Drug Distribution L3

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  • Created by: Stephanie
  • Created on: 13-04-14 14:21
What is distribution?
The movement of a drug from systemic circ to cells and interstitium of tissues.
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Can hydrophilic and large drugs cross the p.memb?
No. Exposed drug targets.
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What does neostigmine target?
Acetylcholine esterase. Prolongs action of acetylcholine. Treats myasthenia gravis where some acetylcholine receptors destroyed.
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What type of drug is simvastatin and what is it's target?
Lipophilic. Can cross memb so intracellular target.Blocks action of HMG CoA reductase which is needed to make cholesterol
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What does the penetration of a drug into a cell depend on?
Size, lipid solubility, degree of ionization (highly ionized can't cross memb)
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What factors affect distribution?
Blood flow (perfusion) and permeability of blood-tissue boundary.
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What does distribution of lipophilic drugs depend on?
can cross ALL blood tissue boundaries. Depends ONLY on perfusion rate to tissue.EXTENSIVE distribution
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Hydrophilic and large drugs have limited distribution. Why?
Distrib is rate limited by permeability of blood-tissue boundary.
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Which tissues have a high perfusion rate and which have a slow?
FAST: liver, brain, heart, lungs, kidney. SLOW: fat, skin, bone
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What is redistribution?
Transfer of a drug from the brain back into blood then peripheral organs.
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Describe the redistribution of I.V anaesthestic(temp loss of sensation)
Liposoluble. Penetrates brain quickly. Quick onset. Short duration of action. Time-dependent redistribution into fat causes depletion in brain.
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Porous capillaries allow?
Paracellular diffusion. Drugs enter ECM then dissolve in interstitial fluid.
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Why must drugs be lipophilic to diffuse into the brain?
Unlike the capillary cells (endothelial) in most tissues, those in the brain have tight junctions and do not allow paracellular diffusion. Thus, drugs must be lipid soluble and take the transcellular route to diffuse quickly into the brain.
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What does P-Glycoprotein (transporter) do?
On the luminal surface (facing into the lumen of the capillary). Uses ATP to pump some drugs out of the endothelial cell so limits entry into the CNS and controls the permeability of the blood-brain barrier.
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How does L-Dopa get into the CNS?
By the L-system which transports large neutral amino acids into the CNS. The “pro-drug” L-DOPA can cross the blood-brain barrier and is then converted into dopamine by DOPA decarboxylase
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“DOPA decarboxylase” also converts L-DOPA into dopamine in the periphery, hence reducing the amount of L-DOPA available to cross the BBB. What can be done to solve this?
Carbidopa is also administered. It blocks DOPA decarboxylase. It can't cross BBB so increases peripheral L-DOPA levels and does not inhibit dopamine conversion in the brain.
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Why would you want a drug not to enter the CNS?
“tweaking” of a drug’s properties to make it less likely to enter the BBB is useful for peripheral acting drugs that have adverse effects in the CNS (e.g. causing sleep disturbances).
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What is the function of the placenta?
Separates foetal and maternal blood. Placental membrane controls exchange of substances between these. Lipophilic can cross the membrane. Acts as a “metabolic barrier”.P-glycoprotein pumps molecules back into the mother’s blood..
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Describe other other membrane barriers that can cause problems for drug distribution
BLOOD-TESTIS BARRIER. The blood capillaries in the testis have tight junctions and P-glycoprotein. SOLID TUMOURS. Malignant cells in centre are poorly perfused so limits diffusion of anticancer drugs. P-glycoprotein.
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Name 2 binding proteins in the blood?
Albumin. alpha-1 acid glycoprotein
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Why can't bound drugs be active?
Drug bound to plasma protein is restricted to plasma because the high molecular mass prevents diffusion across cell membranes
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Why does binding to plasma proteins lead to drug-drug interactions?
Because drugs compete for binding sites.
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Give an example of a drug-drug interaction
Aspirin displaces warfarin from its binding sites on albumin. Warfarin is an anticoagulant so prevents blood clots. Asprinin increases the unbound concentration of warfarin so enhances its pharmacological effect. May lead to haemorrhage.
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Unbound drugs are inactive. True or false?
False. Only the unbound form is avaliable for diffusion into tissues and pharmacological action. Unbound conc determines rate of difffusion into the tissue.
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Many drugs bind reversibly to proteins within tissue. What does this lead to?
Accumulation is a tissue/tissues
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Give an example of a drug that binds to proteins within tissue.
Griseofulvin (antifungal) which binds strongly to the protein keratin found in hair, nails and skin. Accumulates in outer layer of skin stratum corneum
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What is a sequestered drug?
A sequestered drug is one that accumulates to a concentration HIGHER than in blood or plasma.
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Dissolution in adipose tissue (partition). Give an example of a drug.
Thiopental.Readily dissolves and accumulate in adipose (fat) tissue. Concentration in higher than that in blood.
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How is distribution influenced by active transport?
Accumulation by active transport of drug into a tissue. eg. Transport of L-DOPA into the brain, then in neurones it is converted into the neurotransmitters noradrenaline (norepinephrine) and dopamine
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Where are large drugs distributed?
In plasma water as cannot get out of capillaries. eg Heparin
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Where are polar drugs such as gentamicin(antibiotic) distributed?
Distributed only in the extracellular fluid as they cannot enter cells
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Lipid soluble drugs (e.g. ethanol) can distribute into total body water. True or false?
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Card 2


Can hydrophilic and large drugs cross the p.memb?


No. Exposed drug targets.

Card 3


What does neostigmine target?


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Card 4


What type of drug is simvastatin and what is it's target?


Preview of the front of card 4

Card 5


What does the penetration of a drug into a cell depend on?


Preview of the front of card 5
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