Pharmacodynamics 2 تفريغ PDF

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer...

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Reem Alhussain Danial Abdulfattah 221-222-223 notes References Student explaintion Deleted  By Dr. Shereen Refaie 2 November 2023 Dr Shereen Refaie Objectives By the end of this lecture, you should: 1. Describe the two-state receptor model 2. Know the four types of drug receptors and their signal transduction mechanisms 3.Describe the general molecular structure and effector pathway of G-protein coupled , tyrosine kinase and nuclear receptors 4.Know the mechanisms controlling receptor density at the cell membrane 2 November 2023 Dr Shereen Refaie  Resting: If we don’t have The two-state model. No stimulation: the equilibrium lies to the left any stimulation. Activated:If we have a stimulation ❑The receptor has two conformational states, 'resting' (R) and 'activated' (R*), which exist in equilibrium. ❑Normally, when no ligand is present, the equilibrium lies far to the left, and few receptors are found in the R* state. Ligand: any substance that activates the receptor activation state (to the right) ex: drug, hormone or enzyme Equilibrium: means it’s continues, activation then resting, activation then resting... R R* equilibrium will lie to the left Usually the receptors are in resting state. The two opposite arrows means continuous change. resting state (to the left) 2 November 2023 Dr Shereen Refaie  Agonists: drugs that bind and activate the receptors Agonists shift the equilibrium towards R*. Agonist attach to the resting state of the receptor and it will lies the reaction to the right. Agonist Response R R* During activated 2 November 2023 Dr Shereen Refaie Constitutive Receptor Activation And Inverse Agonists An appreciable level of activation may exist even when no ligand is present. Receptor mutations occur-either spontaneously, in some disease states, or experimentally created that result in appreciable activation in the absence of any ligand (constitutive activation). in abnormal conditions certain amount of receptors will be activated without any stimulation Receptor mutation can occur: ex: patients with epilepsy, focus in the brain become stimulated uncontrollably as a result, all of a sudden spontaneously Exposuring to chemical, uncontrollable severe muscle contraction will occur. radiation… in resting phase. 2 November 2023 Dr Shereen Refaie For constitutively active receptors, an appreciable proportion of receptors adopt the R* conformation in the absence of any ligand. without any ligand the reaction lies to the right which is abnormal R R* 2 November 2023 Dr Shereen Refaie An inverse agonist binds with constitutively active receptors , stabilize them and thus reduce their activity (negative intrinsic activity) so shifts the equilibrium to the left. example of inverse agonist: ‫أدوية علاج‬ ‫ الصرع‬Benzodiazepines(class of drugs act as anti-epileptic drug) Inverse inverse agonist will attach to the in this condition the patient has activated state of the receptor and receptors in the brain which are then taking the equilibrium to the abnormally activated sending resting state(to the left) Agonist signals that cause seizures so inverse agonist will help inactivate these receptors. R R* The name of the drug seems not important because the doctor mentioned it only in females’ lecture, while in males’ lecture it’s not mentioned. 2 November 2023 Dr Shereen Refaie Dose response curve from resting to stimulate the receptor activation Blockage of the zero efficacy receptor negative efficacy from activated to resting state 2 November 2023 Dr Shereen Refaie  Type 1,2,3 receptors are embedded Type of receptors in the cell membrane “outside the cell” While type 4 receptor is located inside the cell & and it's the slowest Type1: Ligand-gated ion channel (ionotropic receptors) fast neurotransmitters it has fast transmission so the response will occur very fast. Type 2: G-Protein coupled receptors (GPCRs) Type 3: Kinase linked and related receptors Type 4: Nuclear receptors gene transcription 2 November 2023 Dr Shereen Refaie 2 November 2023  ThisThisreceptor is made of 5 subunits receptor is made of 5 (2 alpha-1beta-1gama-1delta)and subunits Type 1 (2they surround the channel(na,k,cl) alpha-1beta-1gama-1delta)and The ion either enters the cell or exit depending theyThe ion channel surround receptors are the channel(na,k,cl) The ion channel receptors are like ligand gated They are usually like Ion channel receptors on the concentration gradient ligand gated They are usually If the ions are high outside(ex.sodium and present innerves nervessoso they transfer fast present in they transfer chloride ions) when the receptor is open they The fast agonist The agonistwill bindtotothethe two will bind will enter but if the ions are high inside(ex. alpha two alphasubunits subunitsthen thechannel then the channel will potassium ions)they will exit when the open then conduction of ions then will open then conduction of ions then the cell will be activated receptor is open. the cell will be activated 2 November 2023 Dr Shereen Refaie In resting membrane potential the inside of the cell is negatively charged. When a cell is stimulated by the entry of the sodium ions(Na+), the inside of the cell will be less negative(more positive)compared to the outside is known as depolarization. It will create electrical charge change that will stimulate the cell for nerve signals or muscle contraction. If chloride ions (Cl-) enter the cell they will make inside the cell more negatively charged is known as hyperpolarizatin. The entry of chloride ions has inhibitory effect on cell signaling.  Single chain amino acid receptor Type2 +G protein= G protein coupled receptor G protein coupled receptors In its normal resting the alpha The G protein is composed of three subunit of the G protein is Single chain amino subunits: alpha (α), beta (β), and acid receptor bounded to GDP (guanosine gamma (γ). diphosphate). However, when the ligand binds to the receptor, 1 2 3 4 5 6 7 it triggers a change in the alpha subunit, causing it to exchange its GDP for GTP (guanosine G protein triphosphate). This transition from GDP to GTP is a critical step in the activation of the G protein." Also known as: Metabotropic ,7- transmembrane receptors, serpentine receptors ‫ مرات‬7 ‫لأنه يدخل ويطلع‬ Latin word means snake 2 November 2023 cell membrane ‫على‬ Dr Shereen Refaie They all operate in the same way, but they produce different results because each type has Gq is like a signal switch inside cells. When it's turned on a different alpha subunit that influences the specific effect of the G protein either (activated), it creates two important messengers: inositol stimulation or inhibition phosphate and diacylglycerol. These messengers mainly work to increase the level of calcium in the cell. There are many classes of G-protein (Gs, Gi, &Gq) Phospholipase C is kind of like the key that starts this process. It breaks down the cell membrane's phospholipids, which leads to the release of calcium inside The main targets for G-proteins are: the cell. 1. Adenyl cyclase (Gs &Gi) : responsible for cAMP formation 2. Phospholipase C (Gq) : responsible for inositol Example of Gi and Gs,The sympathetic nervous system activates the beta receptors which are G just stimulation protein Coupled receptors. phosphate and diacylglycerol (DAG), particularly -There are beta-1 receptors found in the heart, if the sympathetic activates the beta-1 receptors it will increase the heart rate? because it is Gs protein. -In the other hand, Beta-2 receptors(found in the increasing calcium level in the cell. lungs) if they get activated by the sympathetic it causes relaxation of the body? because it is Gi Gs=Stimulatory G-proteins(increasing production of cAMP) protein. Gi=Inhibitory G-proteins(inhibiting production of cAMP) cAMP=Cyclic adenosine monophosphate 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 1. Ligand approach the receptor Once the drug binds to the receptor, the GDP that is attached with α subunit is replaced with GTP. With this, α subunit get activated and separated from G-protein. Now the activated α subunit activate an enzyme called adenylate cyclase. this enzyme convert ATP—>cAMP(cyclic adenosine monophosphate) and α subunit goes back into its original form 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 2. Binding site is introduced to fit closely with ligand Same explanation: Normally GDP is attached to α but when the Ligand bind with the receptor, GDP will be released and GTP (energy source) will attach to α. After that, α will disassemble from the receptor & Beta & Gama. Then it will attach to enzyme called adenylate cyclase and activate it. Finally, the enzyme adenylate cyclase will convert ATP to cAMP. 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 3. Receptor conformation change: Alpha subunit of G-protein loses GDP 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 4. When GTP binds to alpha subunit of G-protein, it dissociates from beta/gamma subunits and receptor. Receptor then loses ligand 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 5. Then the "activated" Alpha subunit finds a molecule of Adenylate Cyclase 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 6. Activated Alpha subunit binds to Adenylate Cyclase, activating it 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 7. Adenylate Cyclase turns ATP into the signaling molecule, cAMP, until GTP -> GDP; Alpha subunit then reverts to original form 2 November 2023 Dr Shereen Refaie  G-protein singling mechanism 2 November 2023 Dr Shereen Refaie  Type3 Tyrosine kinase receptor The extracellular part is the position where the drug bind to the receptor The most famous receptor. The intracellular part is an (insulin receptor) enzyme(tyrosine kinase) The transmembrane part connects the two parts. Extracellular part transmembrane part Intracellular part 2 November 2023 Dr Shereen Refaie  Tyrosine kinase receptor 1- binding of the drug to the extracellular part. 2-the two receptors get closer to each other(pairing of the receptor). 3-both of the tyrosine kinase enzymes (intracellular parts) activate each other (phosphorylation). 4-other enzymes bind to the tyrosine kinase and get activated. the tyrosine kinase receptor is also called the insulin receptor so an example of the tyrosine kinase receptor is the insulin receptor The insulin attaches to the extracellular part of the receptor then two receptors get close to each other then both of them activate each other then enzymes get activated that will do metabolism of the glucose. 2 November 2023 Dr Shereen Refaie  Type4 this type is the only receptor which is inside the cell The nuclear receptor is present ether in the nuclear receptors 1-The drugs that bind to intracellular receptors should be highly lipophilic to be able to cross the cell cytoplasm or the nucleus, if it is located in the membrane cytoplasm, after it binds to a drug, it migrate into 2-DNA transcription takes time so the effects will be the nucleus and starts affecting the DNA delayed( it affects the protein synthesis) hours to days transcription either by increasing or decreasing it. if the receptor is in the nucleus the drug will have to go to it’s place in the nucleus to activate it. Example :steroid (corticosteroid ,sex hormone) Ex: corticosteroids in the liver have metabolic action while in the bone have catabolic action Ligand : so this is why if we take the drug for long it causes Highly lipid soluble osteoporosis. Delayed effect 2 November 2023 Dr Shereen Refaie  Desensitization And Tachyphylaxis continuously stimulation of the receptor in a short period of time diminishes the effect The effect of some drugs gradually diminishes when they are given continuously or repeatedly 1. Desensitization and tachyphylaxis are synonymous terms used to describe this phenomenon, which often develops in the course of a few minutes (i.e., acute tolerance) If it is continuously stimulating In dose response curve In dose response curve increasing theincreasing dose will the dose will increase thetheresponse increase response until it If we give the same dose it will exceeds the E.max it will cause toxicity. give the same response But If we give the cell Time to relax If we give thecontinuously same dosewithout with relaxation (tachyphylaxis) happen it will give the same desensitization relaxation response But continuously without relaxation desensitization (tachyphylaxis)will happen 2 November 2023 Dr Shereen Refaie  ‫مثال‪ :‬عندما ترغب في قيادة سيارتك‪ ،‬تبدأ أوًلا بتشغيل المحرك‪ ،‬ثم إذا ضغطت‬ ‫على دواسة البنزين بعد ذلك مباشرًة فإن السيارة لن تتحرك‪ ،‬لأنك تحتاج إلى‬ ‫وضعها على وضع القيادة (‪.)D-Driving‬‬ ‫هكذا هو المستقبل (‪ )receptor‬عندما تعطيه جرعات زائدة في وقت قصير‬ ‫(‪ ،)Very Short Time‬فإنه سيتعب ثم سيفصل الـ(‪)signal transduction‬‬ ‫وهو وضع القيادة في مثالنا السابق‪ ،‬فمهما زدت الجرعات (ضغط دواسة البنزين)‬ ‫الـ(‪ )receptor‬لن يستجيب (السيارة لن تتحرك)‪.‬‬  Usually as a result of Tolerance ‫أخذ الدواء لفترة طويلة لما ما يعطي استجابة فنضطر‬ addiction (‫)الإدمان‬ ‫نزيد الجرعة وبعد فترة ممكن نضطر نزيدها‬ The effect of some drugs gradually diminishes when they are given continuously or repeatedly 2. Tolerance is gradual decrease in responsiveness to a drug, taking days or weeks to develop Chronic tolerance among weeks and months Ex. The narcotic analgesics as morphine cause tolerance. Also, anti-depression drugs ‫والمنومات‬ 2 November 2023 Dr Shereen Refaie  Mechanisms this type of phenomenon include: ❑ Change in receptors ‫نفاذ أو استنزاف‬ ❑ Translocation of receptors Continuous use can reduce the ❑ Exhaustion of mediators mediators that let the drug works The liver will increase ❑ Increased metabolic degradation of the drug the metabolism ❑Active extrusion of drug from cells Cells might actively pump the drug out extrusion=throwing ex. Antibiotics resistance 2 November 2023 Dr Shereen Refaie  The number of receptors that are expressed on the surface of the cell is not constant Control of receptor expression Short-term regulation of receptor function generally occurs through desensitization Long-term regulation occurs through 1. An increase of receptor expression (Up-regulation): Examples of this type of control include the proliferation of various postsynaptic receptors after long use of antagonists (i.e continuous inhibition ) Continuous blocking—>increasing the number of receptors expressed on the surface of the cell ‫علاقة عكسية‬ 2. Decrease of receptor expression (Down regulation): following continuous Continuous stimulation —>decreasing stimulation (prolonged use of agonists) the number of the receptors expressed on the surface of the cell Postsynaptic receptors are located on the cell membrane of postsynaptic neurons (the receiving neurons) and interact with neurotransmitters 2 November 2023 Dr Shereen Refaie released from presynaptic neurons (the sending neurons). Q1/the drug which stabilize and Q2/ Which of the following is a reduce the activity of the property of a drug acting in type 4 Constitutive receptors? receptor? A-Full agonist A-High ionization B-Partial agonist B-High lipids solubility C-inverse agonist C-High molecular weight D-High water solubility Q3/ which of the following Q4/ All of the following are components is a target of drug considered as second messenger binding: Except: A-cell membrane A-cAMP B-Diacylglycerol B-ion channel C-G-protein C-nucleus D-inositol triophosphate  Q5/What term that describes the Q6/Tachyphylaxis is decrease in unresponsive to a drug A-a rapid onset of anaphylaxis that develops within few minutes B-a form of rapid drug resistance A-Hypersensitivity C-rapid drug tolerance B-Super sensitivity D-a form of rapid but non- C-Tachyphylaxis competitive drug antagonism D-Tolerance Q7/A decrease in response Q8/Drugs that act on G-protein activate which of the following after repeated administration enzymes: of a certain drug is termed as: A-Adenylyl cyclase A-Hypersensitivity B-Phospholipase A B-Super sensitivity C-phospholipase C C-Tachyphylaxis D-Tolerance  Q9/Drugs act on Q-Protein coupled Q10/Which of the following is a receptors activate which of the good example of life equilibrium following enzyme A-Metabolism A-Adenylyl cyclase B-Growth B-Phospholipase A C-Response to environmental C-phospholipase stimuli C D-Guanylyl cyclase Q11/Which of the following Q12/ Masking (internalization) of mechanism play a major role for receptors contribute toward which transport of drug across the one of the following activities biological metabolism A-Down regulation of receptors. A-Active B-Up regulation of receptors B-Endocytes C-Change in the affinity of an agonist. C-Active diffusion D-Change in the affinity of an D-Passive diffusion antagonist.  Q13/Which one of the following types of receptors is expected to produce a delayed response due to gene regulation A-G-protein coupled B-Tyrosine kinase C- Ionotropic D- Steroid 1-C 2-B 3-B 4-C 5-C 6-C 7-D 8-A.223 ‫جميع األسئلة منقولة من تفريغ‬ 9-C 10-C 11-D.‫جميع األسئلة ُأِخ ذت من تجميعات السنوات السابقة‬ 12-A 13-D  team Wishes you the best