General Principles Week 5 Flashcards
Topic 1 – Pharmacodynamics I
TLO 1.1 Four Molecular Drug Targets and Their Functions
Receptors – These are specialized proteins that bind to endogenous ligands (such as neurotransmitters or hormones) or drugs to initiate a physiological response. They play a key role in signal transduction.
Example: Beta-adrenergic receptors are G-protein coupled receptors (GPCRs) that mediate the effects of epinephrine and norepinephrine. Drugs like propranolol (a beta-blocker) inhibit these receptors to reduce heart rate and blood pressure.
Ion Channels – These are pore-forming proteins in cell membranes that regulate ion flow based on electrochemical gradients. Drugs can either block or modulate ion channels.
Example: Calcium channels allow calcium influx into cells. Nifedipine, a calcium channel blocker, inhibits this process to cause vasodilation, reducing blood pressure.
Enzymes – These biological catalysts facilitate biochemical reactions. Drugs can act as inhibitors (preventing enzyme function) or activators (enhancing enzyme function).
Example: Acetylcholinesterase (AChE) breaks down acetylcholine. Neostigmine, an AChE inhibitor, prolongs acetylcholine activity, improving muscle contraction in myasthenia gravis.
Transporters (Carrier Proteins) – These membrane proteins facilitate the movement of substances across cell membranes, including ions, nutrients, and neurotransmitters.
Example: The serotonin transporter (SERT) is responsible for reuptake of serotonin from the synaptic cleft. Fluoxetine (an SSRI) blocks SERT, increasing serotonin levels and improving mood in depression.
TLO 1.2 Four Receptor Subtypes and Their Signaling Mechanisms
The four primary receptor subtypes, based on their signaling mechanisms, are:
- G protein-coupled receptors (GPCRs),
- ligand-gated ion channels,
- receptor tyrosine kinases (RTKs), and
- intracellular receptors; each activating distinct intracellular pathways upon ligand binding.
Explanation of each receptor subtype and its signaling mechanism:
G protein-coupled receptors (GPCRs):
Structure: A seven-transmembrane domain protein embedded in the cell membrane.
Mechanism: When a ligand binds to the GPCR, it activates a G protein on the cytoplasmic side, which then interacts with downstream effector molecules like enzymes or ion channels, triggering a cellular response.
Example: Adrenaline receptors, which activate the “fight or flight” response.
Ligand-gated ion channels:
Structure: A transmembrane protein with a pore that opens when a specific ligand binds.
Mechanism: Ligand binding directly causes the ion channel to open, allowing ions to flow across the cell membrane, rapidly changing the cell’s membrane potential and triggering a cellular response.
Example: Nicotinic acetylcholine receptors at the neuromuscular junction.
Receptor tyrosine kinases (RTKs):
Structure: A transmembrane protein with an intracellular tyrosine kinase domain.
Mechanism: Upon ligand binding, the receptor dimerizes, activating its intrinsic tyrosine kinase activity which phosphorylates tyrosine residues on target proteins, initiating a signaling cascade.
Example: Insulin receptor.
Intracellular receptors:
Structure: Located within the cytoplasm or nucleus of the cell.
Mechanism: Small, hydrophobic ligands diffuse through the cell membrane and bind to the intracellular receptor, which then translocates to the nucleus to regulate gene expression by binding to DNA.
Example: Steroid hormone receptors like estrogen and testosterone.
Key points to remember:
Different receptor subtypes have different ligand specificities, meaning only certain molecules can bind and activate them.
The downstream signaling pathways activated by each receptor type can vary depending on the cell type and the specific receptor involved.
Many drugs target specific receptor subtypes to modulate cellular processes.
Ligand-Gated Ion Channels (Ionotropic Receptors) – These receptors are directly coupled to ion channels and open upon ligand binding, allowing ions to pass through.
Example: The nicotinic acetylcholine receptor (nAChR) at neuromuscular junctions allows sodium (Na⁺) entry upon acetylcholine binding, triggering muscle contraction.
G-Protein Coupled Receptors (Metabotropic Receptors) – These receptors activate intracellular signaling cascades via G-proteins upon ligand binding. They influence cell function indirectly through second messengers like cyclic AMP (cAMP) or calcium (Ca²⁺).
Example: Beta-adrenergic receptors (Gs-protein coupled) activate adenylate cyclase, increasing cAMP levels, leading to increased cardiac contractility.
Kinase-Linked Receptors – These receptors mediate effects through phosphorylation cascades, leading to gene transcription and protein synthesis.
Example: The insulin receptor is a tyrosine kinase receptor that, upon insulin binding, triggers glucose uptake via GLUT4 translocation in muscle and fat cells.
Nuclear Receptors – These receptors are intracellular and function as transcription factors when activated.
Example: The glucocorticoid receptor binds cortisol, moves to the nucleus, and modulates gene expression, reducing inflammation.
TLO 1.3 Gating Properties of Ion Channels
Ion channel gating refers to the opening and closing of ion channels, which is controlled by stimuli like voltage, ligands, or mechanical forces. Gating is a conformational change in the protein that makes up the channel.
Types of gated ion channels
Voltage-gated ion channels: Open and close in response to changes in the voltage across the cell membrane
Ligand-gated ion channels: Open and close in response to binding of ligands to the channel
Mechanosensitive channels: Open and close in response to physical deformation of the cell membrane
Phosphorylation-gated ion channels: Change their structure and permeability by phosphorylation
Leakage ion channels: Are constantly activated
Ion channel gating mechanisms
Activation: The transition from the resting state to the open state
Inactivation: A self-restraint mechanism to limit ion conduction
Ion channel function
Ion channels are responsible for the electrical excitability of muscle cells, and they mediate most forms of electrical signaling in the nervous system
Types of Gating:
Voltage-gated: Open or close in response to changes in membrane potential (e.g., voltage-gated Na⁺ channels in neurons).
Ligand-gated: Open when a specific molecule binds (e.g., GABA-A receptor allowing Cl⁻ influx).
Mechanically gated: Respond to physical forces like stretch (e.g., mechanoreceptors in touch-sensitive neurons).
Modulation Mechanisms:
Phosphorylation: Addition of a phosphate group can enhance or inhibit channel activity.
Ligand Binding: Agonists/antagonists can modulate ion flow.
Voltage Changes: Ion channels respond to depolarization/hyperpolarization.
Selectivity Mechanisms:
Determined by pore size, charge distribution, and amino acid composition, allowing selective ion passage.
Topic 2 – Pharmacodynamics II
TLO 2.1 Drug Action Properties
Selectivity: A drug’s ability to preferentially bind to a specific target (e.g., atenolol selectively blocks beta-1 receptors, sparing beta-2 receptors).
Affinity: Strength of drug binding to its receptor, measured by dissociation constant (Kd).
Potency: The drug concentration required to elicit 50% of its maximal effect (EC₅₀).
Efficacy: The maximum effect a drug can produce, regardless of dose.
TLO 2.2 Types of Agonists
Full Agonist: Produces maximal receptor activation (e.g., morphine at opioid receptors).
Partial Agonist: Produces a submaximal response even at high concentrations (e.g., buprenorphine).
Inverse Agonist: Produces the opposite effect of an agonist by stabilizing the inactive receptor conformation (e.g., propranolol at beta receptors).
TLO 2.4 Orthosteric vs. Allosteric Modulation
Orthosteric: Binds at the receptor’s active site (e.g., atropine at muscarinic receptors).
Allosteric: Binds at a separate site, modifying receptor activity (e.g., benzodiazepines enhance GABA-A receptor function).
TLO 2.3 Competitive Antagonists
Reversible: Compete with agonists but can be displaced by increasing agonist concentration (e.g., naloxone for opioid overdose).
Irreversible: Bind covalently, permanently blocking receptor activity (e.g., phenoxybenzamine, an alpha-blocker for pheochromocytoma).
Topic 3 – Pharmacokinetics I
TLO 3.1 Drug Absorption Factors
Drug ab- sorption involves the movement of the drug across a cell membrane and is largely dependent on diffusion. The absorption rate is deter- mined by the preparation of the drug, route of administration, size of the molecule, concentration gradient, degree of protein binding and lipid solubility of the drug
The first-pass metabolism of a drug that mainly takes place in the gastrointestinal tract (GIT) and liver greatly reduces the systemic bioavailability as well as the efficacy of an orally administered drug as compared to the parenteral drugs
Lipid Solubility: Lipophilic drugs cross membranes more easily.
pH & Ionization: Weak acids (e.g., aspirin) absorb better in acidic environments (stomach), while weak bases (e.g., morphine) absorb in alkaline environments (intestine).
First-Pass Metabolism: Hepatic metabolism before systemic circulation reduces bioavailability.
TLO 3.2 Routes of Administration
Oral: Most convenient but undergoes first-pass metabolism.
Intravenous (IV): Immediate effect, 100% bioavailability.
Intramuscular (IM)/Subcutaneous (SC): Slower, sustained absorption.
Other information
Drugs are introduced into the body by several routes. They may be
Taken by mouth (orally)
Given by injection into a vein (intravenously, IV), into a muscle (intramuscularly, IM), into the space around the spinal cord (intrathecally), or beneath the skin (subcutaneously, sc)
Placed under the tongue (sublingually) or between the gums and cheek (buccally)
Inserted in the rectum (rectally) or vagina (vaginally)
Placed in the eye (by the ocular route) or the ear (by the otic route)
Sprayed into the nose and absorbed through the nasal membranes (nasally)
Breathed into the lungs, usually through the mouth (by inhalation) or mouth and nose (by nebulization)
Applied to the skin (cutaneously) for a local (topical) or bodywide (systemic) effect
Delivered through the skin by a patch (transdermally) for a systemic effect
TLO 3.3 Drug Bioavailability
The fraction of the administered dose reaching systemic circulation unchanged.
IV = 100%, oral varies due to first-pass metabolism and solubility.
Absolute bioavailability is defined as 100% of the substance reaching the bloodstream, which can only be achieved through an intravenous (IV) means. Relative bioavailability is the amount of the substance that reaches the bloodstream through other means of administration, like oral and sublingual.
TLO 3.5 Drug Distribution
Factors Affecting Distribution:
Blood flow (high in liver, kidneys, brain; low in fat, bone).
Plasma protein binding (e.g., albumin).
Tissue permeability (lipophilic drugs distribute widely).
Absorption, distribution, metabolism, and excretion
TLO 3.6 Two-Compartment Model
Central compartment: Rapidly perfused organs (heart, liver, kidney, blood).
Peripheral compartment: Less-perfused tissues (fat, muscle).
The two-compartment pharmacokinetic model describes the evolution of drug levels in the organism by depicting the body as two pharmacokinetic compartments (the central and the peripheral compartments, also commonly referred to as compartment 1 and compartment 2, in that order).
Topic 4 – Pharmacokinetics II
TLO 4.1 First-Pass Metabolism
Hepatic metabolism before reaching systemic circulation.
Reduces oral drug bioavailability (e.g., nitroglycerin).
The first-pass metabolism or the first-pass effect or presystemic metabolism is the phenomenon which occurs whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced, thus showing subtherapeutic action
TLO 4.2 Phase 1 & 2 Biotransformation
Phase 1: Oxidation, reduction, hydrolysis (CYP enzymes).
Phase 2: Conjugation (glucuronidation, sulfation).
Phase I reactions involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis); these reactions are nonsynthetic. Phase II reactions involve conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine); these reactions are synthetic.
TLO 4.3 CYP Enzymes in Drug Interactions
CYP3A4: Metabolizes many drugs; inhibitors (e.g., ketoconazole) and inducers (e.g., rifampin) alter metabolism.
An overly active CYP enzyme will render the drug ineffective. However, if these enzymes are not active enough, the drug can stay in the body for a prolonged duration leading to toxicity. Of all the different CYP proteins that are present in the human body, six of them are involved in the metabolism of 90% of drugs.
Cytochrome P-450 (CYP) enzymes are a family of enzymes that metabolize many drugs. They are often involved in drug interactions, which can lead to adverse reactions or therapeutic failures.
How do CYP enzymes cause drug interactions?
Inhibition
Drugs can inhibit CYP enzymes, which can increase the amount of a drug that is absorbed and increase its bioavailability.
Induction
Drugs can induce CYP enzymes, which can reduce the amount of a drug that is absorbed and reduce its bioavailability.
Genetic variability
Genetic differences in CYP enzymes can affect how a patient responds to certain drugs.
Examples of drugs that interact with CYP enzymes warfarin, antidepressants, antiepileptic drugs, and statins.
How can clinicians use this information?
Clinicians can use knowledge of CYP enzyme substrates, inducers, and inhibitors to help determine therapeutic strategies and doses for drugs.
Clinicians can ask patients about their use of complementary and alternative medicines when considering the use of a medicine that is altered by CYP3A4
TLO 4.4 Drug Excretion
Renal: Filtration, secretion, reabsorption.
Biliary: Liver to bile, excreted in feces.
Pulmonary: Volatile drugs via respiration.
Renal, biliary, and pulmonary excretion are all ways that drugs are eliminated from the body.
Renal excretion
The primary way that drugs are eliminated from the body
The kidneys filter drugs from the bloodstream, and some are reabsorbed back into the bloodstream, while the rest are excreted in the urine
The kidneys are the main organs responsible for excreting water-soluble substances
Biliary excretion
The liver excretes waste and byproducts into the bile
Some drugs and their metabolites are excreted in the bile
Pulmonary excretion
The lungs eliminate drugs like alcohol and anesthetic gases
Pulmonary excretion is important for gaseous lipophilic substances
Drugs diffuse from the plasma into the alveolar space and are excreted during expiration
Other routes of excretion transcutaneous loss, saliva, sweat, and breast milk.
Drug elimination is the irreversible removal of a drug from the body. The process of drug elimination is characterized by pharmacokinetic parameters, such as clearance.
Topic 5 – Applied Principles of Pharmacokinetics
TLO 5.1 Therapeutic Index (TI)
Definition: The ratio of the toxic dose (TD₅₀) to the effective dose (ED₅₀). A higher TI indicates a safer drug.
Formula:TI=TD50ED50TI=ED50TD50
Example: Warfarin has a low TI, meaning small dosing errors can lead to toxicity. Penicillin has a high TI, making overdoses less dangerous.
TLO 5.2 Renal Clearance
Definition: The volume of plasma cleared of a drug per unit time, usually in mL/min.
Factors influencing renal clearance:
Glomerular filtration (small, unbound drugs pass into urine).
Tubular secretion (active transport of drugs into urine).
Reabsorption (lipophilic drugs may diffuse back into blood).
Example: Creatinine clearance is used to estimate renal function.
TLO 5.3 Plasma Half-Life (t1/2t1/2)
Definition: The time required for the plasma concentration of a drug to decrease by 50%.
Formula (First-Order Kinetics):t1/2=0.693×VdCLt1/2=CL0.693×Vd where VdVd is the volume of distribution, and CLCL is clearance.
Clinical Importance: Determines dosing intervals. Drugs with short half-lives require frequent dosing.
Plasma half-life (t1/2) is the time it takes for the concentration of a substance in the plasma to decrease by half. It is an important pharmacokinetic parameter that helps determine the dosing interval of a drug.
Here are some examples of plasma half-lives for different substances:
Caffeine: 5 hours
Alcohol: 4-5 hours
Nicotine: 2 hours
THC: 30 hours
Water: 7-14 days
The plasma half-life of a substance can be affected by a number of factors, including age, weight, liver function, and kidney function.
For example, the plasma half-life of caffeine is shorter in smokers than in non-smokers.
TLO 5.4 First-Order vs. Zero-Order Kinetics
First-Order Kinetics: A constant fraction of drug is eliminated per unit time (most drugs follow this).
Zero-Order Kinetics: A constant amount of drug is eliminated per unit time (seen with saturation of enzymes).
Example: Ethanol follows zero-order kinetics at high doses because alcohol dehydrogenase becomes saturated.
TLO 5.5 Drug Interactions in ADME (Absorption, Distribution, Metabolism, and Excretion)
Drug interactions occur when two or more drugs (including prescription medications, over-the-counter drugs, herbal supplements, or even certain foods) interact with each other in ways that can affect their intended effects, metabolism, or safety. These interactions can lead to various outcomes, such as increased or decreased drug effectiveness, enhanced side effects, or even new adverse reactions that wouldn’t have occurred if the drugs were taken separately.
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📍 Drug interactions occur when two or more medications or substances interact with each other in a way that affects their efficacy, safety, or both. These interactions can lead to changes in the way drugs are absorbed, metabolized, distributed, or eliminated from the body.
📍 There are several types of drug interactions:
* Pharmacokinetic Interactions
* Pharmacodynamics Interactions
* Synergistic Effects
* Antagonistic Effects
* Food and Drug Interactions
* Drug-Disease Interactions:
* Herb-Drug Interactions
* Drug-Laboratory Test Interactions
📍 It’s important to note that not all drug interactions are harmful. Some interactions are intended and can be beneficial, such as combining medications to enhance their therapeutic effects. However, others can lead to adverse effects or reduced treatment efficacy.
Absorption: Chelation (e.g., tetracyclines + calcium) reduces drug absorption.
Distribution: Plasma protein displacement (e.g., warfarin + aspirin increases free warfarin).
Metabolism: CYP inhibition (e.g., grapefruit juice + statins increases statin levels).
Excretion: Probenecid inhibits penicillin renal clearance, prolonging its effect.
There are several types of drug interactions:
- Pharmacokinetic Interactions: These interactions involve changes in the absorption, distribution, metabolism, or elimination of a drug. They can affect how the body processes a drug, potentially leading to changes in its effectiveness or toxicity. For example, one drug might inhibit the enzymes responsible for breaking down another drug, leading to higher levels of the second drug in the body.
- Pharmacodynamic Interactions: These interactions occur when two drugs with similar or opposing effects are taken together. For instance, taking two drugs that lower blood pressure can cause excessive lowering, leading to dizziness or fainting.
- Combined Toxicity: Some drugs can cause toxic effects when taken together, even if they wouldn’t cause harm when taken individually.
- Additive Effects: When two drugs with similar effects are taken together, their combined effect might be stronger than expected. This can be desirable in some cases, but it can also lead to overmedication.
- Antagonistic Effects: Drugs that work against each other can lead to reduced therapeutic effects. For instance, an antacid taken with an antibiotic might interfere with the antibiotic’s absorption.
- Food-Drug Interactions: Certain foods can interact with drugs, affecting their absorption or metabolism. For example, grapefruit juice can inhibit the activity of enzymes responsible for breaking down certain drugs, leading to higher drug levels in the body.
- Herb-Drug Interactions: Herbal supplements and alternative medicines can also interact with conventional medications, leading to unpredictable effects.
It’s important to note that drug interactions can occur with both prescription and over-the-counter medications, and even with supplements. To minimize the risk of potential interactions:
Communication: Keep your healthcare provider informed about all the medications you are taking, including prescription drugs, over-the-counter medications, supplements, and herbal remedies.
Pharmacist Consultation: When picking up a new prescription, talk to your pharmacist about potential interactions with your current medications.
Read Labels: Always read labels and package inserts to identify potential interactions and contraindications.
Patient Education: Educate yourself about your medications and their potential interactions. Many drug interaction resources are available online and in various medical references.
Personal History: Your age, gender, genetics, and overall health can influence how your body metabolizes drugs, so consider these factors when discussing medications with your healthcare provider.
Timing: Taking medications at specific times of day or with or without food as directed by your healthcare provider can help minimize interactions.
Remember, healthcare professionals are your best resource for understanding and managing potential drug interactions. Always consult them before making any changes to your medication regimen or starting new medications or supplements.
Topic 6 – Autonomic Nervous System (ANS) Pharmacology
TLO 6.1 Sympathetic vs. Parasympathetic Nervous System
*Sympathetic (“Fight or Flight”)
Neurotransmitter: Norepinephrine (NE)
Effects: ↑ Heart rate (HR), ↑ Blood pressure (BP), bronchodilation, pupil dilation (mydriasis)
Key receptors: Alpha (α) and Beta (β) adrenergic receptors
Example Drug: Albuterol (β₂ agonist) for asthma
*Parasympathetic (“Rest and Digest”)
Neurotransmitter: Acetylcholine (ACh)
Effects: ↓ HR, ↑ digestion, pupil constriction (miosis), bronchoconstriction
Key receptors: Nicotinic & Muscarinic (M) receptors
Example Drug: Bethanechol (M agonist) for urinary retention
TLO 6.2 ANS Neurotransmitters
*Preganglionic Neurons
Release ACh (both sympathetic & parasympathetic systems).
Bind to nicotinic receptors in ganglia.
*Postganglionic Neurons
Sympathetic: Release norepinephrine (NE) (except sweat glands, which release ACh).
Parasympathetic: Release ACh onto muscarinic receptors.
TLO 6.3 Cholinergic and Adrenergic Receptors
Cholinergic Receptors (Bind ACh):
Nicotinic (N): Fast ligand-gated ion channels (e.g., NMJ, ganglia).
Muscarinic (M): GPCRs (e.g., M2 in heart ↓ HR, M3 in glands ↑ secretions).
TLO 6.3 Cholinergic and Adrenergic Receptors
Adrenergic Receptors (Bind NE/Epi):
Adrenergic Receptors (Bind NE/Epi):
Alpha-1 (α1): Vasoconstriction (e.g., phenylephrine).
Alpha-2 (α2): Decrease NE release (e.g., clonidine).
Beta-1 (β1): Increases heart rate & contractility (e.g., dobutamine).
Beta-2 (β2): Bronchodilation & vasodilation (e.g., albuterol).
TLO 6.4 Neurotransmission Modulation
Blocking Receptors:
Beta-blockers (e.g., metoprolol) → ↓ HR.
Muscarinic blockers (e.g., atropine) → ↓ secretions.
Enzyme Inhibitors:
Acetylcholinesterase (AChE) inhibitors (e.g., neostigmine) → ↑ ACh levels.
TLO 6.5 Other ANS Neurotransmitters
Dopamine (DA): Modulates blood pressure & renal function.
Serotonin (5-HT): Affects mood, gut motility.
Nitric Oxide (NO): Vasodilator, relaxes smooth muscle.
