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Pharm-dynamic

  1. what is a drug?
    An exogenous substance, other than a nutrient or essential dietary ingredient, that produces a biological effect when administered to the body
  2. What is pharmacology?
    Study of drugs and their effects on the function of living systems
  3. What is pharmacodynamics?
    • how drugs affect/influence the body
    • ►Mechanism of action
    • ►Adverse vs therapeutic effects
    • ►Clinical application
  4. What is pharmacokinetics?
    • how the body affects drugs
    • ►Absorption
    • ►Distribution
    • ►Storage
    • ►Elimination
    • ►Metabolism
    • ►Excretion
  5. What is the proprietary name?
    • ►Manufacturer-derived brand or trade name
    • ►Copyrighted
    • ►Can be multiple names
    • can refer to combination drug formulations
    • ex: hydrocodone + acetaminophen= vicodin
  6. What is a generic name?
    • ►Government approved
    • ►Only one name
    • chemical name is the same, drug name may change

    ex. Ibuprofen
  7. What is a chemical name?
    • ►Given by International Union of Pure and Applied Chemistry (IUPAC)
    • ►Describes chemical composition, specific to their structure
  8. Identify:

    -Ibuprofen:
    -Fluoxetine:
    -Nifedipine-
    • -pain killer
    • -antidepressant
    • -antihypertensive
  9. Drugs act by influencing what?
    a target molecule.... the receptor!

    often cell receptors for endogenous molecules
  10. Receptors can be present:
    • ►on the cell surface (plasma membrane)
    • ►… or inside the cell
    • ►…on organelle membranes
    • ►…within the cytosol
  11. Target receptors can be:
    • Enzymes
    • ►e. g. Acetylcholinesterase (AChE) – breaks down acetylcholine (inhibited by neostigmine)
    • ►e. g. Cyclooxegenase (COX) – synthesizes prostaglandins (inhibited by aspirin)Transporters/pumps- sit on biological membranes►e.g. serotonin reuptake transporter (inhibited by fluoxetine)
    • Ion channels- transports ions across membranes
    • ►e.g. Neuronal voltage-gated Na+ channels (blocked by lidocaine)
    • Second messenger-linked receptors
    • e.g.►G protein-coupled opioid receptors (activated by morphine)
    • DNA transcription factors- proteins that canbind and interact without DNA e.g.►Estrogen receptor (inhibited by Tamoxifen)
  12. Drug-receptor interactions follow basic principles underlying:
    chemical equilibrium (Law of Mass Action)

    • ►Most clinically useful drugs reversibly associate and disassociate from their receptors
    • ►Some drugs can bind irreversibly to their receptors; usually an undesirable property (e.g. AChE inhibitor, Sarin), but see phenoxybenzamine
    • ►Ideally, drugs primarily bind specific receptors (exhibit selectivity)
    • ►No drug is completely specific for a single target receptor
  13. Why is it desirable for drugs to be selective for specific receptors?
    More selective, the more control you have, you can have less side effects.
  14. Agonist:
    binds to a receptor and activates it

    ex. morphine at micro-opioid receptor
  15. Pharmacological antagonist:
    • binds receptor, but DOES NOT activate it.
    • prevents agonist from binding receptor

    ex. naloxone at micro-opioid receptor
  16. drug receptor interactions:
    given amt of drug + given amt of receptor = given amt of drug-receptor complex
  17. Law of Mass Action

    Interaction between drug and receptor depends on:

    Amount of drug-receptor rcomplex determines:

    A minimum number of drug-receptor complexes required/ not required to surmount measurable effect threshold

    ►When R is saturated by D, response can/ cannot be increased further
    • ►on relative concentration/amounts
    • ►effect magnitude
    • required
    • cannot

    Increase [D] + [R] <-> increase [DR] ->increase response
  18. ►            partly depends on probability of collision between drug and receptor
    ►At low [D], collision likely/unlikely, binding unlikely; i.e. low [DR]
    ►As [D] increases, collisions increase, likelihood of binding increase/decreases; i.e. [DR] increases
    ►Relationship is               on a linear concentration scale (x-axis)
    ►… but sigmoidal on a logarithmic scale
    • ►Binding partly depends on probability of collision between drug and receptor
    • ►At low [D], collision unlikely, binding unlikely; i.e. low [DR]
    • ►As [D] increases, collisions increase, likelihood of binding increases; i.e. [DR] increases
    • ►Relationship is parabolic on a linear concentration scale (x-axis
    • )►… but sigmoidal on a logarithmic scale
  19. Affinity:

    depends on:
    strength of the bond, how a drug binds and unbinds to a receptor

    • 1)Binding affinity of drug for its receptor
    • 2)How much drug changes activity of receptor upon binding (efficacy)

    Bound/unbound and inactive/active states are usually in dynamic equilibrium
  20. How easily/ what influences the drug binding a receptor?
    • Influenced by…
    • 1. Size and shape of drug
    • 2. Stereochemistry of binding site(s
    • )►# binding sites per receptor
    • ►Spatial arrangement
    • 3. Intermolecular forces involved in drug binding
    • ►Van der Waals – weak and transient interactions
    • ►Hydrogen bonds – Intermediate strength (hold water molecules together)
    • ►Ionic interactions – between +ve and –ve charges
    • ►Covalent bonds – Strong. Tend to underlie irreversible binding
  21. what is the KD?
    • ►Binding affinity quantified by drug’s dissociation equilibrium constant, KD
    • ►KD = k2/k1  = drug concentration required to occupy half the available receptors
    • ►The lower the KD, the higher the binding affinity
    • KD- how quickly it binds
  22. Two types of drug selectivity:
    • ►Selectivity by binding
    • ►Selectivity by distribution
  23. Selectivity by binding:
    • ►Receptors selectively accommodate drugs with specific structural characteristics
    • ►Selectivity between drugs and receptors is vital to achieving specificity of action
  24. selectivity by binding example:
    B-adrenergic receptors (B-ADRs)

    • Respond to endogenous nor-epinephrine and epinephrine
    • Three types: b1, b2 and b3
    • ►Activation of b1 increases heart rate/contractility and blood pressure
    • ►Activation of b2 causes bronchodilation
    • b-ADR antagonists (“beta blockers”) used to treat cardiac arrhythmia, hypertension and anxiety
    • ►However, non-selective beta blockers unsuitable for patients also suffering from asthma
    • ►b1-ADR inhibitors are preferable
    • ►Similarly, b-ADR agonists used to treat asthma must be selective for b2-ADRs, so as not to cause cardiovascular problems
  25. Selectivity by distribution:
    • ►Cell/tissue sensitivity conferred by expression of receptors that bind a given drug
    • ►Drugs targeting receptors distributed in many tissues can have diverse physiological effects
    • ►High likelihood of undesirable side-effects
    • ►Drugs targeting receptors largely expressed in a single tissue will have greater effect specificity
    • ►Knowledge of receptor distribution among tissues is important for predicting the specificity of the drugs action
  26. Selectivity by distribution example:
    • NSAIDs
    • Prostaglandins contribute to…
    • ►… inflammatory pain
    • ►… protection of gut lining from acid
    • NSAIDs inhibit prostaglandin synthesis
    • ►Block cyclooxygenase (COX) enzymes
    •       ►COX-1 – active in many tissues
    •       ►COX-2 – active only in inflamed tissue
    • Aspirin and ibuprofen target both COXs
    •     ►Side effects – irritation of gut lining (can cause/exacerbate peptic ulcers)Acetaminophen specifically targets COX-2
    • ►fewer undesirable side effects
    • ►but a greater toxicity concern
  27. Efficacy:
    • When an agonist binds a receptor, it affects a conformational change in the receptor’s structure…
    • ►…this is the first step towards triggering the response
    • ►Some agonists are more efficacious at eliciting a receptor-mediated response than others
    • ►Agonists can differ in the maximal response they can elicit

    once its bound how well it pushes the drug to its active state. Referred to as "potency"
  28. Full agonist-
    Partial agonist-
    Pharmacological antagonist-
    inverse agonist-
    • -produces maximum response
    • -produces smaller maximum response relative to full agonist
    • -produces no response, but blocks agonist binding
    • -for constitutively active receptors, these drugs reduce activity
  29. What is drug potency? and what does it depend on?
    • the ability for a drug to illicit a response  
    • Depends on:
    • 1)Binding affinity of drug for its receptor – informed by KD
    • 2)How much drug changes activity of receptor upon binding (efficacy) – informed by EMax
  30. What constitutes a response?
    • ►Any physiological change associated with drug administration
    • ►Can be at the level of the whole animal, organ, tissue, cell, or even molecule etc

    • ►Change in blood pressure
    • ►Change in blood vessel diameter
    • ►Change in smooth muscle tone
    • ►Change in intracellular Ca2+ concentration in smooth muscle
    • ►Change in function of InsP3R Ca2+ channel
  31. Concentration-response curve:
    • what we know the conc of the drug is at the site of the reaction.
    • ►Plots relationship between elicited response and known drug concentration receptors are exposed to
    • ►Commonly expressed as moles* per liter (mol l-1)
  32. Dose response curve:
    •  this is how much I administered and this is the response I get.
    • ►Plots relationship between elicited response and administered drug concentration
    • ►May be different from the actual drug concentration at the tissue expressing the target receptors
    • ►Commonly expressed as milligrams of drug per kilogram of body weight (mg/kg)
  33. Graded response curve:
    charts relationship btwn [drug] and response magnitude
  34. Quantal response curve:
    when measured response is all-or-none, the conc/dose-dependence of the freq of the response is determined

    Counting a frequency, did it change or didn’t it change. Looking at a freq rather than a graded affect
  35. Emax:
    EC50:

    what are these useful for?
    the maximum response elicited by a given drug

    concentration of drug required to evoke a half-maximal (50%) response

    useful for assessing drug action
  36. TD50:
    LD50:
    TI:
    Therapeutic window:
    • "Median toxic dose”
    • Dose that produced toxic effects in 50% of patients/specimens

    • “Median lethal dose”
    • Dose that produced lethal effects in 50% of patients/specimens

    • in animals TI= LD50/ED50
    • in humans TI= TD50/ED50
    • larger ratio values correlate lesser risk of toxicity

    Range of drug dosages  within therapeutic range but outside of toxic range
  37. antagonism:
    opposition in physiological action; especially: interaction of two or more substances such that the action of any one of them on living cells or tissues is lessened
  38. Physiological (functional) antagonism:
    • Activating opposing pathways
    • e.g.►Lung airway diameter regulated by autonomic/hormonal input
    • ►Adrenergic à dilation
    • ►Cholinergic à constriction
    • ►B2-ADR agonist, Salbutamol, used for asthma
  39. Chemical (physical) antagonism:
    • Chemical antagonist
    • ►Does not interact with the target receptor
    • ►Acts on the endogenous ligand directly
    • ►( don’t act at receptor level, rather chemical or phys interaction btwn drug and endogenous target substance)
    • e.g.►Antacids like Mg(OH)2 neutralize H+ ions in the gut
    • e.g.►Antibodies directed towards cocaine reduce the drugs effects
  40. Pharmacokinetic antagonist:
    • ►Reduces concentration of another drug
    • ►… by decreasing absorption and/or distribution
    • ►… by speeding metabolism and/or excretion

    ►Useful for dealing with harmful chemicals ►e.g. Activated Charcoal to sequester certain ingested poisons in GI tract
  41. Pharmacological antagonists:
    Vast majority of clinical antagonists

    Produce little or no effect alone at target receptor, but block binding by endogenous agonists (neurotransmitters, hormones etc)

    • Different variants
    • ►Reversible and irreversible competitive antagonism
    • ►Reversible and irreversible non-competitive antagonism
  42. Competitive antagonism:
    Antagonist competes with agonist for same binding site (drugs that bind to the exact same receptor)
  43. Competitive antagonism : Reversible-
    • ►Antagonist binds and unbinds receptor according to its affinity and the Law of Mass Action
    • ►Response determined by relative occupancy of receptor by antagonist vs agonist

    e.g.►In presence of [agonist], increase in [antagonist] reduces response amplitude

    ►  increase [antagonist] shifts [agonist] concentration response curve to the right
  44. IC50:
    [antagonist] required to inhibit response by 50%.
  45. Competitive antagonism : Reversible examples-
    Example: propanolol antagonism of isoprenaline-evoked contractions of guinea pig atria

    (These drugs act primarily at b-adrenergic receptors)
  46. Competitive antagonism : Reversible
    Dose ratio-
    Agonist ED50 in presence of antagonist/ Agonist ED50 in absence of antagonist

    The larger the dose ratio, the further the agonist response curve has been shifted to the right
  47. pA2-
    an index of antagonist affinity for the receptor. It is the negative log  [antagonist] that necessitates a two-fold increase in [agonist] to achieve same effect observed in absence of antagonist
  48. Competitive antagonism : Irreversible-
    • ►Once bound, antagonist remains associated with receptor
    • ►Effect of irreversible competitive antagonist is both concentration-dependent AND time-dependent
    •          ►i.e. the longer the antagonist is around the more likely it will interact and irreversibly bind target receptor
  49. allosteric antagonism:
    • Antagonist binds to separate site
    • ►Allosterically inhibits receptor activation by agonists
    • ►Either by...
    •        ►Altering agonist binding site
    •        ►Reducing efficacy of bound agonist
    •        ►Uncoupling receptor from signaling pathway
    •        ►Effect insurmountable
  50. example of allosteric modulation:
    • GABAA
    • ►GABAA is a neuronal ion channel
    •     ►Activation by inhibitory neurotransmitter g-aminobutyric acid (GABA) depresses neuronal transmission

    • Efficacy of GABA enhanced by numerous allosteric modulators:
    • ►Benzodiazepines: e.g. diazepam
    • ►Barbiturates: e.g. phenobarbitol
    • ►General anesthetics: e.g. propofol
    • ►Ethanol
  51. Activity of protein kinases:
    activity of protein phosphatases:
    • ►Phosphorylation/dephosphorylation = rapid, reversible switch
    • ►Activity of numerous proteins modulated by phosphorylation state
    • ►Protein kinases add phosphate (PO4-) groups to proteins, using nucleotides such as ATP as the source of PO4-
    • ►Protein phosphatases remove PO4- groups from proteins
  52. Ion channels:
    • ►Receptor and signal transduction mechanism (ion permeable pore) contained within single protein
    •          ►Several polypeptide subunits
    • Can be on plasma membrane and intracellular membranes

    • ►Ion flux can alter membrane potential
    • ►Ca2+ influx can regulate numerous intracellular processes
  53. Ion channels are activated ("gated") by:
    • Ligands
    • ►Neurotransmitters
    • ►Exogenous drugs

    • Change in membrane potential
    • ►Voltage-operated Na+, K+ and Ca2+ channels

    • Mechanical stretch
    • ►Piezo channels

    • Changes in temperature
    • ►Noxious heat, TRPV1
    • ►Noxious cold, TRPM8
  54. G protein-coupled receptors:
    • ►Largest family of membrane receptors (>700 members)
    • ►Comprise >50 % of pharmaceutical targets
    • ►Receptor and signal transduction element are separate proteins
    • ►Receptor’ is formed by a 7-transmembrane protein
    • ►Intermediate signal transduction element is a GTP-binding protein
    • ►Most activated by diffusible drugs
    •         ►Some activated by proteases
  55. Activation of G proteins:
    • ►Activation of 7-helix receptor causes exchange of GTP for GDP at nucleotide binding site of Ga subunit
    • ►Ga and bg dissociate
    • ►Free Ga and bg subunits regulate activity of effector proteins (e.g. Adenylyl cyclase, ion channels)
    • ►bg dimer signals until reassociated with GDP-bound Ga
    • ►Ga signals until intrinsic GTPase activity hydrolyses bound GTP back to GDP (facilitated by GTPase-activating proteins)
  56. Enzyme-linked receptors:
    • ►Extracellular domain forms receptor ►Intracellular domain is an enzyme
    • ‒Catalytic activity regulated by receptor
    • ►Mainly protein kinases (Tyr kinases, Ser/Thr kinases
    • ‒Phosphorylate other proteins
    • ‒Phosphorylation and dephosphorylation regulate activity of many proteins

    • e.g.►Epidermal growth factor receptor (EGFR or ErbB)
    •         ►Neurodegenerative disease, cancer
  57. Type 1 nuclear receptors:
    • Present in the cytosol, but translocate to the nucleus upon activation
    • Form homodimers

    • e.g.►Glucocorticoid hormone receptor
    • ►Estrogen receptors
    • ►Bound receptor can have genomic and non-genomic effects

    Heat shock proteins involved in folding and unfolding of other proteins
  58. Type II nuclear receptors:
    Bound to DNA within the nucleus at all times

    • e.g.►Thyroid hormone receptor
    • ►Retinoic acid receptor
Author
merazar15
ID
193092
Card Set
Pharm-dynamic
Description
Exam 1
Updated

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