PHA316 Practical Test Revision PDF

PHA316 Practical Test Revision ============================== **4 Types of drug antagonism :** - Chemical antagonism - interaction in solution =\> affecting drug availability - Competitive antagonism - competition for same receptor site - Physiological antagonism - producing opposing p...

PHA316 Practical Test Revision ============================== **4 Types of drug antagonism :** - Chemical antagonism - interaction in solution =\> affecting drug availability - Competitive antagonism - competition for same receptor site - Physiological antagonism - producing opposing physiological effects through different pathways - Non-competitive antagonism - inhibits response without directly competing for agonist binding site **PA2 Value** Represents agonist potency. Value that requires you to double the conc of Ach(agonist) to get same response as Atropine(antagonist). Higher PA2 (less of it is needed to block agonist)=Higher potency (the concentration of agonist at EC50 doubles ) The pA₂ value tells us how much antagonist is needed to \"block\" an agonist\'s effect by half. The pA₂ value can be calculated if you know the concentration of an antagonist \[A\] that causes the agonist to require twice as much to achieve the same effect. The formula is: PA2= - log\[A\] *Example: In an experiment, you are studying the effects of an antagonist called Drug X on the response of a specific receptor to an agonist. Without any antagonist, the effective concentration of the agonist needed to produce a particular response is 5 µM. When Drug X is added at a concentration of 2×10−6 M the effective concentration of the agonist required to produce the same response doubles to 10 µM.* Given info: - Agonist w/ antagonist 10uM - Agonist w/o antagonist 5uM - Drug X is the antagonist And when @ 2x10\^-6M it requires 10M to produce the same response. (double agonist to get same response) Use equation : Pa2= -log\[A\] PA2= -log (2x10\^-6) = 5.7 PA2= 5.7 **EC50** Half maximal effective concentration. (Potency of drug at 50%) **What does agonist potency depend on?** Affinity and efficacy **Affinity** Occupancy, binding of drug to receptor. Reflects the strength of the binding between a drug and its receptor , influencing the occupancy of receptors by the drug. **Efficacy** Ability of a drug to produce a maximum biological response once bound to its receptor. Eg. increase in HR / Contraction of a muscle **What determines drug affinity ?** Determined by the specific interactions between a drug & its target receptor\ - Influences likelihood & strength of drug binding to receptor\ - As we increase agonist of agonist-receptor complex =\> reaction reaches max. as no. of receptors is finite\ \ 1. Equilibrium constant (KA) - affinity of agonist for receptor\ - Smaller KA = higher affinity = drug binds more tightly\ \ 2. Equilibrium Dissociation constant (KD)\ - Tendency of agonist-receptor complex to dissociate\ - Reciprocal of KA\ - Smaller KD = stronger binding **What determines drug efficacy?** 1. Receptor Activation:\ - The efficiency with which a drug activates its target receptor\ 2. Intrinsic Activity:\ - Ability of a drug-receptor complex to activate cellular processes Drugs with high intrinsic activity are more efficacious in producing a response.\ 3. Effector Systems:\ - The downstream cellular pathways influenced by the drug-receptor interaction impact efficacy. Drugs may differ in their ability to stimulate or inhibit these pathways.\ \ 4. Receptor Reserve:\ - If a biological system has a receptor reserve (more receptors than necessary for a maximal response), a drug may be considered efficacious even if not all receptors are occupied.\ \ 5. Cellular Context\ - The response to a drug can depend on the specific cell type and its physiological state. The same drug may have different efficacy in different tissues. **Competitive Antagonism** Agonist & antagonist both compete for same binding site on receptor\ - Both agonist & antagonist bind reversibly to receptor\ - Reaction depends on 2 equilibrium constants: agonist - KA & antagonist -KAnt\ - If KAnt less than KA = Antagonist has greater affinity for receptor\ - To overcome antagonists binding to receptor =\> increase conc. of agonist **Non-Surmountable Antagonism** Antagonist can\'t be overcoming by increasing conc. of agonist\ - Antagonist has persistent effect\ - Not easily reversible by higher agonist conc. **Non-competitive Antagonism** Antagonist binds to diff site to that of agonist **Irreversible Antagonism**  Antagonist binds irreversibly to either agonist or non-agonist binding sites on receptor through covalent bonds\ - Reduces no. of available receptors for agonist(drug) to bind to\ (Affecting overall response)\ \ - Reduces slope\ - Depresses maximum **Does Atropine act as a competitive or non-competitive agonist?** Competitive Antagonist\ - Competes with ACh for binding to muscarinic receptors\ - By binding reversibly to these receptors - atropine blocks actions of ACh (neurotransmitter)\ - Produce identical slope that shifts to the right (without altering maximal response (efficacy) **Relationship between log concentration of atropine and negative log values?** Direct linear relationship\ - \*Competitive antagonist =\> as conc. of antagonist increases - rightward shift in dose-response curve of agonist without affecting maximal response (efficacy) **Dose Ratio**\ The dose-ratio is the factor by which the dose of an agonist must be increased to produce the same effect in the presence of an antagonist compared to when the antagonist is absent.\ DR = EC50 with atropine / EC50 without atropine **A full agonist evokes a 100% effect, what % effect does an antagonist evoke?** An antagonist typically evokes 0% effect on its own.\ \ - Antagonists bind to receptors but do not activate them\ - Their primary function is to block or inhibit the effects of agonists.\ =\> In the absence of an agonist - antagonists do not produce any physiological response **Molar Concentration Formula** Conc(M) = Dose (g) / Body weight (kg) x MW (g/mol) ** A human receives a dose of atropine to treat a bradycardia of 0.02 mg per kg (atropine molecular weight is 289). Calculate the molar (M) concentration of atropine in the blood stream (assume even distribution in body, body fluid volume of 50 litres and a body weight of 80 kg.** Use above formula **Why is aeration important in the tissue organ bath system?** To provide O2 to the guinea pig ileum.\ =\> Oxygenation supports tissue viability & helps in the mixing of drugs applied to the bath - ensuring accurate & physiological responses. **What does Acetylcholine (ACh) do?** Increases rate and strength of contraction in ileal smooth muscle. **Major difference between an agonist and an antagonist?** Agonist: Activates or enhances a biological response. Mimics the action of endogenous substances.\ \ - Antagonist: Blocks or inhibits a biological response. Often competes with agonists for receptor binding. **Give details of the effects of ACH in presence and absence of Atropine. Suggest potential receptors that might mediate this response.** In the Absence of Atropine:\ ACh induces concentration-dependent contractions in the guinea pig ileum.\ At higher conc, the response reaches a plateau.\ \ In the Presence of Atropine:\ At lower conc, atropine seems to enhance the response to ACh.\ At higher concentrations, atropine attenuates the ACh-induced response.\ \ Potential Receptors:. Muscarinic Acetylcholine Receptors (mAChRs):\ M3 receptors mediate smooth muscle contraction.\ M2 receptors may mediate inhibition, & their blockade by atropine could enhance the overall response.\ \ 2. Cholinergic Neurons:\ Interactions with pre- & post-synaptic receptors on cholinergic neurons might contribute to the observed effects. **Solution** Consists of a single phase of two or more components in which they are dispersed at molecular level. **Solvent** The substance in which the solute dissolves. **Acetylsalicylic Acid = Aspirin** **What effects solubility?** Temp and polarity **SDS= sodium dodecyl sulfate** -- surfactant which reduces surface tension between molecules allowing it t perform several functions such as emulsification , foaming and cleaning. **What is a surfactant?** It possessed both hydrophilic and lipophllic groups so therefore is amphiphilic. **Where do ampiphilic species localise?** The interface between immiscible liquids aka the liquid air interface. **What happens when the interfacial region is saturates with amphiphilic molecules?** No further reduction in surface tension and micelles will form. **What is CMC?** Critical Micelle concentration; surface layer is saturated with surfactant molecules and no further decrease in surface tension is possible; at this concentration surfactant forms micelles. **Saturated Solution** A solution that cannot dissolve any more solute under the given conditions. **Where is aspirin located in the micelles of the sds?** Inner core of the micelles of sds as the aromatic ring of aspirin is hydrophobic and therefore prefers non aqeuous environments Hydrophobic core -- no water in here. **relationship between the surfactant and aspirin** increase in the conc of the surfactant (leads to CMC Increase in formation of micelles) led to an increase in the solubility of aspirin because this is where the aspirin dissolves. **DRABCs- Assessing a Casualty** **D**anger- don't cause any danger to yourself or others if trying to help a casualty.\ **R**esponse- check to see if there is any response eg shout their name.\ Shout for help- to bystanders and call 999\ **A**irway- tilt head back until mouth opens, lifting chin.(Ensure tongue isn't blocking airway)\ **B**reathing- check for 10s for any chest movement/breath. \*\* Common to see agonal breathing if the heart is stopped- this is infrequent gasps for breath. If they have agonal breathing -- start CPR immediately. If casualty is breathing normally- place in recovery position and treat any other injuries.\ **C**irculation- injuries that cause bleeding can lead to shock which is serious. Only check for circulation if you are sure the casualty is breathing- as it would waste crucial CPR time. Rescue breaths are only given to children and infants since the covid-19 pandemic. Hard,flat surface. **Adult Rate** **30 chest compressions (100-120 per minute) pressing down 5-6cm(keeping elbows straight.)** **Chain of survival\ ** Recognising cardiac arrest\ Early 999 request for help to the emergency services\ Early basic life support -- CPR\ Early defibrillation\ Early advanced life support.(Oxygen therapy/IVs etc.) **When to stop CPR:\ ** Professional help takes over\ The infant starts to wake up, move, open eyes and breathe normally\ You become exhausted\ If there is another trained first aider present - A surfactant, or amphiphile, is a molecule that has distinctive polar and non-polar regions. (hydrophilic and hydrophobic) - The non-polar regions are usually aliphatic chains or cyclic structures. The polar regions are subdivided into: anionic, cationic, zwitterionic and non-ionic according to the nature of the functional group(s) involved. - For example, sodium dodecyl sulfate (SDS), also known as sodium lauryl sulfate, is an anionic (due to O- ) surfactant. Sodium is the counterion -- helps stabilise it to counteract the charge. Always forget about the counterion when labelling it. Surfactants (and other amphiphilic molecules) seek to orient themselves so that contact between the non-polar group and an aqueous environment is minimised. - When an interface is present, the surfactant inserts itself into the interface so that the polar end is exposed to the aqueous environment, while the non-polar end is within the other phase. This lowers the interfacial tension. Traube's Rule - Depends on the balance between hydrophilic and hydrophobic properties. - Homologous series of surfactants: Increase length of hydrocarbon chain results in increased surface activity -- decreasing surface tension. - This was shown by Isidor Traube (1884). He found that for every additional methyl group in a surfactant, the surface tension decreased by 3.2. - Add CH3 = Dec by 3.2 - Exception to the rule: Polyoxyethylated non-ionic surfactants Insoluble Monolayers - Surfactants adsorbed on the surface exist in equilibrium with the surfactant molecules in the bulk liquid - If the surfactant has a long alkyl chain it will have insufficient water solubility to be present in the bulk liquid. (Around 12 C atoms long) - Thus it will form an insoluble monolayer at the surface. (cant form micelles) Positions in the same way heads down, tails out of water. - In this case, the **insoluble monolayer can be formed by dissolving the surfactant in a suitable volatile solvent** and carefully injecting it onto the surface. - ALL molecules injected are on the surface, none in the bulk liquid. - Not all insoluble substances will form a monolayer. - Only two classes of material will do so: - 1\. Water insoluble amphiphiles - Orientate themselves at the surface with the polar head group acting as an anchor and the hydrocarbon chain protruding into the vapour phase(Steric Acid) - 2\. Polymeric compounds - Examples are proteins and synthetic polymers **Solubility of Weak Electrolytes** Weak electrolyte- a drug that has the ability to act as a weak acid/base- may be in salt form. Phenobarb- very old drug used in epilepsy management -- generally used for animals now. Produced as oral solution -- because only vet surgeon can administer as a injection but oral drops anyone can give. When introduced into water 2 things happen: 1. Ions dissociate because water has a high dielectric constant and insulates them, nothing holding them together so they separate. 2. Hydrogen bonding with water \*Benzene ring affects solubility but it is reasonably soluble. **Also Equation: (Given in class test )** **Drug** **MoA** --------------- --------------- ------------------------------------------------------------------------------- *Agonists:* Noradrenaline **Alpha=** vasoconstriction. (Slight effect on Heart as not fully selective) Adrenaline **Alpha and Beta**. (More on heart as slightly more beta effective) Isoprenaline **B receptors** (Very potent in low doses.) Rapid HR increase *Antagonist:* Prazosin Blocks **a-1 receptors** Atenolol Blocks **b-1 receptor** (cardio selective -- still slightly blocks b2) Propanolol **Blocks b1 and b2** **Receptor** **Heart Rate** **Blood Pressure** ------------------------ -------------------------- ---------------------------------------------------------- Alpha-1 (arteries) Vasoconstriction Alpha -2 (supress CNS) Decrease (supressed SNS) Decrease (inhibition of norepinephrine/reduced SNS tone) B-1(myocardium) Increase Slight increase (increased contractility) B-2 (arteries) Vasodilation Chronotropic AKA heart rate Inotropic = contraction force of the myocardium **Drug** **HR** **BP** --------------- ----------------- ---------- Noradrenaline Slight Increase Increase Adrenaline Increase Increase Isoprenaline Increase Decrease **Drug** **HR** **BP** -------------------------- ----------------------------------- --------------- **Prazosin** **Increase (reflex tachycardia)** **Decreases** Noradrenaline + Prazosin Increase (RT) Decrease Adrenaline + Prazosin Increase(RT) Decrease Isoprenaline + Prazosin Increase (RT) Decrease **Drug** **HR** **BP** -------------------------- ----------------------- ---------------------------------------------------------------------------- **Atenolol** **Decrease** **Decrease (By blocking b1 -- you decrease contractility- decreasing BP)** Noradrenaline + Atenolol Decrease or no change Increase Adrenaline + Atenolol No change Slight increase Isoprenaline + Atenolol Decrease Decrease **Drug** **HR** **BP** ----------------------------- -------------- -------------- **Propranolol** **Decrease** **Decrease** Noradrenaline + Propranolol Decrease Increase Adrenaline + Propranolol No change Increase Isoprenaline + Propranolol No change No change Huge inc in Hr with alpha-1-receptor blocker (even though you don't find these in the heart- reflex tachycardia) and baroreceptor response. Opening up blood vessels , HR inc to try and increase BP back to normal. Expected response. REFLEX TACHYCARDIA ***[Dose-Dependent Blood Pressure Effects: Adrenaline and Isoprenaline ]*** **LOW DOSES** **HIGH DOSES** ------------------ ------------------------------------------------ --------------------------------------------------------- **Adrenaline** B-2-vasodilation predominates. DECREASE IN BP. Alpha-1 vasoconstriction predominates. RISE IN BP. **Isoprenaline** Beta-2 causes vasodilation. DECREASE BP. Beta-1 increased HR and contractility will INCREASE BP. \*\* Asthmatics require beta-2 agonist receptor for bronchodilation to keep the airways open. This means non-cardio selective beta blockers should be avoided in these patients. \*\* Beta 2 adrenergic receptors are responsible for vasodilation in non-coronary arteries hence the dilation in the bronchioles. **[Pharmacokinetics ]** Clearance = volume of plasma from which drug is removed from per unit time. Cl= Dose /AUC Volume of Distribution= indicates how extensively a drug has distributed through body tissues. Vd= Dose / Co Elimination Rate Constant= rate at which drug is removed from body Ke = Cl/Vd Half Life = time taken for drug concentration to fall by h alf. T1/2= 0.693/ke Switching Dose Formulations Oral Dose= IV Dose/ F Loading Dose / Bolus Dose= large initial dose to get treatment started LD/BD= (Css x Vd)/F LD/BD= Vd x Co Maintenance Dose= (Css x Cl x t) / F Bioavailability= AUC (Oral) / AUC (IV) Bioavailability= (AUC X Cl ) / Dose Rate of Infusion = Css x Cl TO ADD \> - Cl~R~ = fu (GFR + CL~s~)(1 - FR) GFR = Glomerular Filtration Rate (typically about 120ml/min, but above 60ml/min regarded as normal) fu = Fraction of unbound drug in plasma Cl~s~ =Clearance of drug by secretion FR =Fraction of filtered drug reabsorbed - ClCr = [(140-age) (weight in kg)] serum creatinine (micromol/L) **Types of antagonism** 1. Physical - Physical properties of the compound lead to antagonism (charcoal absorption of alkaloid)\ \ 2. Physiological - Inverse agonists antagonising each other\ (Glucagon and Insulin)\ \ 3. Pharmacokinetic - Antagonist decreases the overall concentration of agonist at the active site\ (St John\'s Wort up-regulates Cytochrome P450 leading to lower bioavailability to oral dose)\ \ 4. Chemical - Would be agonist combining (usually in solution) to create complexes with no effect (antagonist).\ (Avastin binds to VEGF protein, inhibiting its binding to its kinase receptor, stopping tumor-promoting vascularization)\ \ 5. Competitive - Antagonist and agonist compete for the same target\ (Noradrenaline and Prazosin for α1 receptors in the vessels, Tamoxifen and Oestrogen for Oestrogen receptors)\ \ 6. Non-Competitive - Antagonist binds to a different site on the drug target, shutting down agonist action\ \ 7. Un-competitive - Antagonist binds to ES complex and shuts down the action\ \ 8. Desensitization - Antagonism by the body\'s natural system of increased tolerance to stimuli\ \ (3 P\'s, 4 C\'s,) **3 Checks to be made before dispensing ?** 1. *[Accuracy check]* -- labels, name , correct medicine, PIL included, correct patient. 2. *[Legal check-]* Name / address of patient DOB, Signed and dated by prescriber, still in date, CD requirements, 3. *[Clinical check-]* drug name,form,strength,route, is it suitable for condition? Any contraindications? \*\*Schedule 2 and 3 CDs must be from the UK\*\* \*\* Schedule 2 and 3 CDs are Not REPEATABLE \*\* Only 4 and 5 are. Sch 5 valid for 6mths Sch 2+ 3 valid for 28 days Address not required on an EEA Rx Identity must be checked and noted when collecting a Sch2 /3 drug on behalf of someone else. Sch 2,3,4pt1 must be denatured before disposal.