Pharmacodynamics Notes PDF

Pharmacodynamics ◦ The study of the physiological and biochemical interactions of drug molecules with their target tissues and receptors responsible for their ultimate drug effects. 34 Drug actions ◦ Specific...

Pharmacodynamics ◦ The study of the physiological and biochemical interactions of drug molecules with their target tissues and receptors responsible for their ultimate drug effects. 34 Drug actions ◦ Specific molecular changes Objective effects resulting from drug binding Measurable drug effects usually to a target site or receptor involving physiological alterations Subjective effects Drug effects Variable drug effects subject to ◦ Widespread alterations in individual experience and interpretation physiology or psychology Psychoactive effects are often subjective resulting from drug actions and depend on the expectation, history of use, dose, administration, and environmental context 35 Multiplicity of drug effects ◦Therapeutic effects ◦drug-target interactions producing the desired physiological or behavioural changes ◦Side effects ◦all other drug effects ◦Adverse effects ◦undesirable or harmful drug effects 36 Terminology Trade name ◦ Diphenhydramine (benadryl) ◦ Antihistamine and decongestant ◦ Therapeutic effects include drying mucous membranes ◦ Side effects include drowsiness ◦ Mild sedative for insomnia ◦ Therapeutic effect includes drowsiness IUPAC name ◦ Side effects include drying of mucous membranes 2-(diphenylmethoxy)-N,N- dimethylethanamine Abbreviated chemical name 37 Specificity of drug effects ◦Specific effects ◦ Occur as a result of biochemical interactions between drug and target receptor ◦Nonspecific effects ◦ Occur as a result of interactions beyond the receptor (e.g. lipid membranes, fluid compartments) ◦ May occur as a result of unique characteristics of an individual or an individual’s state 38  Placebo effect ◦ Measurable therapeutic effect of a treatment without specific activity for the respective condition ◦ Affected by expectancy and conditioning ◦ Particular confound in neuropsychopharmacology ◦ Antidepressants have efficacy of ~ 50-70% in major depression ◦ Placebo is effective in 20-40% of cases ◦ During development fluoxetine (Prozac) had to endure 5 clinical trials to achieve 2 showing significantly better response than placebo ◦ Classic experiment (Levine 1973) on ulcer patients given placebo ◦ Group A given placebo by physician who assured the medication would give relief (efficacy of 70%) ◦ Group B given placebo by nurse who described it as experimental in nature (efficacy of 25%) 39 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Drug-receptor interactions ◦Ligand – any molecule that binds to a receptor ◦ Drug – exogenous ligand ◦ Neurotransmitters, hormones, peptides – endogenous ligands ◦Receptor – protein molecule on cell surface or within the cell that is the initial site of action of a biological agent (neurotransmitters, hormones, peptides, drugs) 40 Defining a receptor 1. Saturability ◦ Finite receptors per cell ◦ Dose-response should reveal saturability 2. Specificity ◦ High binding affinity to elicit a biological response 3. Reversibility ◦ Binding to receptors should be reversible ◦ Ligand should be dissociable and recoverable ◦ Distinguishes receptor-ligand interactions from enzyme-substrate interactions 41  Two distinct classes of receptors bind water-soluble or lipid-soluble ligands. Extracellular receptors are localized to the cell surface and bind water-soluble ligands (e.g. neurotransmitters) while intracellular receptors bind lipid-soluble ligands within the cell (e.g. steroid hormone receptors) © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford 42 Receptor types Extracellular receptors Intracellular receptors ◦ Common target for psychoactive drugs ◦ Common target for steroid hormones ◦ Accessible to water-soluble drugs and lipophilic compounds (and some ◦ Different signalling based on function of drugs) the receptor ◦ Glucocorticoids (stress hormones) ◦ Ligand-gated ion channels ◦ Androgen/estrogens (sex hormones) ◦ Postsynaptic neurotransmitter receptors ◦ Endocannabinoids (intracellular GPCR) ◦ G-protein coupled receptors (GPCR) ◦ Located in cytoplasm ◦ Metabotropic receptors ◦ Intracellular second messenger ◦ Hormone receptors ◦ Receptor kinases ◦ Translocate to nucleus on hormone binding ◦ Common for cytokine, peptide hormone ◦ Function as transcription factors receptors (e.g. Insulin) ◦ Directly induce changes in gene expression by binding to specific response element 43  Receptor-ligand interactions ◦ Specific recognition of ligand is key to receptor function ◦ Agonist interactions are those that elicit a biological effect on the receptor ◦ Antagonist interactions are those preventing or blocking a biological effect 44 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Agonism and antagonism are spectral 45  Agonist function Agonist activity at a receptor can be measured by examining the dose-response. With increasing concentration of agonist, the biological response is greater. Dose-response tends to follow a characteristic sigmoidal shape (S- curve). Potency - ED50 is the dose required to elicit a half-maximal effect. 46 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Comparable curve-shape of dose-response plots is suggestive of conserved mechanisms. While ED50 shows differing potency, all three opioids have the same efficacy. Aspirin differs in both potency and efficacy. © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford 47  Therapeutic index (TI) Dose-response can be measured for adverse effects of drugs. TD50 is a measure of the potency of a drug at eliciting a toxic response. LD50 measures the potency at eliciting a lethal effect. Therapeutic index reflects the margin of safety between drug efficacy and adverse effects TI = TD50 / ED50 48 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Antagonism Antagonists have a variety of binding states Reversible antagonists can be displaced by the endogenous agonist Competitive antagonism Reduces agonist potency but not efficacy Non-competitive antagonists cannot be displaced by agonists Reduce drug efficacy and sometimes potency 49 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Non-competitive antagonists Irreversible antagonists - Binds irreversibly to the same binding site as an endogenous ligand Allosteric modulators Binds to a different site on the receptor than the endogenous ligand Affects receptor function through other conformational effects on the protein Penicillin analogue covalently bound to the active site of penicillin-binding protein PDB: 1HVB 50  Pharmacological agonists Partial agonists Binds same site as endogenous ligand but elicit a less than maximal response Can decrease efficacy of the endogenous agonist Inverse agonists Binds receptor with constitutive activity Has opposite effect to full agonist 51 https://commons.wikimedia.org/w/index.php?curid=34657034 Long term effects of drug use Tolerance Sensitization Diminished effect of a given dose of Enhancement of a particular drug drug over time effect on repeated exposure Reversible Prior exposure to cocaine increases Dependent on frequency and dose repetitive and hyperactive behaviours in Varies with different drugs animals (head bobbing) Can be limited to specific drug effects Less common than tolerance Multiple mechanisms Cross-sensitization occurs between Cross-tolerance can cause drug drugs acting on the same receptor interactions (e.g. cocaine and amphetamines) 52 Forms of tolerance Metabolic tolerance (drug disposition Behavioural tolerance tolerance) Context-specific tolerance Increased metabolism through enzyme Involves learning and memory induction Demonstrated by tolerance in familiar but Decreased bioavailability of drug not novel environments Habituation Pharmacodynamic tolerance First administration causes greater alteration of Changes in nerve cell function in response normal behaviour to drug Diminished with subsequent administrations Receptor down-regulation results in Conditioning saturation and diminished effect Environment or paraphernalia act as a conditioned stimulus to initiate response 53  Behavioural tolerance Behavioural tolerance can be readily demonstrated in humans and in animal models. Administration of drug in a conditioned environment can elicit a different physiological response than in a novel environment. 54 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Drug dependence Drug tolerance can occur rapidly and transiently (e.g. cocaine) or slowly and persistently (e.g. alcohol) Balance of factors differs for different drugs Persistence of tolerance influenced heavily by metabolic and pharmacodynamic mechanisms Drug dependence results from tolerance mechanisms and is considered a key component contributing to drug addictions Most significantly influenced by pharmacodynamic mechanisms Dependence is the requirement for drug use in order to maintain ‘normal function’ after the development of drug tolerance 55  Dependence develops from compensatory mechanism(s) to restore homeostasis Acute administration disrupts homeostasis Repeated administration initiates adaptations that compensate to restore homeostasis Withdrawal of administration results in compensatory disturbance in homeostasis 56 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Demonstration of dependence In vitro studies demonstrate the cellular effects of morphine Acute morphine treatment decreased cellular cAMP With chronic exposure (48 h) cAMP levels normalized to restore homeostasis Steady-state cAMP levels were maintained in the presence of morphine Withdrawal of morphine resulted in a dramatic rebound well above normal 57 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford  Rebound withdrawal Withdrawal is heavily influenced by mechanisms of drug tolerance and dependence Pharmacodynamic mechanisms Removal of drug upsets homeostasis in the opposite direction of drug use Withdrawal produces neurochemical and behavioural changes that are often opposite the effects of intoxication Rebound hyperactivity 58 © 2023 Meyer’s Psychopharmacology 4e Sinauer/Oxford Key points: Pharmacodynamics Ligand – endogenous or exogenous molecule that binds to a decrease potency or efficacy receptor Tolerance – reduced drug effect over time Receptor – cell surface or intracellular – site of any ligand Sensitization – increased drug effect over time binding Classical receptor – saturable, specific, reversible Dependence – requirement for drug use to maintain ‘normal’ level of physiological/psychological function Agonist – any interaction resulting in a biological effect Full agonist – elicits full biological effect Cross-sensitization / cross-tolerance contribute to drug Partial agonist – elicits less than full biological effect (reduced interactions efficacy) Different drugs having similar sites of action (e.g. cocaine & Inverse agonist – elicits opposite biological effect from amphetamines) endogenous ligand Metabolic tolerance – increased metabolism through Antagonist – any interaction that blocks a biological effect enzyme induction Reversible – competitive antagonism, reduces potency but NOT Pharmacodynamic tolerance – receptor downregulation at efficacy site of drug action Irreversible – non-competitive, inactivates receptor, reduces efficacy, sometimes potency Behavioural tolerance – Habituation and conditioning Allosteric modulators – non-competitive, binds to different leading to context-specific tolerance 59 site on protein than endogenous ligand – increase or