Student 1 Principles of Pharmacology SP25 PDF

Module 1: Foundations Principles of Pharmacology Structure and Function of the Nervous System Chemical Signaling of Neurotransmitters  A. The Science of Drug Action B. Pharmacokinetic Factors Determining Principles of Drug Action Pharmacolo C. Pharmacodyna...

Module 1: Foundations Principles of Pharmacology Structure and Function of the Nervous System Chemical Signaling of Neurotransmitters  A. The Science of Drug Action B. Pharmacokinetic Factors Determining Principles of Drug Action Pharmacolo C. Pharmacodynamics: Drug–Receptor Interactions gy D. Biobehavioral Effects of Chronic Drug Use Ch 1: Principles of Pharmacolo gy A. The Science of Drug Action Pharmacology Drug Action vs Drug Effect Therapeutic Effects vs Side Effects and the Placebo Effect Pharmacology : The Science of Drug Action Pharmacology: Study of the actions of drugs and their effects on living organisms. Neuropharmacology: Study of drug-induced changes in nervous system cell functioning. Psychopharmacology: Emphasizes drug-induced changes in mood, thinking, and behavior.  The Drug Action vs Drug Effect Science of Drug Action: molecular changes produced by a drug when it binds to a Drug target site or receptor Where a drug acts can predict the effect. Action:  The Drug Action vs Drug Effect Science of Drug Action: molecular changes produced by a drug when it binds to a Drug target site or receptor Where a drug acts can predict the effect. Action:  The Drug Action vs Drug Effect Science of Drug Action: molecular changes produced by a drug when it binds to a Drug target site or receptor Where a drug acts can predict the effect. Action: Drug Effect : molecular changes alter physiological or psychological functions. Example: Drug Action vs Drug Effects Drug action and effects can take place a different sites Atropine: topical applied to the eye Blocks the action at ACh receptors on muscles in the eye (action) Dilates the pupil (effect) Example: Drug Action vs Drug Effects Drug action and effects can take place a different sites Morphine: ingested, injected Stimulates receptors in autonomic nervous system (PNS branch; action) Constricts pupils (effect)  Therapeutic Effects (TE) vs Side Different types of Drug Effects: Effects (SE) Therapeutic effects: Effects on behavior or physiology that are desired. Side effects Effects on behavior or physiology that are not intended TE vs SE Example: Amphetamines Prescribed for narcolepsy: TE: insomnia SE: appetite suppressant Prescribed for weight loss: TE: appetite suppressant SE: insomnia TE vs SE Example: Cannabis Taken recreationally: TE: getting stoned SE: appetite stimulant Prescribed to chemotherapy and HIV- AIDS patients: TE: appetite stimulant SE: getting stoned Good vs Bad Drugs? Drugs have effects that are desired or undesired Good/bad are value judgments Specific vs Nonspecific Drug Effects Specific drug effects Based on physical and biochemical interactions of a drug with a target site in living tissue. Nonspecific drug effects Based on certain unique characteristics of the individual, (e.g., mood, expectations, perceptions, attitudes). General molecular effects Specific vs Nonspecific Drug Effects: Example Alcohol Specific drug effects Based on physical and biochemical interactions of a drug with a target site in living tissue. Example: Alcohol molecule interacts with the GABA receptor in the brain stem, can cause respiratory depression Nonspecific drug effects Based on certain unique characteristics of the individual, (e.g., mood, expectations, perceptions, attitudes). Exaple: Alcohol consumption can sometimes make you sleepy, sometimes it’s invigorating. Different effects in same person on different occasions, different effects across individuals. Drug Actions and Effects Effects (SE, TE, Specific, Nonspecific) influenced by: Drug action site Location of Receptor Receptor or subtype of receptor Drug Actions and Effects Effects (SE, TE, Specific, Nonspecific) influenced by: Drug action site Location of Receptor Receptor or subtype of receptor Drug Actions and Effects Effects (SE, TE, Specific, Nonspecific) influenced by: Drug action site Location of Receptor Receptor or subtype of receptor Individual differences Nonspecific Drug Effect Example: Placebo Drug Placebo is a pharmacologically inert compound (example: saline) Can produce symptom improvement (therapeutic effects) as well as side effects Nonspecific Drug Effect Example: Placebo Drug Expectation (Cognitive Factor) Experiment: a. Hidden Application- patient unaware of when drug is delivered b. Open Application- physician announces when drug is being administered https://www.nature.com/articles/nrd3923 Nonspecific Drug Effect Visit Drug Example: Placebo Drug 1 Effects Pill (Not placebo) Learning (Cognitive Factor) Experiment: Visit a. Visit 1: Pill given that alleviated 2 issue b. Visit 2: Visit/pill associated with efficacy, alleviates issue Nonspecific Drug Effect Example: Placebo Drug Learning: (Cognitive Factor) Experiment a. Visit 1: Pill given that alleviated issue b. Visit 2: Visit/pill associated with efficacy, alleviates issue https://www.nature.com/articles/nrd3923  Nonspecific Drug Effect Example: Placebo Drug Minimize: during drug development, placebo effect must be minimized to understand true drug effects and possible therapeutic outcome Maximize: during patient care, understand how expectation and learning can influence drug efficacy and therapeutic outcomes Personalize: consider individual’s genetic predisposition, personality, past medical history, treatment to influence therapeutic outcome  A. Pharmacology: The Science of Drug Action Principles of B. Pharmacokinetic Factors Determining Drug Action Pharmacolo C. Pharmacodynamics: Drug–Receptor Interactions gy D. Biobehavioral Effects of Chronic Drug Use B. Pharmacokinetic Factors Determining Drug Action Methods of administration and their impact on the onset of drug action/effects Factors that modify drug absorption Depot binding Biotransformation and elimination of drugs Pharmacokinet ics Pharmacodynamics: What the drug does to the body Pharmacokinetics: What the drug does to the body  Bioavailability- Fraction (%) of a drug that reaches the target site. Drug must be present in sufficient quantity at the drug action site to produce an effect. https://www.researchgate.net/publication/ 49789861_Understanding_the_time_course_of_pharmacological_effect_A_PKPD_approach Methods of Administration: Impact on Drug Effects Example: Insulin Insulin has low bioavailability when delivered orally (>1%) Pharmacokinetic factors that determine the bioavailability of drugs 1. Influences how quickly drug reaches target tissue 2. Influences how much drug reaches target  Route of Administration: Inhalation Route of administration How administration impacts onset and intensity of drug effects Example Cannabis: Where is the target for the psychoactive effects of cannabis? Route of Administration: Oral (per os) Give an equivalent concentration of psychoactive ingredients: Which produces the quickest effect? The circulatory system provides transportation for drugs from site of admin to site of action The circulatory system provides transportation for drugs from site of admin to site of action Inhalation would produce the most rapid effects, as active drug would enter the circulatory system more quickly, thereby reaching the target stie more quickly.  Route of Administration: Oral Steps of Drug Absorption: 1. Oral Cavity 2. Stomach 3. Liver 4. Intestine: site of absorption into circulator system  Route of Administration: Oral Pharmacokinetic considerations: Mouth: Degradation by acids and enzymes Some drugs can be absorbed in the mouth Stomach: Degradation by acids and enzymes Example: Insulin is not resistant and cannot be given orally. Absorption impacted by: food in stomach type of food physical activity  Route of Administration: Oral Pharmacokinetic considerations: Liver: Frist-Pass Metabolism: Enzymes in the liver catalyze the breakdown of drugs upon the drugs first pass through the liver Reduces bioavailability of drug First-Pass Metabolism and Bioavailability Example: Oral Contraceptive Orally delivered drugs are subject to first-pass metabolism (occurs in the liver) Drugs can change enzyme activity levels in the liver Some antibiotics increase liver enzyme activity (enzyme induction) that metabolize some oral contraceptives Increasing metabolism of the contraceptive reduces bioavailability -------------------------------------------------------- Question: would other forms of contraception (ring, patch) also be impacted? Routes of Administratio n Oral: Benefits: cost effective, safe Considerations: Slow, variable absorption rate Reduced bioavailability due to breakdown of drug (first-pass metabolism) Routes of Administratio n Rectal Benefits: effective for infants or adults who cannot take oral administration Considerations: Placement of drug Routes of Administratio n Rectal Benefits: effective for infants or adults who cannot take oral administration Considerations: First-pass metabolism can be by-passed, depending on placement of drug in the rectum Routes of Administratio n Intravenous (IV) Benefits: Most rapid and accurate method. Considerations: Rapid onset offers little time to correct an overdose or allergic reaction Drug can’t be removed from the body quickly Intramuscular (IM) Subcutaneous (SC) Intraperitoneal (IP) Routes of Administratio n Inhalation Drug is absorbed through the membranes of the lungs into blood circulation Psychoactive drug effect is rapid Nicotine, THC in cannabis, crack cocaine.  Route of Administration Impacts Bioavailability Drug is degraded by the liver with each pass The amount of time it takes to distribute the full dose of drug throughout the body, the less drug will be bioavailable The number of cell layers a drug must pass through, the longer it takes to distribute, the less drug will be bioavailable Route of Administration Impacts Bioavailability Drug is degraded by the liver with each pass, therefore the amount of time it takes to distribute the full dose of drug, the less drug will be bioavailable The number of cell layers a drug must pass through, the longer it takes to distribute, the less drug will be bioavailable Pharmacokinetic factors that determine the bioavailability of drugs Drug Absorption and Distribution The number of cell layers a drug must pass through, the longer it takes to distribute, the less drug will be bioavailable Factors that Modify Drug Absorption and Distribution Important factors in determining plasma drug levels: Transport across membranes Lipid solubility Ionization Other factors Factors that Modify Drug Absorption and Distribution The rate of passage through cell membranes is the largest factor on bioavailability Cell membranes: Made of Phospholipids- arranged in a bilayer Head: negatively charged region (hydrophilic) Tails: two uncharged lipid regions (hydrophobic) es Attract: Positive hydrogen region on water molecule attracts negatively charged head of phospholipid IV Administration: bypasses all cells Oral Administration: drug passes through many cell layers Factors that Modify Drug Absorption and Distribution Important factors in determining plasma drug levels: Transport across membranes Lipid solubility Ionization Other factors Factors that Modify Drug Absorption and Distribution Lipid solubility: Highly lipid drugs cross membranes via passive diffusion Lipid solubility: drug is easily dissolved in fat Movement is in a direction of higher to lower concentration. The larger the concentration gradient, the faster the diffusion. Factors that Modify Drug Absorption and Distribution Important factors in determining plasma drug levels: Transport across membranes Lipid solubility Ionization Other factors Factors that Modify Drug Absorption and Distribution Ionization (meaning a particle carries a charge): Most drugs are weak acids or weak bases, when placed in water (~60% of the body), they are broken into components that are ionized. Ionized particles do not readily pass through the membrane Factors that Modify Drug Absorption and Distribution Important factors in determining plasma drug levels: Transport across membranes Lipid solubility Ionization Other factors Factors that Modify Drug Absorption and Distribution Other factors: Rate at which stomach empties Most drugs are absorbed in the intestine (larger surface area than stomach) Direction: take before meals Size and body composition of individual Size: the large the person, the more diluted the drug will be Composition: lean vs obese changes the water content of the body Body surface area better indicator Sex of individual Females on average are smaller in size and have larger amount of adipose tissue Factors that Modify Drug Absorption and Distribution Specialized barriers: Fenestrations Once in the blood stream, 1-2 min to deliver throughout body Blood capillaries have pores called fenestration that allows molecules to be delivered to organs Factors that Modify Drug Absorption and 20% Distribution Drug Distribution Highest concentration of a drug will be distributed to area where blood flow is greatest. Heart, kidneys, liver, brain Brain receives 20% of blood leaving the heart Factors that Modify Drug Absorption and 20% Distribution Drug Redistribution Drug will be delivered to organs, which will reduce plasma concentrations Higher concentration in organ vs plasma will encourage movement of drug away from organs and back into plasma Exchange will occur until equilibrium is reach between organs and plasma Note: the liver continues to clear drug at each pass Factors that Modify Drug Absorption and Distribution Specialized barriers: Blood–brain barrier (BBB): Created by the astrocytes holding the fenestrations “closed”, creating tight junctions Keeps chemicals that are large, non-lipid soluble from interacting with neurons Nutrients and waste are removed via active or selective transport, which is selective (selective permeability) Factors that Modify Drug Absorption and Distribution Some brain areas are not isolated by the BBB: Area postrema (CTZ) Vomit center Located in the medulla Butt Chugging severely hinders this region from saving you from stupid Factors that Modify Drug Absorption and Distribution Placenta forms a barrier between the maternal blood circulation and the fetus. Acute toxicity: Exposure to high levels of chemicals in the mother’s blood Deprivation of oxygen Produce dependence Teratogens- Chemicals that produce abnormalities in fetal development Pharmacokinetic factors that determine the bioavailability of drugs Depot Binding Prevents drug from reaching the target site or liver, impacting magnitude and duration of drug Bound drug produces no drug effect Bound drug remains in the system, not metabolized immediately Binding sites: Plasma proteins (e.g., albumin), muscle, and fat. Pharmacokinetic factors that determine the bioavailability of drugs Biotransformation and Elimination Drugs are eliminated via biotransformation (metabolism) and metabolites are excreted. Intravenous administration used to determine clearance rate Drug clearance from the blood is usually exponential (first- order kinetics). Constant fraction is removed from circulation at each time interval. Rate of clearance is concentration-dependent. Biotransformatio n and Elimination Half-life Amount of time required for removal of 50% of the drug (t½). Half-life determines interval between doses. Pharmacokinetic Factors Determining Drug Action -Biotransformation and elimination of drugs T0: Injection of- 100mg 50% T1: 1hr post IV- 50mg T2: 2hr post IV- 25mg clearance time is dependent upon concentration of drug T0: Injection of- administered at T0 200mg T1: 1hr post IV- 100mg 50% T2: 2hr post IV- halved halved halved halved  Dosing: Biotransformat A drug given once a day should ion and have a half-life of about 8 hours. Longer half-life could lead to Elimination accumulation, which increases potential for side effects and toxicity. Steady state: Absorption/distribution = metabolism/excretion Steady State: First Order Kinetics 937 mg 968 mg 875 mg Goal of 750 mg 1000mg 468.75mg 437.5mg +500mg +500mg 375mg 500mg +500mg 250mg +500mg Biotransformation and Elimination Zero-order kinetics Occurs under certain circumstances for some drugs (high levels ingested) Routes of metabolism or elimination are saturated. Molecules are cleared at a rate P450 not determined by concentration. After 1 hour only a certain AMOUNT can be metabolized 1 hr After 1 hour only a certain AMOUNT can be metabolized 1 hr After 1 hour only a certain AMOUNT can be metabolized 2 hr After 1 hour only a certain AMOUNT can be metabolized 3 hr After 1 hour only a certain AMOUNT can be metabolized 4 hr After 1 hour only a certain AMOUNT can be metabolized 5 hr: 50% cleared Figure 1.10 Zero-order rate of elimination Figure 1.10 Zero-order rate of elimination P450 Biotransformation and Elimination Microsomal enzymes: Liver enzymes that catalyze the metabolism drugs. They lack strict specificity and can metabolize a wide variety of foreign chemicals Cytochrome P450 (CYP450) enzyme family are responsible for oxidizing most psychoactive drugs.  Factors that modify biotransformation Biotransform capacity include: Enzyme induction ation and Enzyme inhibition Elimination Drug competition (type of Inhibition) Individual differences in age, gender, and genetics. Biotransformation and Elimination Enzyme induction: Repeated use increases number of enzyme molecules and speeds biotransformation. Can affect other drugs that are transformed by the same enzyme Drug tolerance and cross tolerance drugs lose effectiveness with repeated use. Biotransformation and Elimination Enzyme inhibition One drug reduces ability of enzyme to metabolize a second drug by directly effecting enzyme activity Reduced metabolism of other drugs. Drug effects are more intense or prolonged Toxicity is possible. Biotransformation and Elimination Drug competition (type of inhibition) One drug reduces ability of enzyme to degrade a second drug through competition for the binding site Elevated levels of one drug reduces metabolism of the second Example: alcohol plus sedatives such as Valium compete for active cite on cytochrome P450.  A. Pharmacology: The Science of Drug Action Principles of B. Pharmacokinetic Factors Determining Drug Action Pharmacolo C. Pharmacodynamics: Drug–Receptor Interactions gy D. Biobehavioral Effects of Chronic Drug Use Pharmacokinetic factors that determine the bioavailability of drugs Drug–Receptor Interactions Pharmacodynamics: Physiological and biochemical interaction of drug molecules with cell receptors in target tissue. How drugs alter the body Receptors: Proteins in the bi-lipid plasma membrane. Ligand: Molecule that binds to a receptor with some selectivity. Drugs and neurotransmitters are ligands Figure 1.4 Cell membran es Drug–Receptor Interactions Most drugs do not pass into neurons, but act on surface receptors. Neuropharmacology Identifies drugs that act at neurotransmitter receptors Enhance or reduce normal functioning of the cell. Figure 1.13 Principal type of receptors Extracellular Area Cell Membrane Intracellular Area Drug–Receptor Interactions Receptors have specificity for ligands due their molecular shapes and composition. Ligands can be: Receptor agonists: Attaches readily to the receptor Produces significant biological effect Receptor antagonists Chemical “fit” at the receptors Produce no cellular effect  Baseline Activity receptor ion channel peptide (second messenger) transcripti kinase on factor (third messenger) enzyme ion channel *kinase is a specialized enzyme that can phosphorylate a protein, which changes activity within the cell Drug–Receptor Interactions Receptor agonist: Full agonist: has best chemical “fit” (highest affinity), produces fullest activation (efficacy) Partial agonist: has less affinity than pure agonist, less efficacy than full agonist Inverse agonist: fits (affinity), has efficacy, but biological effect is in the opposite direction of what agonist produces Decreases constituent activity Example: antihistamines ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195115/)  Baseline Activity receptor ion channel peptide (second messenger) transcripti kinase on factor (third messenger) enzyme ion channel *kinase is a specialized enzyme that can phosphorylate a protein, which changes activity within the cell Drug-Receptor Interactions  Drug–Receptor Interactions: Ligand binding summary slide Receptors are bound by ligands (neurotransmitters and drug) When unbound by a ligand, the receptors displays “constituent activity” Binding of an agonist ligand alters constituent activity: Agonist: has the highest affinity, produces fullest activation (efficacy) Partial agonist: has less affinity than pure agonist, less efficacy than full agonist Inverse agonist: has good affinity, has the opposite effect the agonist has – can silence constituent activity. Binding of an antagonist produces no effect, but prevents an agonist from binding Drug-Receptor Interactions Characteristics of receptors Recognize specific molecules Lock and key Binding by molecules is temporary Binding produces physical change in the shape of the receptor protein Drug-Receptor Interactions Characteristics of receptors Receptors have life cycles The number and sensitivity of receptors can change. Up-regulation: number of receptors increases Down-regulation: number of receptors is reduced in response to absence of ligands or chronic activation. Drug-Receptor Interactions Dose-response curve Used to measure activation of receptors by a drug by assessing the biological or behavioral effect that is produced by a drug Threshold: Smallest dose that produces a measurable effect in respondents Does at which the fewest number of target receptors occupied to produce detectable results Drug-Receptor Interactions Dose-response curve ED50 (50% effective dose) Effective dose for 50% of population The dose the half the respondents find effective Assumes that half of all target receptors are occupied Drug-Receptor Interactions Dose-response curve Potency- Absolute amount of drug necessary to produce a specific effect Efficacy- The ability of a drug to produce a desired effect Drug-Receptor Interactions Dose-response curve Ice water task: Measure time Ps can keep hand submerged Ps receive analgesic medicine Remeasure time Ps can keep hand submerged Potency and efficacy of different analgesic medicines? Hydromorphone Morphine Codeine Aspirin Dose–response curves for four analgesic agents Respons e Assume that “100” on the Response axis represents a doubling of the time Ps left hand in ice bath Chemical Structure of Analgesics Dose -Response Summary Slide Drug binds to a receptor and produce a response (specific effect such as pain relief) The more receptors that are activated, the larger the response Potency is is a measure of the dose necessary to produce a specific effect The more potent the drug, the less you need (lower dose) to produce an effect Efficacy is the ability of a drug to produce a desired effect and reflects what receptors are being activated. Example: Activating the opioid receptors produces the best pain relief (in general), though we can also relieve pain by targeting other systems, such as those involved in inflammation. Hydromorphone and methadone target the opioid receptor system and is very efficacious Aspirin targets COX enzymes, which reduce swelling and inflammation. This is efficacious, but less than opioid drugs Drug-Receptor Interactions Dose and Response curve Method can be used to determine therapeutic index Therapeutic Index (TI) is a measurement of drug safety. Ratio of the drug that causes adverse effects in 50% of Ps to the dose that is efficacious in 50% of Ps The ratio that compares the dose at which a drug is toxic and the dose at which the drug is effective The higher the TI, the lower possibility there is of the drug working without toxic side effects Drug-Receptor Interactions Therapeutic Index (TI) is a measurement of drug safety. Ratio of the drug that can cause adverse effects ED50: Dose that is effective in 50% of the patient population during clinical trials. (ED=Effective Dose) TD50: Dose at which 50% of the Ps pop. experiences specific undesired effect (TD=Toxic Dose) Drug-Receptor Interactions TI Calculation: TI = TD50/ED50 Drug-Receptor Interactions TI for treating anxiety w/o sedation: TD50= 30µg/kg ED50= 15µg/kg TI= 2 TI for producing sedation w/o respiratory depression: TD50= 120µg/kg / kg / kg /k g µg µg g ED50= 30µg/kg 5 12 µ TI= 4 1 30  A. Pharmacology: The Science of Drug Action Principles of B. Pharmacokinetic Factors Determining Drug Action Pharmacolo C. Pharmacodynamics: Drug–Receptor Interactions gy D. Biobehavioral Effects of Chronic Drug Use Biobehavioral Effects of Chronic Drug Use Tolerance Sensitization Biobehavioral Effects of Chronic Drug Use Drug tolerance: Diminished response to a drug after repeated exposure. Increasing doses must be administered to obtain the same magnitude of biological effect. Different mechanisms explain multiple forms of tolerance Metabolic Pharmacodynamic Behavioral Biobehavioral Effects of Chronic Drug Use Metabolic tolerance: Repeated use of a drug increases rate of metabolism Reduces amount of the drug available at the target tissue. Pharmacodynamic tolerance: Changes in nerve cell function compensate for continued presence of the drug. Up- or –down regulation Reduced/increased activation Biobehavioral Effects of Chronic Drug Use Behavioral tolerance Develops when drug is repeatedly paired with items in the environment Occurs through learning Biobehavio ral Effects of Chronic Drug Use Biobehavioral Effects of Chronic Drug Use Following repeated administration paraphernalia becomes associated with arousal and euphoria, such that they alone can produce these effects. Cues can produce the same or similar responses as the drug itself, through learning mechanisms Biobehavioral Effects of Chronic Drug Use How Learning and Tolerance are Related Tolerance is due to a learned association between the effects of a given drug and the environmental cues that reliably precede the drug effects Cues can produce the opposite response as the drug, through learning mechanisms ”Anticipatory response” The anticipatory response contributes to tolerance Anticipatory Response and Tolerance Example Rats placed in chamber, then given morphine injection repeatedly for 10 days Morphine induces an increase in body temperature. Rats become tolerant to this effect during the 10 day period- their body temp did not increase as much on the 10th day  Group A Anticipatory Group A Response and Tolerance Example On test day, rats divided into two groups. Group A is placed in same chamber prior to receiving injection Group B is placed in different chamber prior to receiving injection Group A rats demonstrated behavioral tolerance; BT didn’t increase much Group B rats lost tolerance; BT increased  Anticipatory Response and Tolerance Example Rats placed in novel environment show less tolerance to changes in body temperature Biobehavioral Effects of Chronic Drug Use Learning Operant conditioning may also play a part in behavioral tolerance. Example: a long-time alcohol user can learn to maneuver efficiently while highly intoxicated. Princess Diana’s drive BAC:.17 Biobehavioral Effects of Chronic Drug Use Sensitization Enhancement of drug effects after repeated administration of the same dose. Can persist over long periods of abstinence. Some drugs induce tolerance for some effects and sensitization for others.