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Cell Physiology And Pharmacology🌟 > SESSION 7 > Flashcards

SESSION 7 Flashcards

1
Q

Define pharmacokinetics

A

The branch of pharmacology concerned with the movement of drugs within the body

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2
Q

What are the four main processes in drug therapy

A

Absorption
Distribution
Metabolism
Elimination

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3
Q

Define the different types of drug administration

A

Enteral- delivery into internal environment of the body- GI tract

  • oral
  • sublingual
  • rectal

Parenteral- delivery via all other routes that are not the GI

  • intravenous
  • subcutaneous
  • intramuscular
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4
Q

Describe drug absorption

A
  • oral route is most common
  • normally little absorption in the stomach
  • drug mixes with chyme and enters the small intestine
  • constant GI movement- presenting drug molecules to GI epithelia

Drug absorption in small intestine:

  • typical transit time: 3-5 hours
  • varying motility time: 1-10hours
  • weakly acidic pH: 6-7
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5
Q

Describe drug absorption on a molecular level with reference to passive diffusion

A

Passive diffusion I

  • common mechanism for lipophilic drugs weak acids/ bases
  • e.g. Steroids diffuse directly down concentration gradient into GI capillaries

Passive diffusion II

  • weak acid/ bases (pKa- 50% ionised) protonated/ deprotonated species can diffuse
  • lipophilic species crosses GI epithelia
  • over transit time 4-5 hours, and very large GI SA valporate diffuse into GI capillary bed
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6
Q

Describe drug absorption on a molecular level with reference to facilitated diffusion

A
  • molecules with net ionic + or - charge within GI pH rang can be carried across GI epithelia
  • passive process based on electrochemical gradient for that solute molecule

SLCs are either OATs and OCTs

  • large family- expressed in all body tissue
  • pharmacokinetically important for drug absorption and elimination
  • highly expressed in GI, hepatic and renal epithelial
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7
Q

Describe drug absorption on a molecular level with reference to secondary active transport

A

not utilise ATP- transport driven by pre- existing electrochemical gradient across GI epithelial membranes, e.g. Renal OATS and OCTS

Example:

  • fluoxetine- SSRI antidepressant co- transported with Na+
  • penicillin co- transported with H+ ion
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8
Q

State the factors that affect drug absorption

A

Physiochemical factors:

  • GI length/ SA
  • drug lipophilicity/ pKa
  • density of SLC (solute carrier) expression in GI

GI physiology

  • blood flow- increase post meal- drastically reduce shock
  • GI mobility- low post meal- rapid with severe diarrhoea
  • food/ pH- low pH destroys some drugs

First pass metabolism by GI and liver

  • gut lumen: bacterial enzymes can denature come drugs
  • gut wall: metabolism by two major enzyme groups:
    - phase I enzymes: P450S
    - phase II enzyme: conjugating
  • larger expression of both enzymes in liver
  • first pass metabolism: reduces availability of drug reaching systemic circulation
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9
Q

Define bioavailability

A

The fraction of an administered dose of unchanged drug that reaches the systemic circulation
When a medication is administered intravenously, its bioavailability is 100%
Most common comparison oral

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10
Q

How do you measure bioavailability ?

A

Amount reaching systemic circulation/
Total drug given IV

F= between 1 and 0
Informs choice of administration route

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11
Q

What is the first stage of drug distribution?

A
  • bulk flow- large distance via arteries and capillaries
  • diffusion- capillaries to interstitial fluid to cell membrane to targets
  • barriers to diffusion- interactions/ local permeability non- target binding
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12
Q

Explain the use of differing levels of capillary permeability

A

Enables variation in entry by charged drugs into tissue interstitial fluid

  • continuous
  • fenestrated
  • sinusoid - intracellular gaps
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13
Q

What major factors affect drug distribution?

A

Drug molecules lipophilicity:
- if the drug is largely lipophilic it can freely move across membrane barriers
- if largely hydrophilic, journey across membrane is dependent on factors
- capillary permeability
- drug pKa and local pH
Presence of OATS/ OCTS

Degree of drug binding to plasma/ tissue proteins:

  • only. Free molecule can bind to target site
  • binding in plasma/ tissue decreased free drug available for binding
  • plasma/ tissue protein bound drug act as ‘reservoir’
  • binding forces not strong- bound/ unbound in equilibrium
  • binding can be up to 100%
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14
Q

Define the 3 main body fluid compartments

A

Plasma water - plasma water - 3 l

Extracellular water - plasma water + interstitial water - 14 l

Total body water- plasma water + interstitial water + intracellular water - 42 l

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15
Q

Define apparent drug distribution

A
  • provides summary measure of drug molecule behaviour in distribution
  • referenced to plasma concentration
  • summarises movement out of plasma –> interstitial –> intracellular compartments
  • smaller Vd values- less penetration of interstitial fluid
  • larger Vd allies- greater penetration of interstitial fluid compartment

Vd= total amount of drug in the body/
Drug blood plasma concentration

Vd unit: litres (assume standard 70kg or litres/kg with reference to weight

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16
Q

Define drug elimination

A
  • metabolic and excretory process
  • both processes optimise drug removal
  • elimination removes both exogenous and endogenous molecular species
  • evolutionary advantage in recognising xenobiotics- potential toxins
  • protective and homeostatic function
17
Q

Describe hepatic drug metabolism: phase I and II

A

Takes place in the liver via phase I and II enzymes
Enzymes expressed throughout body tissues
Very large hepatic reserve

18
Q

What do phase I and II enzymes do?

A

Metabolise drugs- increase ionic charge enhance renal elimination
Lipophilic drugs diffuse out renal tubules back into palms

Drugs usually inactivated after metabolism

19
Q

Describe how phase I metabolism is carried out by cytochrome P450 enzymes

A

Metabolism.a very wise range of molecules
Metabolism drugs have increased ionic charge
Metabolised drug eliminated directly and go to phase II

20
Q

Describe how phase I metabolism can activate prodrugs

A

Pro-drugs activated by phase I metabolism to active species
E.g. Codeine to morphine
0-15% of codeine metabolised by CYP2D6 to morphine
Morphine x200 codeine affinity for opioid u- Receptor

21
Q

Describe how phase II metabolism is carried out by hepatic enzymes

A

Mainly cytosolic enzymes
Generalists but exhibit more rapid kinetics than CYP450s
Enhance hydrophilicity by further increasing ionic charge
Enhanced renal elimination
Metabolised drugs increased ionic charge

22
Q

Define cytochrome P240 enzymes

A

Cytochrome P450 enzymes include 3 super families:

  • three super families CYP 1,2,3
  • 6 isozymes metabolise 90% of prescription drugs
  • each isozymes optimally metabolise specific drugs

Isoenzyme- each of two or more enzymes with identical function but different structure

23
Q

What factors affect drug metabolism?

A

Many factors of direct clinical relevance:

  • age
  • sex
  • gender heath/ dietary/ disease
24
Q

Describe CYP450S induction

A

Other drugs can induce specific CYP450S isoenzymes by the mechanisms of:

  • transcription
  • increased translation
  • slower degradation

If another drug in the body is metabolised by induced CYP450S isoenzyme then its rate of elimination will be increased:

  • plasma levels of the drug will fall
  • this may have serious therapeutic consequences if levels drop significantly
  • occurs over a few weeks
25
Q

Give an example of CYP450 induction

A

Carbamazepine (CBZ):

  • CBZ is an anti- epileptic drug
  • primarily metabolised by CYP3A4
  • CBZ induces CYP3A4 lowering its ow levels affecting the control of epilepsy
  • careful monitoring of the prescription drug
26
Q

Describe CYP450 inhibition

A

certain drugs inhibit CYP450 isoenzymes
inhibition mechanism:
- competitive/ non- competitive inhibition

If another drug in the body is metabolised by inhibited CYP450 isoenzyme then its rate of elimination is slowed:

  • plasma levels of drug will then increase
  • serious side effects if levels rise significantly
  • occurs over a few days
27
Q

Give an example of CYP450 inhibition

A

Grapefruit juice:

  • grapefruit juice inhibits CYP3A4
  • CYP3A4 metabolises verapil which is used to treat high blood pressie
  • consequence can be much reduced blood pressure and fainting
28
Q

Give an example of how genetic variation affect cytochrome 450 isoenzymes

A

Genetic variants of CYP2D6- converts codeine to morphine
Poor- may not convert codeine to morphine so don’t experience pain relief
Ultra- rapid: lead to morphine intoxification

29
Q

State the routes of drug elimination

A
  • kidney- main route
  • bile
  • lungs
  • breast milk
  • sweat
  • tears
  • saliva
  • genital secretions
30
Q

Describe the route of renal excretion

A

Glomerular filtration

  • glomerulus- 20% renal blood flow
  • unbound drug enter via bowmans capsule

Proximal tubular secretion

  • 80% blood via peritubular capillaries
  • high expression of OATs and OCTs
  • carry ionised molecules
  • rapidly pull them in and then kick them out (phase I and II metabolism)
  • facilitated diffusion/ secondary active transport

Proximal tubular secretion:

  • along tubule length water reabsorbed
  • in tubule salutes increase in concentration
  • If they are lipophilic they pass back into the blood
  • if pH is pKa favourable then there is neutralisation of species and they are reabsorbed back into the blood

Distal tubular reabsorption- examples:
OATs: urate (gout), penicillin
OCTs: morphine, histamine
Transport is subject to competition- if the patient is taking more than one drug they may interact with each other affecting each drug half life

31
Q

Define clearance

A

Clearance is the rate of elimination of a drug from the body
Total body clearance =
hepatic clearance + renal clearance

  • CL is measured in ml/mm
  • Vd- apparent volume of distribution
  • real blood plasma volume is 3 litres
  • real volume of plasma cannot be completely cleared of drug via glomerular filtration/ tubular secretion
32
Q

What is the relevant of clearance?

A

Clearance predicts how long a drug will stay in the body

Together CL and Vd proved an estimate of drug half- life

33
Q

Define drug heals- life

A

The amount of time over high the concentration of a drug in plasma decreases to one half of that concentration value it had when it was first measured

Drug half- life is dependent on Vd and CL

34
Q

What is the drug half- life equation?

A

T1/2 = 0.693 x Vd/CL

If CL (clearance) stays the same and Vd (volume of distribution) increases then t1/2 also increases

If CL increases and Vd stays the same then t1/2 decreases

35
Q

Why are linear elimination kinetics linear?

A

The rate of metabolism/ excretion is proportional to concentration of drug

Conditions are:

  • plenty of phase I/ II enzyme sites
  • plenty of OAT/ OCT transporters

The rate of metabolism will be proportional to the number of molecules occupying a catalytic site per unit of time

36
Q

What happens when elimination processes become saturated?

A

When processes are saturated they become rate limited
They cannot go any faster- saturated
When this happens the elimination kinetics are referred to as saturate zero order

37
Q

What is the clinical importance of zero order kinetics?

A

Drugs near therapeutic dose with saturation kinetics are more likely to result in adverse drug reaction

Relative small dose changes can:

  • produce large increments in plasma
  • lead to serious toxicity

Half- life is not calculable so cannot easily predict drug regime

38
Q

Explain drug monitoring

A

Relatively few drugs in adults have zero kinetics at therapeutic does
Problem in elderly and infants with decreased/ immature capacity
Problem in seriously ill patrons - liver disease
As there is reduced hepatic renal capacity so easier to saturate

Examples:

  • prozac which is anti depressant
  • 20 tablets of paracetamol skulls in salutation of both phase I and II metabolism - fatal

Cell Physiology And Pharmacology🌟 (8 decks)

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