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Year 3 Sem 1 COPY COPY > PA30324 3. Medicines design > Flashcards

PA30324 3. Medicines design Flashcards

1
Q

> 98% of small-molecule drugs and virtually all large-molecule drugs cannot enter the brain from the systemic circulation.

Why?

A
  • The brain requires significant amounts of small, hydrophillic molecules such as glucose and amino acids
  • Ion concentrations need to be tightly controlled
  • CNS and peripheral pools of neurotransmitter & neuroactive agents need to be kept separate
  • Brain interstitial fluid has ↓↓protein, ↓Na+, ↓ K+, ↑ Mg2+ than blood plasma, otherwise similar
  • The passage of these species is very tightly controlled by specific barriers to ensure the brain has exactly the right biochemical make up, excluding potential neurotoxic compounds
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2
Q

Describe the Blood-Brain Barrier (BBB) and its function

A
  • Separates blood and brain interstitial fluid (ISF)
  • Acts as a physical & biochemical barrier
  • The constituent cells of the blood brain barrier are referred to as the neurovascular unit (NVU)
  • barrier function is regulated by complex yet dynamic communication between cells of the NVU
  • Tight junctions are key to the BBB’s ability to physically restrict passage of molecules
  • Many disease states disrupt the barrier function, e.g stroke, Alzheimer’s, HIV, brain tumours
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3
Q

Describe how BBB acts as a biochemical/molecular barrier

A
  • due to transporters and metabolic enzymes
  • extracellular enzymes include peptidases and nucelosidases
  • Intracellular enzymes include monoamine oxidases and cytochrome P450 isoforms
  • In whole brain, glutathion S-transferases and cathchol-O-methyl transferase expression is higher than in liver
  • Sulphotransferases present but at low level
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4
Q

Describe Passive diffusion across the BBB

A
  • The main mechanism by which the majority of small drug molecules enter the brain
  • Non-saturable diffusion down a concentration gradeient
  • Lipophilicity, MW and H-bonding are key parameters
  • Ideal LogP around 1.5-2.5
  • Ideal MW ~400
  • Reduced PSA compared to oral
  • Lower number of H-bonds tolerated
  • Lipinski’s rule of 5 does not apply
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5
Q

What are the strategies for Drug delivery to the Brain?

A

Non-invasive delivery

  • Chemical methods
  • Biological methods
  • Nanomedicine

Invasive delivery

  • BBB disruption
  • Implants
  • Interstitial, Intraventricular & intrathecal delivery

Alternative routes
- Bypassing the BBB

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6
Q

Describe Non-invasive drug delivery to the Brain through chemical methods

A

Strategies include
- improving peripheral PK e.g peptide and nucleic acid analogues, protein PEGylation

  • improving lipophilicity, esterification, conjugation of lipid moieties, reduction of H-bonding
  • pro-drug approaches
  • mimicking transporter substrates e.g gabapentin
  • inhibiting efflux transporters
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7
Q

Describe inhibiting efflux systems in Non-invasive drug delivery to brains

A
  • Efflux transporters are widespread in the body
  • Inhibiting them can improve drug absorption
  • P-gp can be inhibited by verapamil, a voltage gated Ca2+ channel blocker
  • possible to inhibit more targeted efflux transporters
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8
Q

Describe inhibiting Biological methods/Nanomedicines in Non-invasive drug delivery to brains

A
  • Drug containing nanoparticles, generally 10-500nm in diamater
  • Can be taken up by cells via a number of mechanisms - transcytosis or direct translocation

Hijacking endogenous cells
- Inflammation in the brain (e.g AD, Parkinson’s, MS, tumours) causes recruitment of monocytes and neutrophils

  • Monocytes and neutropihls are phagocytic
  • Micro- and nanoparticles can be loaded with drugs and targeted to these cells
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9
Q

Describe the Invasive Drug delivery to the Brain through CSF

A
  • For conditions including bacterial meningitis leukaemia and brain tumours
  • Intrathecal or epidural injection in the spine
  • Ommaya reservoir delivers drugs into the ventricles and allows sampling of the CSF
  • Also for interstitial delivery
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10
Q

Describe Invasive drug delivery to the brain by Convectiton-Enhanced Delivery (CED)

A
  • Continuous positive-pressure infusion of a solute containing therapeutic agent (pump and catheter)
  • Advantages of CED
    : bypasses BBB
    : targeted to diseased region
    : can be monitored in real-time (with contrast agent)
    : better penetration than diffusion-based delivery
    : lower dose, reduced toxicity
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11
Q

Describe Invasive drug delivery to the brain by Disruption of the BBB

A

Biochemical disruption
- Some vasoactive molecules, such as leukotrienes, histamine and bradykynin, can selectively increase permeability of abnormal brain capillaries

  • The enzymatic barrier present in normal BBB endothelium is reduced or missing in diseased areas of the brain
  • Selectively increases BBB permeability of abnormal brain capillaries, not healthy ones
  • Less invasive and more selective than hyperosmotic infusion
  • Delivery window lasts about 15 mins

Physical disruption

  • Protein drugs are big
  • These do not normally penetrate BBB
  • BBB can be pertubed temporarily by FUS (Focused ultrasound)
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12
Q

Describe Bypassing the BBB (Alternative routes)

A
  • Olfactory epithelium is about ~4cm^2
  • Effectively an area where the BBB is not present
  • Drugs can enter the brain directly via paracellular diffusion or axonal transport through olfactory nerves, e.g dopamine and cocaine
  • Offers a promising future route for peptide delivery to the CNS
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13
Q

What is Buprenorphine?

A
  • opioid used to treat opioid addiction, acute pain, and chronic pain
  • It can be used under the tongue, by injection, as a skin patch or as an implant
  • mu partial agonist, kappa & delta antagonist
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14
Q

Why do we have limited range of treatment options for depression?

A
  • limited understanding of the precise neurobiological mechanisms associated with depression
  • most development of therapeutic drugs is based on the ‘monoamine hypothesis’ which suggests that decreased concentration of monoamine neurotransmitters plays a role in MDD
  • In reality we know its complex in nature, heterogenous and associated with other comorbid psychiatric disorders
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15
Q

Describe the role of the kappa opioid system regarding antidepression

A
  • Activation of CREB (Cyclic AMP Responsiv-Element-Binding protein) by stress mediates the induction of dynorphine (kappa agonist), which then contributes to anhedonia-like symptoms.
  • CREB is activated by D1 dopamine receptor or by Ca2+ or tyrosine receptor kinase B
  • antagonists of kappa receptors might block the consequences of CREB-induced increases in dynorphine activity and exert antidepressant effects in some individuals
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16
Q

SUMMARY of Antidepressants JUST READ

A
  • Depression is a complex and heterogeneous disorder
  • No easy tests for the ‘type’ of depression somebody has
  • Animal models have their limitations, but are crucial for this research area
  • Kappa opioid antagonist: lots of preclinical evidence of efficacy and some limited clinical evidence
  • The message-address concept allows for the rationale design of selective kappa antagonists
17
Q

Why does non-linearity occur?

A

A) most freuqently

  1. Many ADME processes involve enzymes and carriers mediated systems, and plasma/tissue binding
    - Proteins have a fixed number of binding sites
    - These processes can be saturated and are described by Michaelis-Menten kinetics
  2. In most cases, saturation of enzymes and transporters occurs at concentrations much higher than those in the therapeutic range
    - In this case, we will observe linear (first order) kinetics

But,

  1. For somedrugs saturation occurs at therapeutic levels
    - this results in non-linear pharmacokinetics

B. There are other reasons for non-linearities e.g solubility

18
Q

Describe the Linear Michaelis-Menten kinetics equation

A

Rate of metabolism = Vmax x C / K.m + C

Rate of metabolism = Cl x C

19
Q

How do you recognise linear or first-order PK?

A
  1. PK parameters Cl, V, F of a drug are constant
    - with administration of different doses in the same individuals
    - during continuous or repeated administration
  2. AUC is proportional to the dose
    - i.e double the dose, double the AUC
    - AUC = F x Dose / Cl
  3. Plasma concentrations are proportional to the dose given
    - IV bolus
    - IV infusion
    - Extravascular
    - Multiple doses
20
Q

Describe Non-linear kinetics

A
  1. Dose-dependent kinetics
    - One or more pharmacokinetics parameters
    - F, Kabs, V, Cl.r, Cl.h, t1/2, k
    - Change with administration of different doses to the same individual
  2. Time-dependent kinetics
    - One or more pharmacokinetics
    - F, Kabs, V, Cl.r, Cl.h, t1/2, k
    - change with continuous or repeated administration in the same individual
21
Q

Why is Phenytoin a difficult drug?

A
  1. Narrow therapeutic window: 10-20 mg/L and poor correlation between dose and Cp
  2. Loss of C and AUC proportionality with respect to dose
  3. Small changes in dosage cause a large, disproportionate difference in Cp
  4. Difficult dose adjustments
  5. ‘Do not switch brands’ advice
  6. Need for therapeutic monitoring
22
Q

Describe the relation between Opioid antagonists and obesity

A
  • The mu, kappa, delta receptors are localised in brain regions mediating food intake and reward
  • Mu knockout mice display reduced motivation to eat and are resistant to diet-induced obesity. In addition, elevated Mu levels are observed in diet-induced obese
  • Opioid receptor antagonists/inverse agonists appear to modulate the incentive value of palatable food and satiety, and, therefore these agents may behave differently than anorectic agents such as phentermine
23
Q

What is Bupropion and its therapeutic use?

A
  • dopamine and norepinephrine reuptake inhibitor with antidepressant effects and used for smoking cessation in the UK
  • Therefore acts to stimulate pro-opiomelanocortin (POMC) neurones
    = anorexigenic output and weight loss
  • but this may lead to compensatory autuinhibitory feedback by endogenous opioids which may explain the modest, limited weight loss
24
Q

Define Pain

A
  • An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
25
Q

Describe Acute pain and Chronic pain

A 
Acute pain
- Sharp and defined onset
- Short duration
- Predominantly nociception mediated
- Inflammatory
- Protective
- Improves with healing
- Responds well to analgesia
Examples: Labour pain, Trauma, Post-operative

Chronic pain
- Persists beyond the time of expected healing
- Dysfunctional
- Serves no function
- Over-protective
- Difficult to treat
Examples: persistant post-surgical pain, neuropathic pain, complex regional pain syndrome

26
Q

What is the impact of persisting pain?

A
  • Sleep problems
  • Loss of fitness
  • Money worries
  • Medication side-effects
  • Feeling low
  • stress, fear, anger, shame
  • grief and loss
  • relationship worries
  • loss of employment
  • social isolation

Year 3 Sem 1 COPY COPY (7 decks)

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