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Pharmacodynamics - Coggle Diagram

- - - - 0<Efficacy<1
    - - -1<Efficacy<0
    - - Efficacy = 1
  - - - The dose-response curve is parallel-shifted towards the right: the potency is reduced, but the efficacy is unchanged. With higher concentration of agonist, the antagonism can be overcome
    - - Irreversible
        
        Can reduce both the efficacy and the potency
      - Agonists binding to sites different from the orthosteric site
  - - - Methadone: full agonist. Due to its prolonged half life and slow action, used to recover from addiction
      - Buprenorphine: partial agonist
      - Naloxone: antagonist. used to treat overdose
- - - - Measured by Kd
      - A property that depends on the chemical-physical properties of the drug and receptor
    - - Dose-response
      - Log dose - response
        
        Plateau = receptor saturation
      - The higher the dose, the higher the response
      - The dose-response and dose-binding curves may not overlap
        
        If the dose-binding curve is shifted towards the right, there could be signal amplification or some receptors may only serve as reserves, meaning that the maximum response is achieved before the maximum receptor occupancy
- - - - Lower EC50, higher potency
- - - - Paracelsus
      - Vitamin A and liver failure at high concentrations; Botulinum toxin used as a treatment for blepharospasm at lower dosage
    - - Therapeutic Index, TI
        
        TD50/ED50
        
        TI>5 is acceptable
        
        The higher the TI, the safer the drug
        
        Does not take into consideration the slope and the degree of overlapping between two curves, so it cannot fully describe safety
      - Therapeutic Range
        
        Range of a drug which can effectively treat patients without causing severe side effects in a large fraction of the population
- - - - PK/metabolic tolerance
        
        Increase in the metabolism of the drug to favor its elimination
        
        ex. Upregulation of EtOH metabolic enzymes (ADH, ALDH) in heavy drinkers
      - PD/physiological tolerance
        
        Depends on loss of receptors, desensitization mechanisms, or exhaustion of mediators or substrates
        
        Desensitization mechanism in GPCR
        
        Quick desensitization
        
        GRK phosphorylates GPCR, and Arrestin binds and inhibits binding to G-protein
        
        Long-term desensitization
        
        Internalization in clathrin coated vesicles + degradation or recycling
        
        Homologous or heterologous
        
        Desensitization mechanism in ligand-gated ion channels: nicotinic receptor in NMJ
        
        Prolonged exposure to Ach and especially nicotine can inactivate channels, leading to impaired muscle contraction
      - Behavioral tolerance
    - - Addiction = Chronic brain disease, characterized by compulsive drug seeking and use despite harmful consequences. Drugs change the structure of the brain, leading to long-lasting changes in functionality
      - Drugs of addiction
        
        2 main characteristics
        
        Act on the CNS
        
        However, the same receptors can be also expressed in the PNS
        
        D2-like receptors
        
        Expressed in BV, kidneys, pancreas, GI, IS
        
        CBRs and opioid receptors
        
        Expressed in all the components of nociception (neurons, IS, keratinocytes)
        
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        Catecholamines transporters
        
        When activated peripherally by stimulants, lead to sympathomimetic effects
        
        Opioid receptors
        
        Opioids inhibit peristalsis in the GI tract. Agonists and antagonists of opioid receptors can be used to treat diarrhea or relieve constipation, respectively
        
        Influence DA levels by acting on the reward circuitry
        
        Most important component of reward system: mesolimbic pathway (VTA-NAc)
        
        There are many neuronal types which establish synapses which are either activatory, like DA and Glu, or inhibitory, like GABA
        
        Drugs of addiction strongly activate such pathways, which normally are activated by natural rewards (food, sex), leading to increased levels of DA
        
        Over time, the body counteract this hyperactivation of DA signaling though changes in gene expression:
        
        Reduction of D2-like receptors
        
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        Reduction of DAT
        
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        Changes in expression occur in the whole CNS, altering for example memory and learning (hippocampus) or motor control (substantia nigra)
        
        Since there are transcriptional modifications involved, changes are stable and lead to modification in the structure and functions of the brain (neuroadaptation)
        
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        These effects are more and more pronounced over time if drug consumption persists
        
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        Unexpected rewards activate this area more than expected rewards
        
        Besides acting on the DA pathway, drugs can also influence glutamatergic and serotoninergic pathways
        
        Not real addiction because the physiological component isn't there, there is only psychological addiction
        
        Influence sleep quality, mood, learning and memory
        
        Drugs of addiction do not always activate a rewarding/euphoric response, but can sometimes create aversion/dysphoria
        
        Cannabinoids
        
        Depending on the pattern of expression of CB1R and CB2R, drugs can either increase (reward) or decrease (aversion) the level of DA)
        
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        Opioids
        
        Depending on the pattern of expression of MOR and KOR, drugs can induce reward (MOR) or aversion (KOR)
        
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        General distinction
        
        Stimulants
        
        Sedative
        
        Sometimes have an effect similar to endogenously produced molecules
        
        Endocannabinoids
        
        Endogenous opioids