Pathways

Propofol is sedative-hypnotic agent injected intravenously to induce and maintain general anaesthesia causing unconsciousness in order to preform surgery. The injection of Propofol produces hypnosis rapidly within 40 seconds from the start of the injection. The rapid rate of induction is caused by the speed in which Propofol can travel through the blood plasma to the CNS. Recovery from Propofol induced anaesthesia is also rapid, with few side-effects. In the CNS Propofol inhibits voltage-gated sodium channels in the axon of neurons. This sodium ions from entering the neuron, and therefore prevents depolarization. The prevention of depolarization means the neuron cannot fire, which means it cannot send an action potential to the presynapse, which then cannot release neurotransmitters to signal the next neuron to fire. Propofol further ensures no action potential can occur by activating GABA A receptors. Propofol attaches to subunit beta-2 and subunit beta-3 of the GABA A receptors. GABA A receptors increase the amount of chloride ions entering the postsynaptic neuron which causes hyperpolarization. Hyperpolarization is when the potential is a negative value, which makes depolarization more difficult to achieve, further preventing neurons from firing action potentials. This inactivity in the brain causes a sedative-hypnotic effect. Propofol also travels to skeletal muscles where it inhibits a voltage-gated sodium channel with protein type 4 subunit alpha. This specific voltage-gated sodium channel is only present in skeletal muscles. Voltage-gated sodium channels in skeletal muscles perpetuate action potentials in the tubule from the depolarization caused by nicotinic Acetylcholine receptors (nAchR). The prevention of action potential in the muscle cell prevents the muscle from contracting.

Propofol is injected intravenously where 95-99% of the drug is bound to serum albumin and hemoglobin. 1-5% of it goes to the brain and skeletal muscles to preform its mechanism of action. The rest travels to the liver where it is transported a liver transporter like OCT1 into the liver. In the endoplasmic reticulum membrane of the liver, Propofol is metabolized by Cytochrome P450 2C9 or Cytochrome P450 2B6 to make the active metabolite 4-Hydroxypropofol. 4-Hydroxypropofol has a third of the hypnotic ability of Propofol. 4-Hydroxypropofol is further metabolized by UDP-glucuronosyltransferase 1-8, UDP-glucuronosyltransferase 1-9 to make the metabolite 1-Quinol glucuronide. 4-Hydroxypropofol can also be metabolized by an unknown enzyme to make the metabolite 4-Quinol sulfate. There is also a possibility that 4-Hydroxypropofol does not metabolize into further metabolites and remains as is. Propofol also metabolizes into the metabolite Propofol glucuronide with the enzyme UDP-glucuronosyltransferase 1-8 or the enzyme UDP-glucuronosyltransferase 1-9. This further is metabolized into the metabolite 1-Quinol glucuronide with an unknown enzyme. All of these metabolites are transported back into the blood via a liver transporter such as MRP3. Here they travel to the kidney where they undergo renal excretion. 4-Hydroypropofol as an active metabolite can have similar effects on the brain as propofol.

Propoxyphene is an analgesic in the opioid category. It primarily acts on the G protein coupled receptors, OP3. Propoxyphene binding to OP3 causes GTP exchange for GDP and inhibit adenylate cyclase causing decreased intracellular cAMP. This leads to the inhibition of nociceptive neurotransmitters such as: substance P, GABA, dopamine, acetylcholine and noradrenaline. Opioids inhibit vasopressin, somatostatin, insulin and glucagon release. Propoxyphene also causes the closure of voltage-gated calcium channels and opens potassium channels causing the hyperpolarization of the membrane and decreasing neuronal excitability. This further reduces the feeling of pain.

Propoxyphene is an opioid analgesic used to treat mild to moderate pain. Propoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central Propoxyphene binds to mu opioid receptors, stimulating 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 is inhibited. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly rectifying potassium channels. This results in hyperpolarization and reduced neuronal excitability. Propoxyphene acts at A delta and C pain fibres in the dorsal horn of the spinal cord. By decreasing neurotransmitter action there is less pain transmittance into the spinal cord. This leads to less pain perception.

Propranolol is a a beta blocker. In the heart it acts as a receptor antagonist of beta-1-adrenergic receptor. Propranolol competes with neurotransmitters for receptors, which inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition cAMP, PKA, SRC and nitric oxide synthase. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower. As a result, propranolol is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.

Propranolol, a non-cardioselective beta blocker, inhibits sympathetic stimulation by competing with neurotransmitters like catecholamines to bind beta(1)-adrenergic receptors of the heart and vascular smooth muscle. Propranolol binding reduces resting heart rate, cardiac output, blood pressure and orthostatic hypotension. Propranolol also reduce sympathetic activity to manage hyperthyroidism, anxiety and tremor. Propranolol also competes for beta(2)-adrenergic receptors on bronchial and vascular smooth muscles.

On the World Health Organization's List of Essential Medicines and a prototypical drug of its class, propranolol is a non-cardioselective beta blocker and it is typically synthesized as a racemic mixture of 2 enantiomers where the S(-)-enantiomer has approximately 100 times the binding affinity for beta adrenergic receptors. It can be administered intravenously to the bloodstream or orally, where it passes through hepatic portal circulation, and enters the bloodstream to act on peripheral cells. This pathway focuses on cardiovascular effects of propranolol but as a relatively lipophilic drug, it can accumulate in the brain. In the brain, it antagonizes serotonergic receptors and inhibits (via receptor antagonism) adrenergic receptors - its psychiatric effects are under research currently. It may also be used for infant hemangioma. In the periphery, propranolol can target beta-1, beta-2, and beta-3 adrenergic receptors (hence its reduced selectivity compared to newer beta blockers, which has clinical implications in the treatment of dysrhythmias) to interfere with the normal epinephrine to adrenergic receptor binding, thus acting as a competitive antagonist - its cardiovascular effects on the beta-1 adrenergic receptor are responsible for its primary therapeutic use as a class II antidysrhythmic agent. It is also an antihypertensive and antianginal agent. In bronchial and vascular smooth muscle, propranolol can compete with epinephrine for beta-2 adrenergic receptors. By competing with catecholamines for adrenergic receptors, it inhibits sympathetic stimulation of the heart. The reduction of neurotransmitters binding to beta receptor proteins in the heart inhibits adenylate cyclase type 1. Because adenylate cyclase type 1 typically activates cAMP synthesis, which in turn activates PKA production, which then activates SRC and nitric oxide synthase, its inhibition causes the inhibition of cAMP, PKA, SRC and nitric oxide synthase signaling. Following this chain of reactions, we see that the inhibition of nitric oxide synthase reduces nitric oxide production outside the cell which results in vasoconstriction. On a different end of this reaction chain, the inhibition of SRC in essence causes the activation of Caspase 3 and Caspase 9. This Caspase cascade leads to cell apoptosis. The net result of all these reactions is a decreased sympathetic effect on cardiac cells, causing the heart rate to slow and arterial blood pressure to lower; thus, propranolol administration and binding reduces resting heart rate, cardiac output, afterload, blood pressure and orthostatic hypotension. By prolonging diastolic time, it can prevent re-infarction. One potentially less than desirable effect of non-selective beta blockers like propranolol is the bronchoconstrictive effect exerted by antagonizing beta-2 adrenergic receptors in the lungs. Clinically, it is used to increase atrioventricular block to treat supraventricular dysrhythmias. Propranolol also reduce sympathetic activity to manage hyperthyroidism, anxiety and tremor. As a result, propranolol is used to treat hypertension, angina, migraine headaches, and hypertrophic subaortic stenosis.