resultant effect is a powerful bronchodilation effect**. **This action relieves all known allergic or histamine- or drug- or asthma- induced bronchoconstriction. A in individuals suffering from an acute asthmatic attack, rapidly relieves dyspnea (labored breathing) and increases the tidal volume (volume of gases inspired and expired).** **c) Hyperglycemia:** **A has a significant hyperglycemic effect because of increased glycogenolysis in the liver - β~2~ effect**, **increased release of glucagon (β~2~ effect on the a cells of the pancreatic islets) & decreased release of insulin (α~2~ effect). A also decreases the uptake of glucose by peripheral tissues. These effects are mediated via the G~i/s~-cAMP mechanism.** **d) Lipolysis:** **[A] initiates lipolysis through its agonist activity on the b-ARs of adipose tissue, cAMP-induced by stimulation of the b-ARs stimulates triglyceride lipase, which hydrolyses triacylglycerols to free fatty acids and glycerol** ***Pharmacokinetics*** **A has a rapid onset but a brief duration of action**. **It is given IV for the most rapid onset of action in emergency situations.** **A injection is available in 1 mg/ml (1: 1 000), 0.1 mg/ml (1: 10 000), and 0.5 mg/ml (1: 2 000) solutions** **It may also be given subcutaneously, by endotracheal tube, by inhalation (1%; 10 mg/ml; 1: 100), or topically to the eye** **Oral administration is ineffective, because A and the other catecholamines are inactivated by intestinal enzymes** ***Therapeutic indications*** **a) [Bronchospasms]: in treatment of acute asthma and anaphylactic shock, *[A] is the drug of choice.*** **Selective β~2~ agonists, such as *salbutamol are presently favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect*** **b) [Glaucoma]**: **In ophthalmology, a *2% epinephrine solution may be used topically to reduce intraocular pressure in open-angle glaucoma***. **It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels** **c) [Anaphylactic shock]: *A is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens*** **d) [In anesthetics:] Local anesthetic solutions usually contain 1: 100,000 parts A.** **Its function is to greatly increase the duration of the local anesthesia** **by producing vasoconstriction at the site of injection, thereby allowing the local anesthetic to persist at the site before being absorbed into the circulation and metabolised.** **Very weak solutions of A (1:100,000) can also be used topically to constrict mucous membranes - control oozing of capillary blood.** **[Adverse effects]** **a) CNS disturbances: A can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor.** **b) Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of BP.** **c) Cardiac arrhythmias: A can trigger cardiac arrhythmias, especially in patients receiving digitalis analogs like digoxin.** **d) Pulmonary edema: Epinephrine can induce pulmonary edema.** **Interactions** **a) Hyperthyroidism: A may have enhanced cardiovascular actions in patients with hyperthyroidism** **probably due to increased production of ARs on the vasculature of the hyperthyroid individual -- leading to a hypersensitive response** **b) Cocaine: Cocaine prevents the re-uptake of catecholamines into the adrenergic neuron; thus NA & A remains at the receptor site for longer periods of time. In the presence of cocaine, A produces exaggerated cardiovascular actions** ***[ii) Noradrenaline]*** **Noradrenaline (norepinephrine; levarterenol) is the major chemical mediator liberated by mammalian postganglionic sympathetic nerves**. **It differs from A only in lacking the methyl substitution in the amino group.** **Theoretically, because NA is the neurotransmitter of adrenergic nerves, it is supposed to stimulate all types of adrenergic receptors like ACh at the cholinergic receptors** b**ut when the drug is given in therapeutic doses to humans, the a-AR is most affected -- but NA is not potent as A on these receptors**. **Their potency differ mainly in stimulating the a~1~- and b~2~-ARs** **[Cardiovascular actions of noradrenaline]: NA causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney -- mediated by the a~1~-ARs. NA causes greater vasoconstriction than does A because it does not induce compensatory vasodilation via β~2~-ARs of blood vessels supplying skeletal muscles. Instead NA constricts blood vessels supplying skeletal muscles (α~1~-ARs effect) further increasing the peripheral resistance. Both systolic and diastolic blood pressures increase** **[Therapeutic uses]** **NA is used to treat shock, because it increases vascular resistance &, therefore, increases blood pressure. However, metaraminol is favored, because it does not reduce blood flow to the kidney, as does NA.** **Other actions of NA are not considered to be of clinically significance**. **It is never used for asthma due to its minimal β~2~-AR affects*.*** ***[iii) Dopamine]*** **Dopamine (DA) is the immediate metabolic precursor of NA**. **It occurs naturally in the basal ganglia of the CNS, where it functions as a neurotransmitter, as well as in the adrenal medulla** **DA has an activity at α- and β-ARs.** **DA is also an agonist at all dopamine receptors (D~1-5~)**. **D~1~ & D~2~ dopaminergic receptors, occur in the peripheral mesenteric & renal vascular beds where binding of DA produces vasodilatation.** **D~2~ receptors are also found on presynaptic adrenergic neurons, where their activation interferes with NA release.** **[Actions]** **[Cardiovascular:] DA stimulates the β~1~-ARs of the heart, having both inotropic and chronotropic effects. At very high doses, DA activates AR receptors on the vasculature, resulting in vasoconstriction (α~1~-ARS).** **[Renal and visceral:] DA dilates renal & splanchnic arterioles by activating dopaminergic (D~1~ & D~2~) receptors, thus increasing blood flow to the kidneys & other viscera** **[Therapeutic uses]** **[Shock:]** **DA is the drug of choice for shock, and is given by continuous infusion**. **It raises the blood pressure by stimulating the heart (β~1~ action). In addition, it enhances perfusion to the kidney and splanchnic areas. In this regard, dopamine is far superior to [NA], which diminishes the blood supply to the kidney and may cause renal shutdown.** **[Adverse effects:]** **DA produces the same effects as sympathetic stimulation**. **It is rapidly metabolised to homovanillic acid, and its adverse effects are therefore short-lived.** ***[h) β-AR agonists]*** **β-AR agonists play a major role in the treatment of bronchoconstriction in patients with asthma or chronic obstructive pulmonary disease (COPD).** **Minor uses include:** - **Management of pre-term labour** - **Treatment of complete heart block in shock** - **Short term treatment of cardiac decompensation after surgery** i**n patients with congestive heart failure** **or myocardial infarction** ***1. Isoprenaline*** **Isoprenaline (Isoproterenol; isopropyl noradrenaline) is a direct-acting synthetic catecholamine. It potently stimulates the β-ARs nonselectively (predominantly stimulates both β~1~- & β~2~-ARs). Its action on α-ARs is insignificant.** **Actions** **a) Cardiovascular:** **Isoprenaline produces intense stimulation of the heart -- positive inotropic & chronotropic effects (β~1~ effect) causing increased cardiac output. It is as active as A in this action & therefore, is useful in the treatment of atrio-ventricular block or cardiac arrest.** **Isoprenaline also dilates the arterioles of skeletal muscle (β~2~ effect) resulting in a decreased peripheral resistance** **Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial & diastolic blood pressure**. **b) Pulmonary:** **profound and rapid bronchodilation is produced by the drug (β~2~ action)**. **Isoprenaline is as active as A & rapidly alleviates an acute attack of asthma when taken by inhalation**. **This action lasts about one hour and may be repeated by subsequent doses** **c) Other effects: Other actions on β-ARs, such as increased blood sugar and increased lipolysis, are not clinically significant** **Therapeutic uses** **Isoprenaline is now rarely used as a bronchodilator in asthma (due to its effects on the heart -- β~1~-AR effect). It can be employed to stimulate the heart in emergency situations -- such as in bradycardia and heart block.** **Pharmacokinetics:** **Isoprenaline can be absorbed systemically by the sublingual mucosa but is more reliably absorbed when given parenterally or as an inhaled aerosol.** **It is a marginal substrate for COMT and is stable to MAO action.** **Adverse effects:** **The adverse effects of isoprenaline are similar to those of A** ***2. Dobutamine*** **Dobutamine is a synthetic, direct-acting catecholamine**. **It is a selective β~1~-receptor agonist**. **It increases cardiac rate and output with few vascular effects** **[Therapeutic uses]: Dobutamine is used to increase cardiac output in congestive heart failure. The drug increases cardiac output with minimal effects on the heart rate. It does not significantly elevate O~2~ demands of the myocardium - a major advantage over other sympathomimetic drugs** **[Adverse effects:] Dobutamine should be used with caution in atrial fibrillation, because the drug increases atrioventricular conduction** **Other adverse effects are the same as those for A** ***[i) Selective β~2~-AR agonists]*** **Some of the major side effects of β-AR agonists in the treatment of asthma are caused by stimulation of the β~1~-ARs in the heart**. **Drugs with preferential affinity for β~2~-ARs have been developed -- however, this selectivity is not absolute and is lost at high concentrations of these drugs.** **The usefulness of these agents in the treatment of asthma has been enhanced by structural modifications made to these agents resulting in lower rates of metabolism and enhanced oral bioavailability:** - **They possess a 3 and 5 hydroxyl group in the phenyl ring (rather than 3 and 4 hydroxyl group of catechol) including metaproterenol, terbutaline, salbutamol** - **These drugs are not substrates of COMT** - **They possess bulky substituents on the amino group -- enhancing their β-AR affinity** **Mostly these agents are administered by small doses of the drug in aerosol form to enhance preferential activation of pulmonary β~2~-ARs.** ***1. Metaproterenol*** **Metaproterenol (orciprenaline) is chemically similar to isoprenaline but;** **is not a catecholamine, and is resistant to methylation by COMT.** **It can be administered orally (40% absorption rate) or by inhalation** **Its actions are primarily at β~2~-ARs, but not as selective as salbutamol and terbutaline -- hence it is more prone to cause cardiac stimulation.** **Metaproterenol produces dilation of the bronchioles and improves airway function**. **The drug is useful as a bronchodilator in the treatment of asthma and to reverse bronchospasm. Effects occur within minutes of inhalation and persist for several hours**. **Onset of action is slower when taken orally, but the effect may last for up to 4 hours** ***2. Terbutaline*** **Terbutaline is a β~2~-selective bronchodilator effective when taken orally, subcutaneously, or by inhalation**. **Effects are observed rapidly following inhalation and may persist for 3 to 6 hours. Parenteral administration - status asthmaticus.** **Oral administration delays the onset of effect for 1 to 2 hours** ***3. Salbutamol (albuterol)*** **Salbutamol is a β~2~-selective bronchodilator with pharmacological properties similar to those of terbutaline. Administered either orally or by inhalation.** **When administered by inhalation it produces significant bronchodilation with 15 minutes, effect persisting for 3 to 5 hours** **Oral salbutamol has a potential to delay labour** ***4. Isoetharine*** **Its degree of selectivity for β~2~-ARs is lower than those of other agents**. **It is used only by inhalation, for the treatment of acute episodes of bronchoconstriction** ***5. Pirbuterol*** **Structurally similar to salbutamol with the dosing frequency of 6 to 8 times a day** ***6. Bitolterol*** **Pro-drug -- it is activated by esterases in the lung to its active metabolite, colterol.** **Its duration of action is 3 to 6 hours** ***7. Fenoterol*** **It has rapid onset of effect following inhalation & its duration of action is similar to that of bitolterol.** ***8. Salmeterol*** **Has a prolonged duration of action over 12 hours**. **It possesses at least 50 times selectivity for β~2~-AR than salbutamol** **It is a effective as ipratropium (M cholinergic receptor antagonist) in the management of COPD -- an additive effect is seen when these two drugs are combined** **It is reported to possess some anti-inflammatory effects -- as a result it is an agent of choice for nocturnal asthma in patients not responding to standard treatment** **It should not be used for more than twice daily (morning and evening) and should not be used to treat acute asthma symptoms (short acting agents like salbutamol are preferred)** ***9. Procarerol*** **Following inhalation, it has prompt onset of action that is sustained for about 5 hours** ***10. Formoterol*** **It is a long-acting β~2~-AR agonists with significant effect observed minutes following inhalation**. **Its effects may persist for up to 12 hours -- major advantage in settings such as nocturnal asthma (like salmeterol)**. **It is highly lipophilic (accounts for its long duration of action) and has a high affinity for β~2~-ARs. It is approved for the treatment of asthma, COPD, & bronchospasms. It can be used in combination with short-acting β~2~-AR agonists, theophylline, and glucocorticoids** ***11. Ritodrine*** **It is a selective β~2~-AR agonist developed specifically for use as a uterine relaxant**. **It has an oral bioavailability of 30%.** ***[j) Adverse effects of Selective β~2~-AR agonists]*** **Tremor is a relatively common adverse effect of these agents**. **Tolerance also develops to the use of these agents** **Tachycardia is a common adverse effect of systemically administered selective β~2~-AR agonists due to β~1~-AR stimulation of the heart**. **Cardiovascular risks are increased in patients taking monoamine oxidase (MAO) inhibitors -- at least 2 weeks must elapse between the use of these agents** **Arterial O~2~ tension may fall -- due to drug induced pulmonary vasodilation** ***[k) Selective α~1~-AR agonists]*** **These agents increases peripheral resistance and rise the BP by activating the α~1~-AR in the vascular smooth muscles**. **Although the clinical application of these agents is limited they may be useful in treating patients with hypotension, including orthostatic hypotension (a drop in blood pressure that is precipitated by changes in body position), or shock** **Phenylephrine and methoxamine (discontinued in the USA) are direct-acting vasoconstrictors and are selective activators of α~1~-ARs**. **Mephentermine and metaraminol act both directly and indirectly** ***[i) Phenylephrine]*** **Phenylephrine is a direct-acting sympathomimetic drug that binds primarily to α~1~-ARs**. **It has β-AR effects only at very high concentrations**. **It is not a catechol derivative &, therefore, not a substrate of COMT**. **Phenylephrine is a vasoconstrictor that raises both systolic & diastolic blood pressures - no effect on the heart itself** ***Therapeutic uses*** **It is often used topically in ophthalmic solutions for mydriasis. Also used topically as a nasal decongestant, & produces prolonged vasoconstriction. (Degoran^®^ or Colcaps^®^)** **Used to raise the BP & to terminate episodes of supraventricular tachycardia (rapid heart action arising both from the atrioventricular junction and atria).** ***Adverse effects*** **Large doses can cause hypertensive headache and cardiac irregularities** ***[ii) Methoxamine]*** **Methoxamine is a direct-acting, adrenergic agonist that binds primarily to α-ARs**. It **favorers α~1~-ARs over α~2~-ARs receptors** **Methoxamine raises BP by stimulating α~1~-ARs in the arterioles, causing vasoconstriction & increasing peripheral resistance** ***Therapeutic indications:*** **Methoxamine is used clinically to relieve attacks of paroxysmal supraventricular tachycardia**. **It is also used to overcome hypotension during surgery involving halothane anesthetics.** ***Adverse effects*** **Include hypertensive headache and vomiting** ***[iii) Mephentermine ]*** **Mephentermine is a sympathomimetic drug which acts both directly and indirectly**. **Since the drug also releases NA cardiac contraction is enhanced, cardiac output, systolic & diastolic BP usually increases**. **It is used to prevent hypotension, which frequently accompanies spinal anaesthesia** ***[iv) Metaraminol ]*** **Metaraminol is also an indirect acting sympathomimetic agent that stimulates the release of NA**. **Used for the treatment of hypotensive states** ***[v) Midodrine ]*** **Midodrine is an orally active α~1~-AR agonist.** **It is a pro-drug -- its active metabolite is desglymidodrine with the half-life of 3 hours**. **It increases the BP via both arterial and venous smooth muscle contraction -- advantageous in treating patients with autonomic insufficiency and postural hypotension** ***[l) Selective α~2~-AR agonists]*** **Selective α~2~-AR agonists are used primarily for the treatment of systemic hypertension**. **Their efficacy as antihypertensive agents is surprising since many blood vessels contain postsynaptic α~2~-ARs that promote vasoconstriction** **The capacity of these agents to lower the blood pressure results from activation of the α~2~-ARs in the cardiovascular control centers of the CNS**. **This activation suppresses the outflow of sympathetic nervous system activity from the brain**. **In addition, the α~2~-AR agonists reduce the intraocular pressure by decreasing the production of aqueous humor** ***[i) Clonidine]*** **Clonidine was previously designed for use as a topical nasal decongestant but found to cause hypotension, sedation, and bradycardia.** **Pharmacokinetics** **Clonidine is well absorbed after oral administration with the oral bioavailability of approximately 100%**. **Its t1/2 = 6 to 24 hours**. **It is also available in the form of a transdermal patch -- an alternative for oral therapy** **Indications** **Clonidine is an α~2~-ARs agonist that is used in essential hypertension (unknown causes) to lower BP because of its action in the CNS. It can be used to minimize the symptoms that accompany withdrawal from opiates or benzodiazepines**. **Also used to produce preoperative sedation and anxiolysis, drying of secretions, and analgesia** **Adverse effects** **The major adverse effects of clonidine are dry mouth and sedation**. **Sexual dysfunction also may occur** ***[ii) Apraclonidine ]*** **Apraclonidine is a relatively selective α~2~-AR agonist that is used topically in the eye to reduce intra-ocular pressure**. **It is capable of reduce the intra-ocular pressure whether accompanied by glaucoma or not**. **Unlike clonidine, it does not cross the BBB and reserved for short term therapy in glaucoma as an adjunct in situations where intra-ocular pressure is not controlled** ***[iii) Brimonidine ]*** **It is also a clonidine analog administered ocularly to lower intra-ocular pressure in patients with ocular hypertension or open angle glaucoma.** **It is a selective α~2~-AR agonist that reduces the intra-ocular pressure both by decreasing the humour production and by increasing the outflow. Unlike apraclonidine, it crosses the BBB.** ***[iv) Guanfacine ]*** **Guanfacine is a selective α~2~-AR agonist that is more selective than clonidine. Like clonidine, it also lowers the blood pressure by activation of brainstem receptors with resultant suppression of sympathetic activity**. **Clonidine and guanfacine have similar efficacy in the treatment of hypertension -- but abrupt guanfacine discontinuation is associated with withdrawal symptoms** ***[v) Guanabenz ]*** **Guanabenz and guanfacine are closely related chemically and pharmacologically** ***[vi) Methyldopa]*** **Methyldopa is a centrally acting antihypertensive agent -- metabolised to a-methylnorepinephrine in the brain**. **These metabolite is believed to activate central α~2~-ARs and lower the blood pressure in a manner similar to that of clonidine** ***[vii) Tizanidine ]*** **Tizanidine is a muscle relaxant used for the treatment of spasticity associated with cerebral and spinal disorders**. **It is also a α~2~-AR agonist with some properties similar to those of clonidine** ***[m) Indirect-acting adrenergic agonists]*** **Indirect-acting adrenergic agonists do not directly affect postsynaptic receptors** b**ut cause NA release from presynaptic terminals. They potentiate the effects of NA produced endogenously** ***[i) Amphetamine]*** **Amphetamine is a powerful CNS stimulant in addition to the peripheral α and β-AR actions common to indirect acting sympathomimetic drugs**. **It is orally effective and its effects last for hours** **Cardiovascular effects**: **Amphetamine raises both the systolic and diastolic BP but the blood flow does not change much. The heart rate is reflexly slowed -- with larger doses, cardiac arrhythmias may occur**. I**ts peripheral actions are mediated primarily through the cellular release of stored catecholamines.** **CNS effects: Amphetamine is a CNS stimulant (like cocaine) -- via the release of biogenic amines (DA, A, 5-HT, & NA) from the storage terminals** - **Fatigue and sleep**: **Amphetamine prevents and reverses fatigue -- its use has been closely monitored in the military and athletics**. **The need to sleep may be postponed, but it cannot be avoided indefinitely**. **Sleeping patterns may take as long as 2 months to return to normal** - **Analgesia**: **Amphetamine and some other sympathomimetic amines possesses some analgesic effects -- but not therapeutically useful**. **It can enhance the analgesia produced by opioids (morphine).** - **Respiration**: **Amphetamine stimulates the respiratory center increasing the rate and depth of respiration**. **It can reverse the respiratory depression caused by centrally-acting drugs** - **Depression of appetite**: **Amphetamine and similar drugs has been use to treat obesity, although this application is questionable**. **Its site of action is the lateral hypothalamic feeding center** **Therapeutic uses** **Amphetamine is used chiefly for its CNS effects**. **It was used off-label for obesity -- but not used anymore due to the risk of abuse**. **It has been approved for the treatment of narcolepsy and attention-deficit/hyperactivity disorder.** **Dependence and tolerance** **The use of both amphetamine and dextroamphetamine is associated with psychological dependence**. **Tolerance develops to the CNS effects of the drug (except for its anti-narcolepsy effects) -- the dose needs to be increased to maintain the mood.** **Adverse effects** **CNS effects include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, dizziness, tremor, tenseness, irritability, weakness, insomnia, fever, aggressiveness, suicidal and homicidal tendencies and euphoria** ***[ii) Methamphetamine (speed)]*** **In the brain, methamphetamine releases DA and other biogenic amines, inhibits the monoamine transporter as well as the enzyme MAO**. **Smaller doses causes CNS effects and are devoid of peripheral effect -- while larger doses produces a rise in systolic and diastolic BP**. **It is illegally produced in many countries and subject to abuse.** **It is used principally for its central effects (similar to those seen with amphetamine) -- which are more pronounced than those of amphetamine and are accompanied by lesser peripheral actions** ***[iii) Methylphenidate (Ritalin^®^)]*** **Methylphenidate is a mild CNS stimulant with more prominent effects on mental than motor activities**. **Its pharmacological properties are essentially the same as those seen with amphetamine** **Methylphenidate is effective in the treatment of narcolepsy and attention-deficit/hyperactivity disorder**. **Its use is contraindicated in patients with glaucoma** ***[n) Mixed-action adrenergic agonists]*** **Mixed-action drugs induce the release of NA from presynaptic terminals, & activate adrenergic receptors on the postsynaptic membrane** ***i) [Ephedrine]*** **The drug is a mixed-action adrenergic agent**. **It not only releases stored NA from nerve endings, but also directly stimulates both α- & β-ARs**. **Ephedrine is not a catecholamine & is a poor substrate for COMT and MAO; thus, the drug has a long duration of action** **Ephedrine has excellent absorption orally, & crosses the BBB. Commonly administered as pseudoephedrine - an isomer of ephedrine. It is eliminated unchanged in the urine** **Cardivascular effects: raises systolic & diastolic BPs** v**ia vasoconstriction & cardiac stimulation** **Respiratory effects: Produces bronchodilation,** **but it is less Potent than A or isoprenaline in this regard**. **It has a slow onset of action**. **Sometimes used prophylactically in chronic treatment of asthma to prevent attacks rather than to treat the acute attacks.** **Commonly used as a nasal decongestant** **due to its local vasoconstrictor action -- used in combination with other drugs in cold & flu preparations**. **It can be used alone (e.g. Sinumed^®^) or in combination with antihistamines, aspirin (Corenza C^®^) or paracetamol (Sinumax®) or ibuprofen (Advil CS®)** **Ephedrine enhances contractility & improves motor function in myasthenia gravis, particularly when used in conjunction with AChE inhibitors** **CNS effects: produces a mild stimulation of the CNS** i**n the form of increased alertness, decreased fatigue, and prevents sleep**. **It also improves athletic performance.** **d-nor-pseudoephidrine (Thinz®; Eatless®, Leanor drops®) found application in obesity as an appetite suppressant**. **Its clinical use are limited by its adverse effects** ***[ii) Phenylpropanolamine (PPA; Norephidrine)]*** **Chemically and pharmacologically related to ephedrine**. **It has for many years been used over-the-counter as** **an appetite suppressant, and in cold and cough preparations as a nasal decongestant** **Its use has been discontinued (recently in SA) due to persistent case of hemorrhagic stroke especially in women**. **The risk is estimated at 1 woman is to 107,000 to 3,268,000 women exposed to PPA appetite suppressant**