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Adrenaline, an endogenous catecholamines, is a hormone and a neurotransmitter secreted by the adrenal medulla on the kidneys and released from sympathetic nerve endings. As a drug it is the strongest vasopressor known. Although there are different formulations, oral administration is not effective as it is rapidly metabolised in the liver and gastrointestinal2 mucosa. Some of the many functions of adrenaline include regulating heart rate, blood vessel and air passage diameter.
Fig 1: Structure of adrenal
Adrenaline is a strong stimulant of the adrenergic receptors á¾³ (alpha) and Î² (beta). These receptors are subdivided into á¾³1, á¾³2 (which are Gq and Gi coupled receptors respectively) and Î²1, Î²2 andÎ²3 which are all linked to GS proteins. Activation of the á¾³ receptors causes vasoconstriction in the skin and viscera, whiles Î²-receptors cause vasodilation in smooth muscle cells with the exception of Î²1 which stimulates heart rate and force, increases blood pressure and increases blood flow to the skeletal muscles2.
When given rapidly by intravenous route, it causes blood pressure to rises rapidly in proportion to the dose until a peak is reached. Adrenaline effect on incremental blood pressure levels, is a threefold mechanism2;
1. Direct stimulation of the myocardia to increase the strength of ventricular contraction (positive inotropic action)2
2. An increased heart rate (positive chronotropic action)2
3. Vasoconstriction in many vascular beds, especially in the precapillary resistance of the skin, mucosa and kidney along with marked constriction of the veins2.
When given slowly by intravenous infusion or by subcutaneous injection the effects are different. Absorption of the drug is slow due to local vasoconstriction. The effect of doses as large as 0.5- 1.5 mg can be repeated by intravenous infusion at a rate of 10 -30 Âµg/min. There is decrease in peripheral resistance due to a dominant action on Î²2 receptors of vessels in skeletal muscle, where blood flow is enhanced, thus diastolic pressure usually falls. Since the average blood pressure is not greatly elevated, compensatory baroreceptors reflexes do not antagonize the direct cardiac actions. Left ventricular work per beat, stroke volume, cardiac output and heart rate are increased as a result of direct cardiac stimulation and increased venous return to the heart, reflected by an increase in right atrial pressure. At slightly higher rate of infusion, there may be no change or a slight rise in peripheral resistance and diastolic pressure, depending on the dose and the resultant ratio of Î² to á¾³ responses in the various vascular beds2.
Although veins and large arteries respond to adrenaline, its main action is exerted on smaller arterioles and pre-capillary sphincters. Various vascular beds react differently resulting in a substantial redistribution of blood flow. Injected adrenaline constricts pre-capillary vessels and small vessels, decreasing cutaneous blood flow resulting in decreased blood flow in the hands and feet. Therapeutic doses of adrenaline in humans increases blood flow to skeletal muscles due in part to a powerful Î²2 mediated vasodilator action that is partially counterbalanced by a vasoconstrictor action on the á¾³1 receptors present in the vascular bed. Giving an á¾³ receptor antagonist, makes vasodilation in the muscle more pronounced with decrease in total peripheral resistance accompanied by fall in mean blood pressure (adrenaline reversal) In the presence of a non - selective Î² receptor antagonist only vasoconstriction occurs and the administration of adrenaline is associated with pressor effect.
Adrenaline effect on cerebral circulation is related to the systemic blood pressure with relatively little constrictor action on cerebral arterioles from usual therapeutic doses, which is of physiological advantage in response to sympathetic tone by stressful stimuli. The presence of auto-regulatory mechanism limits increase in cerebral blood flow as a result of elevated blood pressure.
Doses of adrenaline that have little effect on mean arterial pressure constantly increase renal vascular resistance and reduce renal flow by 40%. As the glomerular filtration rate is only slightly altered the filtration fraction is constantly increased. Excretion of chloride, potassium and sodium ions are decreased, urine volume may be increased, decreased or unchanged. Although direct pulmonary vasoconstriction occurs, redistribution of blood from the systemic to the pulmonary circulation, due to constriction of the more powerful musculature in the systemic great vein plays an important part in the increase in the pulmonary pressure. High concentrations of adrenaline results in pulmonary oedema, brought about suddenly by raised pulmonary capillary filtration pressure and possibly leaky capillaries.
Fig 3: Activity of Ca2+influx/efflux and vascular smooth muscle contraction/ Effect of adrenaline on Î²2 and á¾³1 adrenoceptors.
Effect of Beta Receptor Activation on Smooth Muscle
Adrenaline binds to both á¾³1andÎ²2 receptors in the vascular smooth muscle. When it binds to á¾³1[ a G-protein coupled receptor with a 7 membrane spanning regions which is complexed with GDP(guanosine diphosphate) in it's unstimulated state] it promotes exchange of GTP for GDP and the release of G"/GTP. The G-protein then activates phospholipase C leading to an increase in the intracellular second messengers, inositol triphosphate(IP3) and diacylglycerol(DAG). The IP3 binds to specific sight on the sarcoplasmic reticulum(SR) and stimulates the release of intracellular Ca2+ causing increase in actin myosin interaction to cause contraction3.
Î²2 receptors follows the signalling cAMP pathway. The G"/GTP complex released when adrenaline binds activates adenylate cyclase causing an increase in intracellular cAMPand activates cAMPdependant protein kinase(PKA). The phosphorylated PKA reduces Ca2+ influx and increase in Ca2+ efflux in the sarcolemma. In the sarcoplasmic reticulum Ca2+ reuptake is enhanced leading to reduced interaction between actin and myosin.The result of calcium inhibition leads to the relaxation of the vascular smooth muscle3.
Although there are more á¾³1 receptors than Î²2 receptors in the vascular smooth muscles, adrenaline has higher affinity for Î²2 than á¾³1. Though Î²2 receptor causes relaxation(vasodilation) and á¾³1 causes constriction(vasoconstriction), at low doses, adrenaline generates vasodilation and at high doses it causes vasoconstriction. This is due to it's relative affinty and degree of receptor occupancy. At low doses adrenaline selectively stimulates Î²2 producing vasodilation, however once the concetration of adrenaline which binds to á¾³1 is reached vasoconstriction occurs. The two effects will oppose one another, however as the concentraion of adrenaline increases the predominant effect will be vasoconstrction3.
Though of little clinical use based on action on bronchial muscles, heart and blood vessels, its major use is for the relief of hypersensitivity reaction including anaphylaxis to drugs and other allergens. Its ability to decrease local blood flow (as mentioned above) helps prolong the action of anaesthetics.
Adverse effects and contraindication
It causes tremor, throbbing headache, restlessness, and palpitation which subside with rest. In patients with cardiovascular disease, angina may be induced. In patients receiving non-selective Î²-adrenergic receptor blocking drugs, it is contraindicated, since its unopposed action on vascular á¾³1-receptor may lead to severe hypertension and cerebral haemorrhage.
ThumbNifedipine, a dihydropyridine is a calcium antagonist (calcium entry blocker) which acts on the L- type channel. It is mainly used as an anti-angina and anti-hypertensive agent. The molecular formula of nifedipine is C17H18N2O6 and Systematic (IUPAC) name is 3,5-dimethyl-2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Pharmacokinetic Data; Bioavailability - 45-56%, Protein binding - 92-98%, Half - life - 2hours, Excretion - Renal: > 50% and Biliary: 5 - 15%, Metabolism: Gastrointestinal and Hepatic.
Recommended starting dose for immediate release capsules is 10mg taken three times daily and for extended release 30-60mg once daily. Other recommendation is to take the extended release formulation on empty stomach and to avoid grape fruit/grape fruit juice, as they raise blood nifedipine levels and also lower CYP3A4 activity3.
In hypertensive emergencies sublingual nifedipine has been used previously, but was found to be very dangerous as it can cause uncontrollable lowering in blood pressure, reflex tachycardia and steel phenomenon in certain vascular beds. Other adverse effect with the sublingual formulation include cerebral ischemia/infarction, myocardial infarction, complete heart block and death. A review in 1995 by the FDA regarding safety and efficacy of sublingual nifedipine in hypertensive emergencies found it neither safe nor efficacious and concluded that the practice should stop.
Effect on Vascular smooth muscle
As a calcium antagonist, it blocks cellular entry of Ca2+ through calcium channels rather than its intracellular actions by targeting á¾³1adrenoceptors innervated in the vascular smooth muscle. The tone of vascular smooth muscle is determined by the cytosolic Ca2+ concentration which is increased by á¾³1- adrenoceptor activation as a result of sympathetic tone. This triggers release of calcium ions from the sarcoplasmic reticulum through the second messenger inositol-1,4,5-triphospate5.
Fig 4: Ca2+ channel blockers
Mechanism Of Action:
As the concentration of cytosolic Ca2+ rises, there is increased contraction of the vascular smooth muscle cells. This is an effect of a sympathetic tone, resulting in the release of Ca2+ from intercellular storage causing contraction of the vascular smooth muscle particularly in some vascular beds. The presence of diverse contractile stimuli in the vascular smooth muscle cells increases cytosolic Ca2+. Hormones and autocoids increase Ca2+ influx through receptor operated channels whiles rise in external concentration of K+ and depolarizing electrical stimuli increases Ca2+ influx through voltage sensitive channels. Nifedipine binds to the Î±1 subunit of the L-type Ca2+ channel and reduce Ca2+ flux through the channel3. Of the three subtypes of the Voltage-dependent Ca2+ channels, only the L-type is sensitive to nifedipine and the other dihydropyridine Ca2+ Channel blockers. Although sodium currents are involved, depolarization of the vascular smooth muscles involves three mechanisms for the influx of Ca2+.
1. Agonist-induced contraction that occurs without depolarization of the membrane as a result of stimulation the Gq-PLC-IP3 pathway to release intracellular Ca2+from the sarcoplasmic reticulum. This triggers further influx of extracellular Ca2+.
2. Receptor operated Ca2+ channels allow entry of extracellular Ca2+ in response to receptor occupancy.
3. Voltage dependent Ca2+channels open in response to depolarization of the membrane. This then allows extracellular Ca2+ to enter the cell by moving down its electrochemical gradient.
As the cytosolic Ca2+ increases, the binding of Ca2+ to calmodulin is enhanced to form a complex which then activates myosin light-chain kinase. The phosphorylation of the myosin light-chain kinase causes interaction between myosin and actin leading to contraction of the smooth muscle. At a concentration lower than required to interfere with the release of intracellular Ca2+or to block receptor operated Ca2+ channels, Ca2+ channel antagonist inhibit the voltage dependent Ca2+ channels in the vascular smooth muscle3.
Most cardiovascular diseases like hypertension and angina involves atheroma formation. Thus any sympathetic activity causing contraction of the smooth muscles leads to vasoconstriction and eventual increase in blood pressure and reduced cardiac preload. Nifedipine inhibits voltage-dependent Ca2+channel, blocking the cascade of Ca2+influx and preventing the formation of the Ca2+-calmodulin complex to trigger contraction. The arterial smooth muscle relaxes to increase the diameter of the vessel, thus lowering blood pressure.
When given intravenously it increases forearm blood flow with little effect on venous pooling, an indication of selective dilation of arterial resistance vessels. The decrease in arterial blood pressure elicits sympathetic reflexes, with resulting tachycardia and positive inotropy. Nifedipine relaxes vascular smooth muscle at significantly lower concentration than those required for direct effects on the heart. Nifedipine helps lower blood pressure and arteriolar resistance, segmental ventricular function and contractility are improved, modest increase in cardiac output and heart rate. Orally administering nifedipine increases peripheral blood flow via arterial dilation but venous tone doesn't change2 .
Patients on immediate release capsules develop peripheral oedema, flushing, headache and dizziness. For long term treatment of hypertension and angina short acting formulation are not the best. In the sustained release formulation, flushing and dizziness are less of a problem.