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:fire:HOME GROUP 1:fire: Aisyah Binti Ayob Aliya Nadira Binti Mohd…

- - - - What is an intrinsic activity?
        
        The ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity
        
        Antagonist lack of intrinsic activity
        
        Antagonists do not have intrinsic activity, but it does not mean they do not have physiological consequences.
        
        Concerning our case study, caffeine does lead to physiological changes by Increase the nerve cells activity and stimulate us to be more alert and energetic
        
        Also known as efficacy.
    - - Adenosine is a full agonist while caffeine is a competitive antagonist.
        
        Caffeine acts mainly as a non-selective A1 and A2A adenosine receptor antagonist
        
        Caffeine binds to A2A which is a transmembrane protein coupled with a G protein in humans.
        
        The third and seventh transmembrane helical domains need to recognize the ligand.
        
        When caffeine present in the system, it will interact with the A2A receptor.
        
        As result, caffeine then binds to A2A receptor
  - - - GPCR is the largest and most diverse group of membrane receptors
        
        mediate the majority of our physiological reactions
        
        offer a wide range of therapeutic possibilities.
      - Heptahelical receptor
        
        have seven helices
        
        pass through the cell membrane seven time
        
        contains seven transmembrane receptors
      - Made up of a single polypeptide folded into a globular shape
    - - GPCRs are found in the cell membranes of a wide range of organisms, including mammals, plants, microorganisms, and invertebrates
      - GPCRs may also be found in intracellular components such as the endoplasmic reticulum, Golgi apparatus, nuclear membrane, and even the nucleus itself.
    - - At inactive state, Gα subunits of G proteins are GDP bound.
      - Upon interaction with activated GPCR where the agonist binds to the receptor, GDP dissociates and GTP binds to the Gα protein.
      - As a result, the Gβ and Gγ subunits dissociate
      - GTP-bound Gα -protein is activated, allowing it to activate adenylyl cyclase and initiate signalling by stimulating the conversion of ATP to cAMP.
      - When G-Protein hydrolyses GTP back to GDP, it reverts to inactivation and the process resets, resulting in the reassociation of the Gα, Gβ and Gγ subunits.
  - - - Potency
        
        Potency is the measurement of dose of drug required to produce a maximal response
        
        Affinity is the primary determinant of drug potency.
        High affinity of the drug to the receptor, high potency of the drug.
        
        In dose-response relationship- a measure of the amount of caffeine necessary to produce an effect of a given magnitude.
        
        Concentration of caffeine producing an effect that is 50 percent of the maximum is used to determine potency and is commonly designated as the EC50
      - Efficacy
        
        Efficacy is the magnitude of maximal response that a drug can produce which also known as intrinsic activity.
        
        The ability of a caffeine to elicit a response when it interacts with a receptor.
        
        Dependent on the number of drugs–receptor complexes formed and the efficiency of the coupling of receptor activation to cellular response.
      - Caffeine act as reversible competitive inhibitor
        Adenosine act as antagonist
        
        During the competition of caffeine-adenosine, the log dose-response curve of the graph will shift to the right of the dose axis without a change in slope or maximum.
        
        The agonist alone (adenosine) will be more potent compared to the presence of adenosine and caffeine together.
        
        The shift of graph from left to right indicates that they are a change in the potency of agonists (adenosine) which is reduced in potency.
        
        Hence, to overcome the effect of an antagonist, an increased concentration of the agonist is needed.
- - - - An individual who continues to consume drugs even though they know it is having an a bad affects especially on health and well being
      - Despite the fact that their social lives and finances are disintegrating, they continue to consume the drugs.
      - When someone uses a medication in a method that is not approved by a doctor
    - - A person who has built up a tolerance to a particular drugs and the body adapts to the drugs taken
        
        Then comes the need to to take more and more drugs to get same effects as before
        
        The body is readily tricked into believing the drug is a vital element of daily functioning, allowing addiction to emerge.
    - - Tolerance: :check:
      - Addiction: :red_cross:
  - - - Pleasurable experiences, as well as learning, memory, motor system function, and more, are all linked to dopamine.
      - Dopamine is a neurotransmitter that communicates between the body and the brain. Dopamine is involved in controlling a person's motions as well as their emotional responses. Chemical messengers are another name for them.
    - - Caffeine enhances dopamine signaling in the brain by antagonizing adenosine resceptors
      - Dopamine works more effectively when adenosine receptors are blocked
        
        Increased unbounded adenosine (caffeine attached to adenosine receptors instead of adenosine) causes the body to produce more adrenaline, which promotes alertness and lowers fatigue.
    - - Dopamine is not the primary cause of tolerance and addiction, although it does play a part in the development of tolerance.
        
        This is because caffeine only produces a small rise in dopamine
      - Dopamine is a motivation rather than a drug that can lead to addiction. Dopamine is released by the brain's reward region in reaction to pleasurable events. It records the event because it is pleasurable.
  - - - Structurally, adenosine and caffeine are similar. Thus, caffeine can bind to adenosine receptor and act as antagonist
        
        Adenosine bounded to adenosine receptors can make people tired. When adenosine receptors bounded with caffeine instead, people will less to feel the tired effects.
        
        People take advantages for this effects and usually consumed coffee when they need to work. Almost 64% US citizens consumed coffee every single day!
    - - Brain cells grow more more adenosine receptors to compensate the un-balanced amount of bounded adenosine
        
        This explains why regular coffee drinkers develop tolerance over time
        
        The regular drinkers have more adenosine receptors over time, more caffeine needed to block receptors to give the same effects (not tired, fully awake)
        
        This is how Caffeine Tolerance develops over time!
- - - - The caffeine in our brain is competing with adenosine and preventing it from binding to A1 receptors. This gives us a jolt of wakefulness.
      - Binding of caffeine to A1 and A2A receptors induce the release of neurotransmitter such as glutamate, dopamine, noradrenaline, acetylcholine.
  - - - Both have 2 rings ; a pyrimidine (6 membered ring) and an imidazole ring (5 membered ring)
      - Both molecules are water and fat soluble so they easily cross the blood-brain barrier.
      - Because of the structural similarity, caffeine could be helped across the barrier by attaching to a
        transporter that is usually associated with adenosine
  - - - Glutamate
        
        responsible for sending signals between nerve cells
        
        plays an important role in learning and memory
      - Dopamine
        
        mediates pleasure
        
        dopamine is also linked to focus, attention, and movement. .
    - - Adrenaline
        
        It makes the heart beat faster
        
        increases blood flow to the brain and muscles
        
        stimulates the body to make sugar to use for fuel
    - - Paraxanthine
        
        Enhances athletic performance by helping fat break down, releasing fats into bloodstream and fueling the muscles.
        
        Helps toreduce inflammation
      - Theobromine
        
        increase the flow of oxygen and nutrients to the brain
        
        dilates blood vessels
        
        increases urine volume
      - Theophylline
        
        Increases the heart rate
- - - - Very potent inhibitor of the liver enzyme CYP1A2
        
        The major P450 isoform involved in the metabolism of caffeine.
        
        Increase the plasma concentrations of caffeine, prolongs its elimination half-life.
      - 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.
    - - Oxandrolone is a anabolic steroids.
        
        help people regain weight they have lost due to certain medical conditions
        
        Used to relieve bone pain (osteoporosis)
      - caffeine alter the excretion of oxandrolone.
        
        A medical case report showed that the ingestion of three cups of coffee (equivalent to 300 mg of caffeine) highly increased (about 20 times) the rate and excretion of oxandrolone.
        
        Excretion rate increases to 150 ng/min after coffee consumption
        
        The maximum excretion rate of oxandrolone is 10 ng/min
    - - Ingestion of coffee slows down the conversion of levodopa into dopamine by inhibiting the decarboxylase enzyme.
        
        facilitates the distribution of levodopa to brain tissues by active transport
        
        Increase the half-life of L-DOPA in the brain.
      - L-DOPA has a t1/2 of 60–90 minutes. When administered with caffeine, the half-life becomes more than double.
      - Levodopa is a dopamine precursor used to treat Parkinson's disease.
  - - - Beneficial
        
        Caffeine is a weak bronchodilator, improving lung function for two to four hours after it is consumed.
        
        Caffeine works in a similar way to theophylline. Theophylline- bronchodilator drug that is taken to relax the muscles in the lungs.
        
        Allows airways to expand
        
        Increase air flow
        
        Easier breathing
        
        caffeine is chemically similar to theophylline and belongs to a group of chemicals called methylxanthines, along with the bronchodilator drug theophylline
        
        Caffeine is 1,3,7-trimethylxanthine
        
        Theophylline is 1,3-dimethylxanthine
      - Harmful
        
        Caffeine produce small amount of theophylline (4%) during metabolism and considered as a weak bronchodilator.
        
        Asthmatic patient need to consume high amount of coffee to get the same results as medicines and to relief the asthma symptoms
        
        This can cause side effects
        
        headache
        
        nervousness
        
        stomach irritation
        
        nausea
  - - - This increase blood flow pressures surrounding nerves, which send pain messages to the brain
        
        Caffeine has vasoconstrictive properties, meaning that blood vessels narrow to restrict blood flow, thereby alleviating the pain.
    - - i) Changing the Gastrointestinal pH
        
        Caffeine enhances the bioavailability of ergotamine
        
        Have quicker onset of action in the presence of caffeine.
        
        Caffeine enhancing ergotamine aqueous solubility through reducing gastric pH
        
        Movement of the drug molecules from gastrointestinal membrane into the blood is the rate-determining step of ergotamine absorption.
        
        Caffeine is a known stimulant of gastric acid secretion (GAS)
        
        Activating several taste type 2 bitter receptors (TAS2Rs) due to its bitter taste.
        
        Decrease in the gastric pH by increasing the hydrochloric acid secretion.
        
        conversion of the drug substance into an insoluble form
        
        altering the drug’s rate of dissolution
        
        acid degradation of the drug
      - ii) Changing Gastric Emptying Time
        
        Aspirin deliver its analgesic effect faster when administered with caffeine.
        
        As the gastric emptying rate increase, the absorption of drug also will increase
        
        Aspirin undergoes a rapid hydrolysis to salicylic and acetic acid in the stomach
        
        Thus shorter gastric residence time reduces the amount of hydrolysis that occurs prior to absorption.
- - - - Bind to non-agonist (allosteric) site on the receptor and prevent activation of receptor
    - - Agonist alone binds to the active site of the receptor and produce the effect.
    - - When competitive antagonist compete with agonist and bind to the receptor, agonist binding is blocked and prevent them from activating the receptor