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HOME GROUP 2 (PHC461), It's governed by the drug's affinity for…

- - - - An inhibitor of a receptor activity. Binding of antagonist to a receptor will not activate the receptor (lack of intrinsic activity) thus, inhibit or dampen biological response.
    - - Chemical antagonism
        
        Occurs when drug reduces the concentration of an agonist by forming a chemical complex
        
        Example
        
        The use of chelating agent (dimercaprol) that bind to heavy metals and thus reduce their toxicity
        
        Does not depend on interaction with the agonist's receptor
        
        Interacts directly with the drug being antagonized
      - Pharmacokinetic antagonism
        
        Reduce the concentration of agonist at the site of action.
        
        Alter the effect of absorption, metabolism and excretion of the agonist.
        
        Example
        
        Reduction of anticoagulant effect of warfarin by phenobarbital
      - Non-competitive antagonism
        
        Antagonist binds to a different site on the receptor (allosteric binding site) than the natural ligand, agonist or partial agonist and inhibit the biological function of the receptor.
        
        Exerting their action by binding to distinctly different binding site as agonist
        
        Example
        
        Ketamine is a non-competitive antagonist at the NMDA-glutamate receptor
      - Physiological antagonism
        
        Bind to different receptor and counteracting effect of the drug it is antagonising
        
        describe the behavior of a substances that produces effect counteracting those of another substances.
        
        Example
        
        Histamine acts on a receptor of the parietal cells of the gastric mucosa, while omeprazole blocks this effect.
      - Competitive antagonism
        
        Reversible competitive antagonism
        
        Effect of the antagonist can be overcome by increasing the concentration of the agonist.
        
        Example
        
        Caffeine act as reversible competitive antagonist toward adenosine receptor.
        
        Antagonist binds reversibly (can be displaced) with the same binding site as the agonist without activating them.
        
        irreversible competitive antagonism
        
        Occurs when antagonist dissociates very slowly, or not at all from receptor
        
        No change in antagonist occupancy
        
        Occur when drug form covalent bond with the receptors
    - - Lack of intrinsic activity
        
        Definition
        
        The measure of the ability of the ability of a drug that is bound to a receptor generate an activating stimulus and produce a change in cellular activity.
        
        Antagonist lack of intrinsic activity but does not mean it have no physical consequences
        
        Example
        
        Caffeine (an antagonist) does lead to physical changes by increasing the nerve cells activity and lead us to be more alert and energetic
  - - - Location of the G-protein is cell membrane
      - How G protein-coupled receptors work?
        
        Signal transduction with a G-protein receptors
        
        Firstly, typical G protein-coupled receptor has a ligand-binding site on the plasma membrane's exterior surface and a G-protein-binding area on the inside. Guanosine diphosphate (GDP) is linked to the G component of the G protein in its inactive state.
        
        Following that, when the agonist (Ag) attaches to the receptor, guanosine triphosphate (GDP) binds to the G protein, causing GDP to dissociate.
        
        After that, GTP activation of the Gα subunit causes the dissociation of the Gα and Gγ subunits.
        
        The G subunit can then activate adenylyl cyclase (AC), stimulating the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (CAMP) (cAMP).
        
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        What Second Messengers Do GPCR Signals Trigger in Cells?
        
        The synthesis of hundreds or even thousands of second messenger molecules might be affected by the activation of a single G protein. (Cyclic AMP [cAMP], diacylglycerol [DAG], and inositol 1, 4, 5-triphosphate [IP3] are tiny molecules that begin and coordinate intracellular signalling pathways.)
        
        Adenylyl cyclase, a membrane-associated enzyme activated by the GTP-bound alpha subunit, catalyses the second messenger cAMP from ATP molecules, is a typical target of activated G proteins. In humans, cAMP has a role in sensory processing, hormone production, and nerve transmission, among other things.
        
        Another typical target of activated G proteins is phospholipase C. From the membrane lipid phosphatidylinositol, this membrane-associated enzyme catalyses the production of not one but two-second messengers, DAG and IP3. This route is essential for a wide range of human physiological functions. Platelet thrombin receptors, for example, employ this route to aid blood clotting.
      - Example of G-protein is muscarinic receptor, adrenoceptors
      - GPCRs bind extracellular compounds like caffeine and transmit signals to an intracellular molecule, which subsequently affects our bodies. Caffeine, for example, can assist us in remaining awake.
      - According to a previous study based on accessible DNA sequences, the human genome encodes over 750 G protein-coupled receptors, with about 350 of these detecting hormones, growth factors, and other endogenous ligands. The functions of around 150 GPCRs discovered in the human genome are unknown.
  - - - The quantity of medication required to achieve a specific effect.
        
        In graded dose-response measurements, the effect chosen is generally 50% of the maximum effect, with EC50 being the corresponding dosage.
    - - Maximal effectiveness is a term that is frequently used. An agonist can have the maximum effect (Emax) when the dosage is increased to extremely high levels.
        
        A graded dosage response curve can be used to measure it.
- - - - like caffeine, consumption of caffeine increases the alertness and does not sleepy at all. It is because of the binding of caffeine at the adenosine receptor. Caffeine can bind to the receptor but not activating it. Adenosine cannot bind to its receptor because of the presence of caffeine. They compete each other. So, adenosine cannot do their job of giving a person sleepiness. therefore, withdrawal symptom can occur when reduce or stop the caffeine intake. because adenosine will bind to the increasing receptor and produced withdrawal symptom like become sleepy.
  - - - When caffeine molecules are blocking those receptors, they prevent adenosine-adenosine receptor complex binding from occurring, thereby generating a sense of alertness and energy for a few hours. Additionally, some of the brain’s own natural stimulants such as dopamine work more effectively when the adenosine receptors are blocked, and all the surplus adenosine floating around in the brain cues the adrenal glands to secrete adrenaline, another stimulant. Thus, the caffeine consumers can feel more alert and not sleepy for a longer time
        
        As time passes by, more adenosine receptor is produced by our body to compensate for the whole situation. Thus, people need more caffeine than usual which explains drug dependence/coffee dependence situation that happen
        
        When we suddenly stop consuming caffeine, our brain has to alter their chemistry because they have too many receptors so they need to decrease the numbers when caffeine is no longer consumed. This will lead to the withdrawal effect
  - - - since dopamine is a chemical messenger, from the ventral tegmental area, it projects dopaminergic action potential to the nucleus accumbens where the feeling of pleasure and reward are mediated. about the bind location, dopamine will bind to dopaminergic receptors present in the nucleus accumbens and prefrontal cortex
        
        Thus, it will affect our mood as we depend on caffeine to feel pleasure. we tend to drink more coffee and because of that we develop dependency and addiction towards coffee
- - - - :star: Caffeine bind to A1 receptor and A2A receptor without activating them. The binding to A1 will cause the neuron to be less active as the low level of CAMP synthesized from ATP by adenylate cyclase Meanwhile, for the A2A, it will cause the neuron to be more active
        
        :star: Fewer receptor are available to the natural “braking” action of adenosine, and neural activity therefore will speeds up. in this case it will causes the pituitary gland to secrete hormones that in turn cause the adrenal glands to produce more adrenalin as the activation of numerous neural circuits by caffeine
        
        :star: The activation of numerous neural circuits by caffeine also causes the pituitary gland to secrete hormones that in turn cause the adrenal glands to produce more adrenalin. Adrenalin is the “fight or flight” hormone, so it increases attention level and gives entire system an extra burst of energy
        
        :star: Another effect when adenosine locks with the A1 receptor, it promotes muscle relaxation and sleepiness and this is the reason people get tired as the day progresses. The caffeine in our brain will competing with adenosine and preventing it from binding to A1 receptors. So it will gives us a jolt of wakefulness
        
        :star: Next caffeine will promotes wakefulness by blocking adenosine A2A receptors in the brain. When it binds, it will induce or interferes with the release of mood-improving neurotransmitters, such as dopamine and glutamate because caffeine is an adenosine-receptor antagonist.
        
        :star: Lastly, caffeine is a reversible competitive antagonist because its binding to the adenosine receptor can be countered by increasing the adenosine level.
  - - - :star: The rise in adenosine levels during the day is caused by ATP chemically reacting, and adenosine is one of the byproducts of this process. Logic dictates that as a person expends more energy during the day, more adenosine is produced.
        
        :star: Excitatory neurotransmitter has the excitatory effect on the neuron which this means they increase the likelihood that the neuron will fire an action potential. However caffeine will not inhibit these excitatory neurotransmitter during it effects
        
        :star: The adenosine effect causes us to feel sleepy. This is due to the fact that when adenosine binds to its receptors, neural activity slows down and causing us to feel sleepy. Adenosine thus promotes sleep and dilates blood vessels, most likely to ensure adequate oxygenation while sleeping. In this case, adenosine is produced more during the day because it will aid in our ability to rest because we expend too much energy during the day.
        
        :star: Dopamine is one of the excitatory neurotransmitter. When caffeine blocks the ability of adenosine to bind to receptors, it allows for dopamine receptors to function at higher levels as caffeine is linked to an increase in dopamine reception, and our bodies associate consumption with the pleasure reward provided by dopamine. Dopamine is commonly known for its role in pleasure .
        
        :star: Dopamine is also associated with concentration, attention, and movement. Caffeine's focusing effect can be contributed to an increase in dopamine because dopamine improves focus and attention. Finally, dopamine aids movement, but its effect is similar to that of a tightrope walker.
        
        :star: However, caffeine does not increase the amount of dopamine our bodies produce, but it does slow the rate at which dopamine leaves our brains and returns to our bodies. At the same time, it has no effect on the rate at which the chemical travels from our bodies to our brains. This causes a brief increase in dopamine levels, which makes us feel good.
        
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  - - - :star: Caffeine is able to easily get into the brain through the brain’s blood barrier as it similarly to other drugs such as alcohol, nicotine, and antidepressant. This is because our brain has blood-brain barrier(BBB). The blood-brain barrier is the barrier between the cerebral capillary blood and the interstitial fluid of brain.
        
        :star: Tight junctions exist between the endothelial cells of the blood brain barrier, allowing only a few types of substances to pass between the cells. Blood-brain barrier is less permeable to water-soluble dug but allows lipid-soluble drugs to pass. Caffeine and adenosine are both water and fat soluble.
        
        :star: caffeine enter blood-brain barrier via simple diffusion and facilitated diffusion. This is because caffeine will attach to a transporter that associated with adenosine
        
        :star: Caffeine molecules contain functional groups such as amine and amide, which make caffeine water soluble. Caffeine is a trimethyl xanthine ( 1,3,7-Trimethylxanthine) with three methyl groups located at positions 1, 3, and 7. A purine alkaloid found naturally in coffee acts as a central nervous system stimulant as well as an adenosine A2A receptor antagonist.
        
        :star: The present of methyl group in caffeine is shows that caffeine is fat soluble
        
        :star: Adenosine and Caffeine structures contain C, H, N, and O molecules that are similar in shape, which is why caffeine can be misidentified by adenosine receptors. Caffeine now has the potential to act as an adenosine receptor antagonist with psychotropic and anti-inflammatory properties as a result of this incident.
        
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- - - - Caffeine is a central nervous system stimulant. This is why it helps in relaxing muscle contractions in blood vessels to improve blood flow. Example: acetaminophen and butalbital. The combinations are used to treat tension headache that are caused by muscle contractions.
      - Caffeine accelerates the absorption rate of analgesics by enhancing the drug solubility through reducing gastric pH. This will lead to quick onset of action of analgesics and allow the patient to feel relief sooner.
      - Caffeine may affect the activity of necessary brain substance called adenosine. Adenosine levels in the blood increase during migraine attacks which it acts by sticking to specific molecules on the surfaces of some brain cells. Caffeine can block the action of these receptors and thereby stop the effects of adenosine.
      - During headache, blood vessels swell causing an increase in blood flow around the brain. This increase blood flow pressure surrounding nerves, which send pain messages to the brain. Caffeine is used in many headache medications due to their vasoconstrictive properties which narrow the blood vessels. Therefore, the blood flow is restricted and pain can be alleviated.
      - Common drugs containing caffeine
        
        Vivarin, Anacin tablets, and Excedrin Caplets.
        
        Ergotamine tablets and Fiorinal capsules.
      - Analgesics that are affected by caffeine
        
        Paracetamol
        
        Caffeine induces the activity of cytochrome P-448 that metabolizes paracetamol. Due to its enzyme-inducing ability, caffeine can lower the concentration of the drug in the plasma, decrease the area under curve, and increase the total body clearance.
        
        Caffeine can also enhance the painkilling effect of paracetamol.
        
        Example: Panadol extra advance tablets, a type of paracetamol, have been specially formulated to allow the paracetamol to be absorbed into the bloodstream faster than standard paracetamol tablets or capsules.
        
        Aspirin
        
        Analgesic effect is faster and more effective when administered with coffee
        
        Due to caffeine's tendency to increase the gastric emptying rate. Faster gastric emptying rate makes the drug available for absorption sooner.
        
        Aspirin and caffeine works by reducing substances in the body that cause pain, fever and inflammation.
        
        Ergotamine
        
        Caffeine enhances the bioavailability of ergotamine.
        
        Quicker onset of action and increase extent would be due to faster and more complete gastrointestinal absorption of ergotamine in the presence of caffeine.
        
        Caffeine accelerates the absorption rate of ergotamine by enhancing its aqueous solubility through reducing gastric pH.
  - - - Caffeine affect the absorption process of drugs by changing the dissolution profile, changing the gastrointestinal (GI) pH, affecting the sink condition of the GI membrane and blood, affecting the GI emptying time, formation of complex, and inhibiting glucose-6-phosphatase.
        
        Coffee are found to interfere with the pharmacokinetic profile of escitalopram oxalate. The absorption of escitalopram oxalate decrease by the formation of complexes between the drug and caffeine. This complex formation reduced the bioavailability of escitalopram oxalate tablets by decreasing their dissolution.
        
        The ingestion of coffee with aspirin can increase the rate of aspirin absorption significantly. The mechanism by which caffeine affects the rate of absorption is by enhancing the gastric acid secretion. The resulting reduction in gastric pH may increase the unionized form of drugs and thus facilitates its absorption.
      - Drug that interacts with caffeine is ephedrine. Both ephedrine and caffeine are stimulant drugs. Hence, consuming caffeine along with ephedrine might cause too much stimulation and sometimes serious side effects and heart problems. It is recommended that we do not take caffeine-containing products and ephedrine at the same time.
      - Fluvoxamine can affect elimination of caffeine.
        
        Consumer will experience side effects such as nausea, vomiting, headache and nervousness due to long time accumulation of caffeine in the body.
        
        Fluvoxamine is an antidepressant that belongs to the group of selective serotonin re-uptake inhibitors (SSRI) used to treat social anxiety disorder (social phobia) or obsessive-compulsive disorders.
        
        Administration of caffeine and fluvoxamine impairs the clearance of caffeine and prolongs caffeine elimination half-life, which is attributable to inhibition of CYP1A2 by fluvoxamine.
      - Ingestion of coffee also slows down the conversion of levodopa into dopamine by inhibiting the decarboxylase enzyme.
        
        Interaction occur at central nervous system (CNS).Levodopa enters the brain across the blood brain barrier (BBB) by an active transport system.
        
        Levodopa is used to treat Parkinson's disease.
        
        A study which is done in Florida, USA has showed that caffeine may behave as an allosteric or competitive inhibitor of an enzyme that participates in converting levodopa to dopamine.
        
        Coffee also able to increase the plasma levels of levodopa.
        
        This inhibition process of coffee has two important applications.
        
        It facilitates the distribution of levodopa to brain tissues by active transport.
        
        It helps to extend the half-life of levodopa in the brain.
        
        Levodopa has a half-life of 60–90 minutes, but the half-life will be more than double when it is administered after ingestion of more than 2 cups of coffee
      - Plasma concentration of clozapine was increased by 97% after administration of 2-3 cup of coffee. Other than that, blood concentration of lithium, theophylline, warfarin and several antidepressant and antipsychotic drugs also increased after ingestion of coffee.
        
        This is because they are metabolized by a similar enzyme with caffeine
  - - - BENEFICIAL
        
        Caffeine is a drug that is very similar to theophylline.
        
        Theophylline is a bronchodilator drug that is taken to relax the muscles in the lungs. This allows the airways to expand, allowing for increased airflow and easier breathing therefore relieve the symptoms of asthma such as wheezing, coughing and breathlessness.
        
        Caffeine is a weak bronchodilator, improving lung function for two to four hours after it is consumed.
        
        Help reduce the fatigue of muscles throughout the respiratory system.
        
        Caffeine belongs to a group of chemical called methylxanthines. This class of drugs have a history of use in respiratory disorder.
        
        Action mechanism of methylxanthines is by the inhibition of the enzyme phosphodiesterase which hydrolyzes cyclic adenosine monophosphate (cAMP)
        
        cAMP is a messenger within the cell that regulates many functions including the contraction and relaxation of smooth muscle
        
        Competitive antagonists for adenosine receptor. One of the effects of adenosine, a chemical regulator, is bronchoconstriction.
      - HARMFUL
        
        Caffeine are needed in such large amounts in order to improve the symptoms of asthma. Large dose of caffeine will cause unwanted side effects
        
        Insomnia, headache, shakiness, upset stomach and bone thinning.
        
        Increase the stress hormone in the body which could induce an asthma attack in some people. Example: norepinephrine and epinephrine that are produced by adrenal glands that causes consumer to feel jumpy.
      - Side effects of caffeine outweighs its benefits.
        
        It's better for asthmatic patients to avoid drinking coffee
        
        Although caffeine can act as a bronchodilator for asthmatic patients, it is considered a weak one.
        
        There are also other drugs like albuterol that acts stronger and faster compared to caffeine.
        
        Even small amount caffeine can affect the results of spirometry. It might looks like their lungs are working better than they really are thus doctor will prescribe a lower dose of drug than what they need to manage asthma.
        
        Overdose can result in death due to convulsion or irregular heartbeat.