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Making drugs into medicines ☆ > Introduction to pharmacodynamics > Flashcards

Introduction to pharmacodynamics Flashcards

1
Q

What is pharmacodynamics (3)

A
  1. Study of the effects of drugs and their mechanisms of actions
  2. including receptor interactions, dose-response relationships, and mechanisms of therapeutic and toxic actions: Action of a drug on the body
  3. What does the drug do to the body?
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2
Q

What is the relevance and/or implications of pharmacodynamics (6)

A
  1. Mechanisms of action of drugs
  2. Ligand/drug or receptor classification
  3. Drug discovery and development
  4. Clinical use of drugs
  5. Understanding drug-drug interactions, side or unwanted effects of drugs, synergism, potentiation, additivity, antagonism, etc.
  6. PD-PK relationships and modelling
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3
Q

What is the difference between pharmacodynamics and pharmacokinetics (4)

A
  1. PD - What the drug does to the body
  2. Drug concentration at the site of action or in the plasma is related to the magnitude of the effect.
  3. PK - What the body does to the drug
  4. Absorption, Distribution, Metabolism, Excretion, (Toxicity) (ADME(T))
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4
Q

How are receptors used as drug targets (3)

A
  1. A receptor is a macromolecular component of a cell with which a drug interacts to produce a response, a protein.
  2. Most drugs act by binding to their targets (drug targets)
  3. Most drug targets are protein molecules, but there are exceptions (e.g., DNA as drug targets for anti-tumour or antimicrobial drugs)
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5
Q

What are examples of unconventional mechanisms of action (10)

A
  1. Disrupting of Structural Proteins (e.g., vinca alkaloids for cancer, colchicine for gout)
  2. Being Enzymes (e.g., streptokinase for thrombolysis)
  3. Covalently Linking to Macromolecules (e.g., cyclophosphamide for cancer)
  4. Reacting Chemically with Small Molecules (e.g., antacids for increased acidity)
  5. Binding Free Molecules or Atoms (e.g., drugs for heavy metal poisoning, infliximab (anti-TNF))
  6. Being Nutrients (e.g., vitamins, minerals)
  7. Exerting Actions Due to Physical Properties (e.g., mannitol (osmotic diuretic), laxatives)
  8. Working Via an Antisense Action (e.g., fomivirsen for CMV retinitis in AIDS
  9. Being Antigens (e.g., vaccines)
  10. Having Unknown Mechanisms of Action (e.g., general anaesthetics)
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6
Q

What are the types of receptors? (7)

A
  1. Enzymes – may be inhibited or activated.
  2. Carrier molecules (transporters) – e.g. Na+ /K+ ATPase
  3. Ion channels

Receptors:

  1. Ion channels: ligand-gated, (voltage-gated)
  2. G-protein-coupled receptors (GPCRs)
  3. Tyrosine kinase receptors
  4. Nuclear receptors
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7
Q

What are some characteristics of drug-receptor interactions (6)

A
  1. Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, covalent
  2. Saturable
  3. Competitive
  4. Specific and selective
  5. Structure-activity relationships (SARs)
  6. Transduction mechanisms
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8
Q

What are receptor transduction mechanisms (7)

A
  1. Ion channel-linked receptors (e.g., Nicotinic ACh receptor (Na+) and GABAA receptor (Cl-))
  2. Second messenger generation:
  3. Adenylate cyclase stimulation or inhibition - cAMP
  4. guanylate cyclase - cGMP
  5. phospholipase C - IP3, DAG
  6. Some receptors are themselves protein kinases.
  7. Intracellular receptors (e.g., corticosteroids, thyroid hormone)
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9
Q

What is affinity (3)

A
  1. Affinity – a measure of the propensity of a drug to bind to a
    receptor
  2. Covalent bonds are stable and essentially irreversible.
  3. Electrostatic bonds may be strong or weak but are usually reversible.
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10
Q

What is efficacy (intrinsic activity) (2)

A
  1. The ability of a drug, once bound, to activate the receptor to produce an effect.
  2. some drugs (antagonists) possess affinity but NOT efficacy.
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11
Q

How do agonists relate to affinity and efficacy (6)

A
  1. An agonist has affinity plus intrinsic activity (efficacy)
  2. A partial agonist has affinity and less intrinsic activity.
  3. Interact with (bind to) the receptor (have affinity) but do NOT elicit a response (have NO efficacy)
  4. Prevent agonist from binding to the receptor.

Two types:

  1. Competitive
  2. Noncompetitive
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12
Q

What are the receptor theory and models (7)

A
  1. Classical model of receptor function
  2. Operational model of receptor function (Black and Leff)
  3. Two-state Theory
  4. The Ternary Complex Model
  5. The Extended Ternary Complex Model
  6. The Cubic Ternary Complex Model
  7. Multi-state Receptor Models
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13
Q

What is the two-state model receptor theory (6)

A
  1. The receptor is shown in two confrontation states, Resting (R) and Activated (R*), which exist in equilibrium.
  2. Normally, when no ligand is present, the equilibrium lies to the left, and few receptors are found in the R* state.
  3. Agonists have a higher affinity for R* than R, so shift the equilibrium to the right.
  4. The greater the affinity for R* with respect to R, the greater the efficacy of the agonist
  5. An antagonist has a higher affinity for R than R* and so shifts the equilibrium to the left.
  6. A neutral antagonist has an equal affinity to R and R*, so it does not by itself affect the conformational equilibrium but reduces by competition the binding of other ligands.
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14
Q

What is the affinity constant (3)

A
  1. k1/k2
  2. k1\k2 = [DR]/[D][R]
  3. the lower the kd, the higher the affinity of the drug
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15
Q

What are some assays and techniques for studying ligand binding to receptors (5)

A
  1. Use of radiolabelled ligands (3H, 14C, 125I, etc.)
  2. Saturation binding
  3. Competition binding
  4. Use of fluorescent ligands to replace radiolabelled ligands (fluorophore coupled to ligand)
  5. Receptor imaging: positron emission tomography (PET) is a non-invasive technique to investigate the distribution of receptors in structures (e.g., living human brain)
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16
Q

What is a competitive antagonist (4)

A
  1. Competes with agonist for receptor site
  2. Surmountable by increasing agonist concentration
  3. Displaces agonist dose-response (DR) curve to the right (dextral shift)
  4. Reduces the apparent affinity of the agonist, i.e., increases Kd.
17
Q

What is a non-competitive antagonist (4)

A
  1. Binds to receptor and stays bound
  2. Usually irreversible – does not let go of receptor.
  3. Produces slight dextral shift in the agonist DR curve in the low concentration range, which looks like that of a competitive antagonist
  4. But, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect.
18
Q

What is potency (5)

A
  1. The relative position of the dose(concentration)-effect curve along the dose (concentration) axis
  2. Usually expressed as the dose or concentration of drug required to achieve half the maximum biological response and is termed ED50 (EC50)
  3. Has little clinical significance for a given therapeutic effect
  4. The more potent of the two drugs is not clinically superior.
  5. Low potency is a disadvantage only if the dose is so large that it is awkward to administer.
19
Q

Why are there spare receptors (3)

A
  1. Spare receptors allow maximal response without **total receptor occupancy – increasing the sensitivity of the system.
  2. Spare receptors can bind (and internalise) extra ligands, preventing an exaggerated response if too much ligand is present.
  3. The receptor theory assumes that all receptors should be occupied to produce a maximal response. In that case, at half-maximal effect, EC50=KD. Sometimes, the full effect is seen at a fractional receptor occupation.
20
Q

What are other mechanisms of antagonism (4)

A
  1. Chemical antagonism: Substances combine in solution (e.g., chelating agents (e.g., dimercaprol) and heavy metals)
  2. Pharmacokinetic antagonism: ‘Antagonist’ reduces the concentration of the active drug at its site of action (e.g., the reduction of the anticoagulant effect of warfarin by acceleration of its hepatic metabolism, e.g., by phenobarbital)
  3. Block of receptor-effector linkage (e.g., calcium-channel blockers verapamil and nifedipine block the contraction of smooth muscles produced by other drugs)
  4. Physiological antagonism: opposing actions of two drugs cancel each other (e.g., histamine (gastric acid secretion stimulation by action on receptors of gastric mucosa parietal cells) and omeprazole, which blocks gastric acid secretion by inhibiting proton pump)
21
Q

What is constitutive activity and inverse agonism (4)

A
  1. Appreciable level of receptor activation in the absence of a ligand
  2. Receptor theory explanation (two-state model, active and inactive states)
  3. More than 85% of antagonists are inverse agonists.
  4. All former H1-antagonists to date have been inverse agonists.
22
Q

What is allosterism (4)

A
  1. An allosteric ligand binds to a site on the receptor that is topographically different from the orthosteric site where the endogenous ligand binds.
  2. Can change potency and/or efficacy of agonist
  3. Useful in attaining subtype-selectivity, reduced unwanted effects in humans
  4. Positive, negative, silent, ago-allosteric/allo-agonists/dualistic
23
Q

What is dimerisation/oligomerisation (4)

A
  1. Two or more receptors of the same receptor (homodimerisation) or different receptors (heterodimerisation) functioning together as if they were a single receptor
  2. The pharmacology of dimer is distinct from that of each of the protomers.
  3. Several GPCRs are dimers. Class C GPCRs (mGluRs, GABABR) are constitutive dimers.
  4. mGluRs are homodimers, GABABR are heterodimers (GABAB1 and GABAB2)
24
Q

What is functional selectivity/biased agonism/ligan-directed trafficking (2)

A
  1. Ligands acting at the same receptor preferring different subsets of the entire repertoire of signalling effectors are possible.
  2. Has consequence for the design of screening assays and translation of pre-clinical characterisation of agonists
25
Q

What is desensitisation (4)

A
  1. Agonists tend to desensitise receptors:
  2. homologous (decreased receptor number)
  3. heterologous (decreased signal transduction)
  4. Antagonists tend to upregulate receptors.
26
Q

What is the time frame of desensitisation, tachyphylaxis and tolerance (4)

A
  1. When the effect of a drug gradually diminishes when it is given continuously or repeatedly
  2. Desensitisation or tachyphylaxis: develops within a few minutes
  3. Tolerance: a more gradual decrease in responsiveness to a drug, which takes days or weeks to develop
  4. Refractoriness: loss of therapeutic efficacy
27
Q

What is the pharmacodynamic principle of tolerance (3)

A
  1. A diminished response to a drug as a result of continued use
  2. Not all drugs produce tolerance.
  3. When tolerance is developed for one drug in a category, cross-tolerance may develop for another drug in the same category.
28
Q

What are the mechanisms underlying desensitisation and tolerance (6)

A
  1. Change in receptors
  2. Translocation of receptors
  3. Exhaustion of mediators
  4. Increased metabolic degradation (enzyme induction, i.e., the liver produces more drug-metabolising enzymes)
  5. Physiological adaptation
  6. Active extrusion of drug from cells (e.g., in cancer chemotherapy)
29
Q

What is effectiveness, toxicity and lethality (3)

A
  1. ED50 - Median Effective Dose 50; the dose at which 50 per cent of the population or sample manifests a given effect; used with quantal DR curves
  2. TD50 - Median Toxic Dose 50 - the dose at which 50 per cent of the population manifests a given toxic effect
  3. LD50 - Median Lethal Dose 50 - dose which kills 50 per cent of the subjects
30
Q

How is the therapeutic index calculated (2)

A
  1. Therapeutic index = TD50 or LD50/ED50
  2. Therapeutic index = Median toxic dose or Median lethal dose/Median effective dose
31
Q

What are the implications of the therapeutic index (4)

A
  1. The higher the TI, the better the drug.
  2. TI’s can vary from 1.0 (some cancer drugs) to >1000 (penicillin)
  3. Drugs with a low ‘Therapeutic Index’ or narrow ‘Therapeutic Window’ need to be constantly monitored, e.g., lithium, digoxin, and warfarin.
  4. Drugs acting on the same receptor or enzyme system often have the same TI (e.g., 50 mg of hydrochlorothiazide is about the same as 2.5 mg of indapamide)
32
Q

How do receptors affect disease (2)

A
  1. Autoantibodies directed against receptor proteins
  2. Mutations in genes encoding receptors, ion channels and proteins involved in signal transduction
33
Q

What are examples of diseases caused by receptors (6)

A
  1. Myasthenia gravis
  2. Thyroid hypersecretion
  3. Activating antibodies in severe hypertension, cardiomyopathy, some forms of epilepsy and neurodegenerative disorders
  4. Inherited mutations in genes encoding GPCRs (e.g., vasopressin, ACTH)
  5. Receptor polymorphism leads to reduced efficacy of agonists (e.g., beta-adrenoceptor agonists in treating asthma)
  6. Mutations in G-proteins (e.g., hypoparathyroidism, hypertension)

Making drugs into medicines ☆ (13 decks)

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