4 - Pharmacodynamics Flashcards
1
Q
What is Pharmacodynamics?
A
- what a drug does to the body (how drugs work)
2
Q
How do Drugs Work?
A
Drugs work by:
1) binding to a target which can be a macromolecule (protein, enzyme)
2) targeting chemical substances such as stomach acid, and neutralize them through chemical reactions
3) Targeting pathogens (virus, bacteria) and altering internal conditions (ie. Osmolarity of bodily fluids)
3
Q
What are drug targets?
A
Drug targets: molecules whose function can be modulated by a drug to produce a biological effect
○ Drug targets are macromolecules
- Most drug targets are proteins
- Drug targets can be located extracellularly, on the plasma membrane, or intracellularly
4
Q
4 Most Important Receptors
A
- G protein-coupled receptors (GPCRs)
→Drugs that treat high blood pressure (antihypertensive drugs) and antipsychotic drugs, such as those used to treat schizophrenia - Enzyme-linked receptors
→ insulin, cancer therapy drugs - Ion channels
→benzodiazepines, a drug used to treat anxiety and epilepsy - Intracellular receptors
→ corticosteroids that are used to treat inflammatory conditions like asthma
5
Q
What are macromolecules?
A
- Macromolecule: large molecule composed of smaller molecules
- Macromolecules control biological functions that can be enhanced or inhibited by drugs
Most common macromolecules targeted by drugs
1) Receptors
2) Enzymes
3) Transport Proteins
4) Other Macromolecules
6
Q
How Do Drugs Target Enzymes?
A
- Drugs target enzymes (such as reductases, transferases, lyases, and hydrolases) to modify their function.
Examples of drugs that target enzymes:
1. Ibuprofen and other NSAIDs
2. Renin and ACE inhibitors (used to treat high blood pressure)
7
Q
What are Transport Proteins?
A
- Proteins that mediate the transport of ions, amino acids, proteins, and other macromolecules are also targets for drugs
○ Ex. SGLT2 inhibitors: glucose-lowering drugs used to treat type II diabetes, which target the SGLT2 glucose transporter in the kidneys.
8
Q
How do Receptors and Ligands Bind?
A
- Receptors are activated by endogenous ligands (originating from within an organism).
→ Ex: Norepinephrine, Acetylcholine, Serotonin.
- Receptors and endogenous ligands control body functions.
→ Ex: Norepinephrine binds to receptors on heart cells, increasing heart rate. - Drugs act by mimicking or blocking the actions of endogenous ligands on their receptors.
- Ligand: Any molecule that binds to a receptor.
- Can be endogenous (hormone, neurotransmitter) or exogenous (therapeutic compound).
- Receptor: A macromolecule that binds a signaling molecule (ligand/drug) and translates it into an effect.
- The drug must have the correct size and shape to fit into the receptor’s binding site.
9
Q
Receptor Binding Sites and Drug Interactions
A
- Orthosteric site: The same site as the endogenous ligand.
- Drugs can bind and compete with endogenous molecules.
- Allosteric site: A different site from the endogenous ligand.
- Drug-receptor interactions are mediated by intermolecular forces, including:
→Ionic bonds, hydrogen bonds, van der Waals forces, and covalent bonds. - Affinity: The strength of drug binding to its receptor
→ Stronger binding/affinity occurs when a drug is more complementary to its receptor. - Selectivity: The preference of a drug for a specific receptor.→ Higher selectivity → Fewer side effects.
→ Lower selectivity → Broader actions, binding to multiple targets.
10
Q
Drug Concentration and Receptor Occupancy
A
- There is a positive relationship between drug concentration, receptor occupancy, and effect.
→ As we increase drug concentration, more receptors are occupied = response increases - the intensity of response is proportional to the number of occupied receptors (not ALL cases)
11
Q
Drug-Receptor Binding and Saturability
A
- The # of receptors is finite (limited), making drug-receptor binding saturable.
- Maximal effect usually occurs when all receptors are occupied.
- Saturable effect: Once all receptors are bound, increasing drug concentration will not increase effect.
Exceptions
- Spare receptors – in some cases, not all receptors need to be occupied for the drug to reach its maximum effect.
12
Q
Why is the Dose- Response Relationship Important
A
- It determines the minimal amount of drug needed to elicit a response
- It provides information on the maximal response a drug can elicit, allowing comparison between different drug
○ Oxycodone can achieve a higher response or higher degree of pain relief than tramadol - It provides information on the effect produced upon dosage adjustments, i.e., how much drug is needed to produce the desired effect
- It provides information on the type of drug-receptor interaction.
○ Ex. does the drug activate the receptor or block the receptor from being activated?
13
Q
What are the 2 Types of Dose-Response Curves?
A
- Graded Dose Response:
→ Shows the continuous relationship between dose and response - Quantal Dose Response:
Shows the effect of various doses of a drug on the response in a patient population.
→ Used to describe “all or none” relationships (i.e. death).
14
Q
Graded Dose-Response Curve Phases
A
1) Phase 1: Dose is too low to elicit a measurable response.
2) Phase 2: Linear/graded relationship – increasing the dose increases the magnitude of the effect (applies to many, but not all, drugs).
3) Phase 3: Maximal response is reached; no additional drug effect occurs because all receptors are occupied.
2 types of curves:
1. Linear curve: Shows drug concentration vs. response
- only shows a narrow range of concentrations
2. Sigmoid curve (log transformation): - Expands the range of drug concentrations displayed.
15
Q
Efficacy and Potency
A
- E (Effect): Response at a given drug concentration.
- Emax (Maximal Effect): The highest response a drug can produce when all receptors are occupied.
- Drug Efficacy: Determines the therapeutic effectiveness of a drug
- EC50 (Potency): The drug concentration needed to produce 50% of the maximal effect.
→ A more potent drug requires a smaller dose to reach EC50 (promote 50% of max response) - Drug Potency: Influences the dosage required for therapeutic effect.
16
Q
Drug Potency
A
Drug Potency: The amount of drug required to produce an effect of a given magnitude.
- Determined by drug affinity (strength of attraction between a drug and its receptor).
- EC50 (Effective Concentration 50%) is used to measure potency.
→Lower EC50 = Higher potency
(requires a smaller concentration to achieve 50% of its maximum effect)
Ex: Morphine is more potent than oxycodone but both provide the same relief.
17
Q
Drug Efficacy
A
Drug Efficacy: The ability of a drug to elicit a response (once bound to a target)
- Efficacy depends on the drug’s ability to stabilize the receptor in an active conformation, allowing biological signals to be triggered.
- Depends on intrinsic activity (how well the drug activates the receptor).
→ Higher intrinsic activity = Higher efficacy. - Maximal efficacy (Emax) is the maximum response a drug can produce.
EX.
- Drug A and B have similar efficacy, both reaching maximum receptor activation.
- Drug C has lower efficacy, meaning it produces a response but not as strong as Drug A or B.
18
Q
Therapeutic Relevance: Potency vs. Efficacy
A
Your patient is in extreme pain. Which analgesic would you suggest?
- Drug with higher efficacy → Provides a stronger effect.
- Drug with lower efficacy → Suitable for mild pain (also lowers risk of adverse effects).
- Drugs with higher efficacy are considered more therapeutically beneficial than highly potent drugs
→ an efficacious drug has HIGHEST maximal response in the dose-response curve
Therapeutic vs. Pharmacological Efficacy:
- Pharmacological efficacy: How much the drug activates the system.
- Therapeutic efficacy: How the patient responds to the drug (influenced by compliance).
19
Q
Dose and Effect
A
- Receptors and endogenous ligands can control more than one function.
→ Ex: Norepinephrine increases heart rate but also induces sweating.
Implications of Dose and Effect
A drug can be prescribed for different conditions.
- Healthcare providers must understand the indication to know what to monitor.
Ex: Nifedipine
→For hypertension → Monitor blood pressure.
→ For angina → Monitor chest pain.
Dose matters.
Ex: Trazodone
- Used for both depression and insomnia.
→ Higher dose needed to improve mood.
→ Lower dose effective for sleep promotion
20
Q
Quantal Dose-Response Curves
A
- Represent the frequency of a defined response in a population at different drug doses
→ show how many people in a group experience a specific effect (like pain relief or sleep) at different doses of a drug
→Instead of measuring how strong the effect is (it just counts how many people respond or don’t respond at each dose) - All-or-nothing effect (e.g., sleep vs. no sleep) – no variation in response intensity.
- Useful for assessing drug safety by obtaining curves for toxic and lethal effects.
- Different from graded dose-response curves, which measure degree of response.
21
Q
Effective, Lethal, and Toxic Dose
A
- Quantal dose-response curves help analyze the therapeutic, toxic, and lethal effects of a drug in a population.
1) ED50 (Effective Dose 50%) – Dose that produces a therapeutic response in 50% of the population.
2) TD50 (Toxic Dose 50%) – Dose that causes toxic effects in 50% of the population.
3) LD50 (Lethal Dose 50%) – Dose that leads to death in 50% of the population.
22
Q
Why are Quantal Dose-Response Curves Important?
A
- Helps establish doses that work for most (50%) of the population
-The dosage is only 1 aspect of the drug response
Other determinants includes:
1) Route of Administration – Affects absorption and effectiveness
2) Timing of Drug Administration – Some drugs work better in the morning/night bc they are trying to mimic/block a physiological process that us more elevated at night/morning
3) Individual Variability – Differences in metabolism etc
- this curve gives a measure of safety of drug
→Bc we can calculate therapeutic index; which is a relationship bw the toxic and effective dose of drug
23
Q
Therapeutic Index
A
- The therapeutic index (TI) is a measure of a drug’s relative safety.
- Formula: TI = TD₅₀ / ED₅₀
→TD₅₀ = dose causing toxicity in 50% of the population
→ED₅₀ = dose producing a therapeutic effect in 50% of the population - Larger TI → Safer drug (e.g., Penicillin has a large TI, meaning toxic doses are far from effective doses).
- Smaller TI → Higher risk of toxicity (e.g., Warfarin has a narrow TI, where therapeutic and toxic doses are close).
EX.
→Warfarin (Anticoagulant): Small TI, risk of hemorrhage.
→Penicillin (Antibiotic): Large TI, low risk of toxicity even at high doses.
24
Q
Therapeutic Window
A
- The therapeutic window is the range of drug concentrations in the blood that provides therapeutic effects without causing toxicity.
- It lies between the minimum effective concentration (for symptom relief or treatment) and the minimum toxic concentration
→ Wide therapeutic window = Safer drug (less monitoring required).
→ Narrow therapeutic window = Smaller therapeutic index (TI), requiring careful dosing to avoid toxicity (ex. Warfarin)
25
Why Do Drugs Produce Adverse Effects If They Are Selective?
1) Receptors mediate multiple processes.
→ Ex: An antihistamine that relieves allergies can also cause drowsiness due to histamine receptors in different body areas.
2) Drugs can bind to more than one receptor.
→ Low-selectivity drugs may bind to unintended targets, causing off-target effects.
→ Ex: Some diuretics for hypertension can bind to androgen receptors, leading to gynecomastia in males.
3) Selectivity is dose-dependent.
→ Even highly selective drugs can bind to other targets if their concentration increases in the blood.
Selectivity does not guarantee safety.
4) Too much of any drug can be harmful.
→ Ex: Excess opioids → Respiratory depression, possibly stopping breathing.
26
Types of Drug-Receptor Interactions
- Drug (D) + Receptor (R) ⇔ Drug-Receptor Complex (DR) → Response
- Receptors exist in different states:
→Inactive
→Resting
- Constitutive (Basal) Activity:
Some receptors can transition from inactive to active state even without a ligand.
Receptor-Drug Interactions:
→A receptor can bind to a drug and do nothing.
→A receptor can bind to a drug and form an active complex, leading to a biological response.
- Drugs can stabilize receptors in different conformations (active or inactive states).
27
Features of Agonists?
- Agonists bind to a receptor and produce a measurable biological effect.
Agonists have:
→Affinity (ability to bind to a receptor).
→Intrinsic activity (ability to activate the receptor).
28
Types of Agonists
1) Full Agonists
→ Bind to receptors and produce the maximal biological response.
- Have high intrinsic activity (maximally activate the receptor).
2) Partial Agonists
→ Bind to receptors but only produce a partial response, even when all receptors are bound.
→Have lower intrinsic activity than full agonists.
3) Inverse Agonists
→ Bind to receptors and decrease their constitutive activity.
→ Stabilize the receptor in an inactive state.
→Reduce the number of activated receptors.
29
Antagonists: Inhibiting Agonist
- Antagonists bind to receptors and inhibit the actions of an agonist.
- Antagonists have affinity (can bind to receptors) but no intrinsic activity (do not activate them).
- No effect in the absence of an agonist—they only work by blocking an agonist’s effect.
Pharmacological vs. Therapeutic Efficacy:
→No pharmacological efficacy (do not activate receptors).
→Have therapeutic efficacy (blocking endogenous ligands can produce a beneficial effect).
- Antagonist response depends on agonist levels—higher agonist levels require more antagonist to block effects.
Non-receptor antagonists:
- Neutralize an agonist before it binds to its receptor.
- Promote opposite effects of agonist
30
Competitive Antagonists
- Bind to the same site (orthosteric site) on the receptor as the agonist.
- Increase EC50 (require higher agonist concentration for the same effect) but do not change maximal efficacy
→ Competitive antagonist do not change efficacy
→ only change the EC50 and potency
- Reversible binding
→ Adding more agonist can displace the antagonist and restore full receptor activation.
Ex: Heart rate regulation:
→ Isoproterenol (agonist) requires higher concentration to achieve the same effect when propranolol (antagonist) is present.
Ex of Competitive antagonists:
1. Acetaminophen
2. Beta blockers
3. Statins
31
Non-Competitive Antagonists
Two types:
Irreversible Antagonists – Bind permanently to the orthosteric site, making the receptor nonfunctional.
Allosteric Antagonists – Bind to a different site (allosteric site), changing receptor shape so the agonist cannot bind or activate it.
Effects on Agonists:
Reduce the total number of available receptors.
Decrease maximal efficacy (system can’t reach full response because fewer receptors are available).
- Do not change EC50 (concentration required for 50% activation remains the same)
- Reduces maximal efficacy (Since fewer functional receptors are available)
Ex. Flumazenil – An allosteric antagonist of GABAA receptors, used to reverse benzodiazepine overdose.
32
Morphine vs. Buprenorphine
Morphine
- Morphine is more efficacious than buprenorphine for pain relief (analgesia).
- Morphine = Full Agonist
→Fully activates opioid receptors for maximum pain relief.
Buprenorphine
- Buprenorphine is more potent than morphine at binding to opioid receptors.
- Cannot fully activate opioid receptors, leading to less pain relief than morphine
1) Partial agonists can act as both agonists and antagonists.
2) Buprenorphine acts as an agonist in the absence of morphine (provides pain relief).
3) In the presence of morphine or at high concentrations of the endogenous ligands, buprenorphine will act as an antagonist (by occupying opioid receptors and preventing full activation)
33
Ligand-Gated Ion Channels
- Ion channels are transmembrane proteins that regulate ion flow across the cell membrane.
- Essential for neurotransmission, cardiac conduction, muscle contraction, and secretion—making them key drug targets.
- Ligand binding → ion conductance change → alters membrane potential or ionic concentration → BIOLOGICAL EFFECT
→ When a ligand binds, there is changes in conduction of ions = change in membrane potential (brings potential of excitable cells closer or further from threshold for AP's - Ca hyperpolarize or depolarize cell)
- Response mediated by ion channels is fast
Types:
1. Ligand-Gated Ion Channels: Open in response to ligand binding.
2. Voltage-Gated Ion Channels: Open in response to changes in voltage.
Examples of Drugs Targeting These Channels:
- Benzodiazepines (positive allosteric modulators) → Bind allosterically, reducing hyperexcitability to relieve anxiety.
34
G-Protein Coupled Receptors
- GPCRs are the most abundant receptor family and are the target of ~50% of all drugs.
Has 3 Major Components:
1) 7 transmembrane spanning receptor with an extracellular ligand-binding domain.
2) G-protein (α, β, γ subunits)—dissociates upon activation.
3) Effector (enzyme, ion channel, or other proteins)
Mechanism of Action:
- Ligand binding → GPCR activation → G-protein dissociation → production of second messengers (e.g., cAMP, IP3, cGMP) which inhibit/stimulate a cell function
- binding of 1 ligand can activate thousands of effectors
Ex. GPCR-targeting drugs:
- Beta blockers, antihistamines, opioids
- These drugs act as antagonist and block activation of GPCR's
35
Enzyme-Linked Receptors (im lost)
- Function: These transmembrane receptors act as both receptors and enzymes - can translate the response between the binding of ligand into a response by activating enzymes
- These receptors regulate metabolism, growth and differentiation.
- Most of these receptors’ enzymes act by adding or removing phosphate groups to/ from amino acid residues on proteins
Ex. When insulin binds, enzymatic domains (tyrosine kinase) get phosphorylated which activates it. this causes translocation of glucose receptors to the membrane which promote glucose uptake
36
What are the 5 Major Classes of Enzyme-Linked Receptors
1. Receptor tyrosine kinases
2. Receptor tyrosine phosphatases
3. Tyrosine kinase-associated receptors
4. Receptor serine/threonine kinases
5. Receptor guanylyl cyclases
37
Intracellular Receptors
- Found inside the cytoplasm or nucleus, not on the cell membrane
- In order to access intracellular receptors, drugs must be lipophilic enough to cross the plasma membrane or need a transport protein to enter the cell
- Drug binds to intracellular receptor → Receptor moves to the nucleus
Binds to specific DNA regions, recruiting co-activators or co-repressors that increase r decrease gene expression
- Gene transcription takes long, so patients may not see immediate effects
Ex. Steroid Drugs (corticosteroids)
38
How is the Response to a Drug Regulated/Terminated?
A drug response can be terminated or regulated by:
1. Elimination: Removal of the drug or drug-receptor complex from the body.
2. Desensitization: Reduction in receptor sensitivity over time.
39
4 Mechanisms of Receptor Desensitization
1) Phosphorylation
→ A phosphate group is added to the receptor.
→ Can partially or completely inactivate the receptor.
2) Receptor Sequestration
→Receptors are pulled into vesicles (endosomes) from the plasma membrane.
→ Causes a temporary decrease in receptor availability and response.
3) Down-regulation
→ Decreases receptor numbers by degradation or reduced receptor synthesis.
→ Since receptors are proteins, they must be synthesized again for recovery.
4) Refractory Period
→ Some receptors enter a temporary inactive state before they can be reactivated.
40
Tolerance VS. Desensitization
- Drug Tolerance: Decreased response to a drug after repeated/prolonged exposure.
→Ex: Reduced response to opioid drugs.
- Tachyphylaxis: A rapid-onset form of drug tolerance.
→Ex: Patients develop tachyphylaxis after taking a few doses of Histamine 2 receptor blockers for heartburn.
*Receptor desensitization is a key mechanism in drug tolerance*
Drug-Response Curve:
A. Drug Tolerance
- Compares a naïve patient (first-time user) vs. a tolerant patient (repeated exposure).
- EC50 is higher in the tolerant patient → Higher drug dose needed for the same effect.
- A naïve patient needs a lower dose for the same response.
B. Tachyphylaxis
- Repeated doses lead to a rapid drop in efficacy.
- At Dose 4, the patient barely responds to the drug.
Clinical Relevance:
- Tolerance → Higher doses needed for therapeutic efficacy.
- Complete desensitization → Patients may stop responding to the drug, requiring alternative therapies.
41
Pharmacokinetics (PK) vs. Pharmacodynamics (PD)
Pharmacokinetics (PK):
→Determines how much of a given drug dose reaches the site of action
→Includes absorption, distribution, metabolism, and excretion
→Determines the dose- concentration
Pharmacodynamics (PD):
→Determines the magnitude of the effect a drug produces at its site of action
→Involves drug-receptor interactions, signal transduction, and biological response
→Determines the concentration-effect
- The "point of connection" between PK and PD is the drug concentration at the site of action, which ultimately influences effectiveness and toxicity.
42
Steady State Concentration
Steady State Concentration: The plasma drug concentration at which the rate of drug administration equals the rate of drug elimination
- Achieved when patients receive multiple doses over time
- Represents an average concentration of the drug in plasma.
- The steady-state concentration reflects the concentration of the drug at the site of action
Goal: Maintain drug levels above the minimum therapeutic concentration
but stay below minimum toxic concentration to prevent toxic effects
43
Factors that Impact Steady State Concentration (Css)
1. Physiological Changes in Pharmacokinetics (PK):
→Alterations in drug absorption, distribution, metabolism, and excretion can influence Css.
2. Disease Processes:
→Conditions affecting liver or kidney function can alter drug clearance, leading to fluctuations in Css.
3. Drug Interactions:
→ Other medications may induce or inhibit metabolism, affecting Css levels.
- Therapeutic Window Matters:
→Large therapeutic window: allows dose adjustments with safety.
→Narrow therapeutic window: small changes in drug levels may lead to toxicity or subtherapeutic effects.
44
Factors Affecting Drug Absorption, Distribution, Metabolism, and Excretion:
1. Surface area
2. Blood flow
3. pH of gastric lumen
4. Gastric emptying time
5. First-pass effect
6. Expression of drug transporters
7. Age
8. Gender
9. Genetic polymorphisms
45
Average Plasma Concentration (Css)
Average plasma concentration=
Dosage interval×Clearance/
Dose×Bioavailability
- Avg plasma concentration: a function of how much we give to the patient,
- Bioavailability: how much makes it to circulation
→Increase in bioavailability results in an increase in drug concentration at the site of action
→ Increase in clearance will result in a decrease in drug concentration at the site of action
- Dosing interval: How often the drug is given
- Elimination: how quickly the body removes it.
46
Half Life
Half-Life: The time required for a drug’s concentration in the blood to decrease by 50%.
- It takes 3-5 half-lives for a drug to be eliminated or reach steady-state concentration.
- Independent of dosage—half-life remains constant regardless of the amount given.
- Longer half-life = longer drug effect, requiring less frequent dosing.
47
Impact of Half-Life (t1/2) on Drug Accumulation & Toxicity
- When dosing continues before 50% of the previous dose is eliminated, the drug accumulates, increasing plasma concentration
Risk with Narrow Therapeutic Window
- Drugs with a narrow therapeutic window have a small margin between effective and toxic doses.
- If accumulation occurs, drug levels may rise into the toxic range, leading to adverse effects
Factors Affecting Half-Life & Drug Concentration
→Bioavailability (how much drug reaches circulation),
→Volume of distribution (how the drug spreads in the body), and
→Clearance (how efficiently the body eliminates the drug).
- Changes in any of these factors can prolong half-life, increasing drug levels and risk of toxicity.
48
Impact of Disease in the PK-PD Interplay
- Diseases affect drug absorption, distribution, metabolism, and excretion.
→Ex: Renal & hepatic failure can impair drug elimination, leading to drug accumulation if dosing adjustments are not made.
- Pathological changes in pharmacokinetics (PK) can increase or decrease drug plasma concentration.
- Drugs with a large Therapeutic Window can tolerate concentration fluctuations without toxicity.
- Drugs with a narrow Therapeutic Window may experience toxic effects even with small concentration changes.
