Pathways

Alfentanil is used to induce and maintain anesthesia, as well as an analgesic. Alfentanil is a short-acting opioid anesthetic and analgesic derivative of fentanyl. It produces an early peak analgesic effect and fast recovery of consciousness. Alfentanil is effective as an anesthetic during surgery, for supplementation of analgesia during surgical procedures, and as an analgesic for critically ill patients. Alfentanil is a synthetic opioid analgesic. Alfentanil interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, alfentanil exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Alfentanil may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Alfentanil depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Alfentanil binds on pre-synaptic mu opioid receptors. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as GABA. Less GABA leads to disinhibition of dopamine cell firing in the spinal cord pain transmission neurons. This leads to less pain signaling and analgesia. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. Alfentanil has many sites of action where it can act on mu opioid receptors. The inhibition of A delta and C pain fibres in the dorsal horn of the spinal cord is very important as it slows the signaling of pain into the spinal cord. Alfentanil can also be used for treating cough. Symptoms of overexposure include characteristic rigidity of the skeletal muscles, cardiac and respiratory depression, and narrowing of the pupils.

Alfentanil is used to induce and maintain anesthesia, as well as an analgesic. Alfentanil is a short-acting opioid anesthetic and analgesic derivative of fentanyl. It produces an early peak analgesic effect and fast recovery of consciousness. Alfentanil is effective as an anesthetic during surgery, for supplementation of analgesia during surgical procedures, and as an analgesic for critically ill patients. It is administered by intravenous injection or infusion. The liver is the major site of metabolism where it metabolised to noralfentanil, 2-(4-ethyl-5-oxo-1,2,3,4-tetrazol-1-yl)acetaldehyde, N-phenylpropionamide and AMX (Ci.I yellow pigment) and excreted in urine via the kidneys. Only 1.0% of the dose is excreted as unchanged drug.

Alfentanil (also known as Alfenta or Rapifen) is analgesic that can bind to mu-type opioid receptor to activate associated G-protein in the sensory neurons of central nervous system (CNS), which will reduce the level of intracellular cAMP by inhibiting adenylate cyclase. The binding of alfentanil will eventually lead to reduced pain because of decreased nerve conduction and release of neurotransmitter. Hyperpolarization of neuron is caused by inactivation of calcium channels and activation of potassium channels via facilitated by G-protein.

Alfacalcidol is a vitamin D analogue used for the management of hypocalcemia, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure, as well as some types of rickets and osteomalacia. Vitamin D is a secosteroid generated in the skin when 7-dehydrocholesterol located there interacts with ultraviolet irradiation - like that commonly found in sunlight. Vitamin D3 produced in the skin undergoes hydroxylation in the liver using the enzyme vitamin D 25-hydroxylase to form 25-hydroxyvitamin D3 (calcidiol). The second hydroxylation happens in the kidneys using the enzyme 25-hydroxy vitamin D 1α-hydroxylase to give 1, 25-dihydroxyvitamin D3 (calcitriol). Calcitriol interacts with vitamin D receptors in the small intestine to enhance the efficiency of intestinal calcium and phosphorous absorption from about 10-15% to 30-40% and 60% increased to 80%, respectively. Furthermore, calcitriol binds with vitamin D receptors in osteoblasts to stimulate a receptor activator of nuclear factor kB ligand (or RANKL) which subsequently interacts with receptor activator of nuclear factor kB (NFkB) on immature preosteoclasts, causing them to become mature bone-resorbing osteoclasts. Such mature osteoclasts ultimately function in removing calcium and phosphorus from bone to maintain blood calcium and phosphorus levels. Moreover, calcitriol also stimulates calcium reabsorption from the glomerular filtrate in the kidneys. Calcitrol is also involved in parathyroid hormone regulation, by lowering parathyroid hormone secretion. In conditions like chronic renal failure, renal bone disease, hypoparathyroidism, and vitamin D dependent rickets, the kidneys' capacity for 1α-hydroxylation is impaired, leading to reduced production of endogenous 1,25-dihydroxyvitamin D and aberrated mineral metabolism. Alfacalcidol is rapidly converted in the liver to 1,25-dihydroxyvitamin D and works to restore the functions and activities of endogenous 1,25-dihydroxyvitamin D.

Alendronic acid is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Alendronic acid passes through the liver and is then excreted from the body mainly through the kidney.

Alendronate is a second-generation bisphosphonate taken orally or IV and used for the treatment of conditions such as osteoporosis, Paget’s disease and hypercalcemia. Alendronate targets the mevalonate pathway in osteoclasts, the cells responsible for the break down of bone tissue. The mevalonate pathway starts off with acetyl-CoA forming acetoacetyl-CoA using acetyl-CoA acetyltransferase in the mitochondria. Acetyl-CoA and acetoacetyl-CoA then form HMG-CoA via HMG-CoA synthase. HMG-CoA is converted to mevalonate using the enzyme HMG-CoA reductase. Mevalonate kinase converts mevalonate into mevalonate-5P, which is then metabolized into mevalonate-5PP by phosphomevalonate kinase. Isopentenyl-PP is then formed from mevalonate-5PP via diphosphomevalonate decarboxylase. Farmesyl pyrophosphate converts isopentenyl-PP to geranyl-PP, then to farnesyl-PP. Farnesyl-PP goes on to form geranylgeranyl-PP through geranylgeranyl pyrophosphate synthase or squalene through squalene synthase. Squalene goes through a series of reactions to eventually form cholesterol. Alendronate binds to bone hydroxyapatite and when bone resorption occurs, alendronate enters the osteoclasts through endocytosis. Acidification of the endocytic vesicles releases the alendronate. Alendronate inhibits farnesyl pyrophosphate synthase, which reduces the production of downstream isoprenoid lipids like farnesyl-PP and geranylgeranyl-PP. these lipids are needed for a process called prenylation, to anchor cell surface proteins in the osteoclast membrane. Without prenylation, the osteoclast cannot attach to the bone, therefore they are unable to function and undergo apoptosis. This decreases bone resorption/ break down as the osteoclasts are no longer able to survive. Adverse effects like GI disturbances like peptic ulcers and oesophagitis, muscle and bone pain, stomach pain, osteonecrosis, diarrhea, constipation, nausea, flatulence, headache, dizziness and inflammatory responses may occur from taking alendronate.