GTN and Morphine: A contrast of the pharmacokinetics and pharmacodynamics
Glyceryl Trinitrate (GTN)
Glyceryl Trinitrate (GTN) can be administered and absorbed ‘intravenously; as a paste; transdermally; as an intradermal implant; through a lingual aerosol and as a sublingual tablet’ (Galbraith 1997, p. 380). A sublingual tablet is the most common route of administration in the NSW Ambulance Service pre-hospital management of ischaemic chest pain, and the site of absorption is the ‘buccal mucosa’ (MIMS Annual 1997, p2-152). Although GTN is rapidly absorbed in the gastrointestinal tract (GIT) the extensive first-pass metabolism in the liver causes the bioavailibity of oral administration to render the drug ineffective. Bryant and Knights state that ‘drugs absorbed through the GIT enter the hepatic portal vein and are taken directly into the liver; therefore, any drug which is metabolized predominantly by the liver may be largely metabolized before it reaches its target site of action’ (Bryant and Knights 2003, p 418). After absorption at the buccal muscosa, the drug is distributed throughout the body via the vascular system; as the circulatory system is the target site, the effects can be seen rapidly. ‘Peak plasma concentration levels are achieved within 4 minutes of sublingual administration’ (MIMS Annual 1997, p. 2-152). Metabolism is predominantly via the liver with excretion being via the kidneys. ‘GTN is predominantly metabolized in the liver by glutthione organic nitrate reuctase. This is completed on the first pass through the portal circulation, resulting in rapid termination of action’ (Oh 1998, p. 155).
Oh states that ‘once nitrate is absorbed and within the circulatory system it is taken up by the vascular smooth muscle where it becomes the active form of nitric oxide’ (Oh 1998, p. 155). Nitric oxide then ‘activates guanylate cyclase, which then catalyses cyclic GTP to cyclic GMP’ (Galbraith 2003, p.378). Cyclic GMP decreases intracellular calcium ion levels and it is this reduction in intracellular calcium ion levels that cause a decrease in vascular smooth muscle strength, causing vasodilatation (Bryant and Knights 2003, p420).
By dilating the veins, GTN decreases the amount of blood returned to the heart (preload), which reduces left ventricular end-diastolic volume. This decrease in blood return helps reduce the myocardial oxygen demand. Galbraith states that ‘by decreasing cardiac preload you decrease the cardiac workload and the myocardial oxygen demand is thus lowered’ (Galbraith 1998, p. 380). Dilating arteries reduces systemic vascular resistance, systolic arterial pressure and mean arterial pressure (afterload), which then lowers myocardial oxygen demand. Dilation of coronary arteries redistributes blood flow along the collateral channels and from the epicardial to the endocardial regions and therefore increases oxygen to the ischaemic aspects of the myocardium (Mayer 2001, p 116).
Administration and absorption can be done through ‘subcutaneous injection, intramuscularly injection and intravenous injection’ (MIMS Annual 2003 p. 4-433). Like GTN, absorption through the GIT is rapid, but as a result of the first-pass metabolism in the liver, oral administration is often ineffective. Morphine is not particularly highly protein bound, at ‘35% being bound to plasma protein’ (Bryant and Knights 2003, p247) and is relatively hydrophilic so it crosses slowly into the CNS. Plasma half-life is achieved between 2-3 hours after administration (MIMS Annual 2003 p. 4 –433). Similar to GTN it is metabolized by the liver and excreted via the kidneys, and small amounts are excreted as bile and feaces (MIMS Annual 2003 p. 4 –433).
Similar to other opiates, morphine acts as an agonist with stereospecific and saturable binding sites/receptors in the brain, spinal cord and other tissues.
Morphine exerts its primary affect on the central nervous system (CNS) and organs containing smooth muscle. Effects include: ‘analgesia, drowsiness, alteration in mood (euphoria), reduction in body temperature, depression of the respiratory drive, cough suppression and miosis’ (Hollinger 1997, p. 384). There are high concentrations of receptors for the body’s natural opioids such as the endorphins and enkephalins in many areas of the CNS, particularly in the ‘grey matter of the midbrain, the limbic system and at the interneruons in the dorsal horn areas’ (Bryant and Knights 2003, p. 235). These areas are known to be involved in pain transmission or perception. The enkephalins (pentapeptides), endophins (larger polypeptides) and dynorphins are believed to be the body’s natural pain-relieving chemicals and act by enhancing the inhibitory effects at opiate receptors (Bryant and Knights, 2003 pp235-6).
The body’s endogenous opiate receptors sites are known as ‘delta, epsilon, kappa, mu receptors’ (Galbraith 1998, p.336) These are inhibitory neurotransmitters which suppress pain messages to the CNS from the periphery. Morphine acts by binding to these opiate receptor sites and blocking the transmission of the substance P (pain). At the spinal level morphine stimulates opiate receptors and thus inhibits the release of substance P from dorsal horn neurons (Bryant and Knights 2003, p.245). At supraspinal levels, ‘opiates act to close the gate in the dorsal horn, thus inhibiting afferent transmission of the substance P’ (Bryant and Knights 2003, p 245). It is also capable of altering perception and emotional responses to pain because opiate receptors are widely distributed in the CNS, especially in the limbic system, thalamus, hypothalamus and midbrain (MIMS Annual 2003 p. 4 –433) When pain perception is inhibited the analgesic effect of morphine is enhanced.
Opiate receptors are G-protein-coupled receptors, ‘activation of which inhibits adenylate cyclase and reduces cylclic adenosisne monophosphate (cAMP) levels’(Galbraith 1997, p.335). Neuronal excitability and transmitter release are both decreased as a result of reduced cAMP, leading to inhibitory effects at the cellular level.