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PHARMACOLOGY. Dr Chris Bax London Metropolitan University Dept. Health & Human Sciences [email protected] Learning Objectives:. Learning Objectives: Pharmacological principles and processes. Learning Objectives: Pharmacological principles and processes

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Dr chris bax london metropolitan university dept health human sciences c bax@londonmet ac uk

PHARMACOLOGY

Dr Chris Bax

London Metropolitan University

Dept. Health & Human Sciences

[email protected]nmet.ac.uk




  • Learning Objectives:

  • Pharmacological principles and processes

  • Drug bioavailability – how do we ensure that a drug is “available”? E.G: will it be absorbed from the gut?

  • Pharmacokinetics – what the body does to the drug.

    A D M E


  • Learning Objectives:

  • Pharmacological principles and processes

  • Drug bioavailability – how do we ensure that a drug is “available”? E.G: will it be absorbed from the gut?

  • Pharmacokinetics – what the body does to the drug.

    A D M E


  • Learning Objectives:

  • Pharmacological principles and processes

  • Drug bioavailability – how do we ensure that a drug is “available”? E.G: will it be absorbed from the gut?

  • Pharmacokinetics – what the body does to the drug:

    A D M E







Recommended books
Recommended Books receptor level; drug receptor interactions)

  • Pharmacology – Rang, Dale Ritter & Flower, 2007. Churchill Livingstone.


Pharmacology receptor level; drug receptor interactions)

  • – the science of drugs


Pharmacology receptor level; drug receptor interactions)

  • – the science of drugs

  • - the interaction of drugs with living tissues


Routes of drug administration: receptor level; drug receptor interactions)

1. Oral


Routes of drug administration: receptor level; drug receptor interactions)

1. Oral

  • Advantages: convenient


Routes of drug administration: receptor level; drug receptor interactions)

1. Oral

  • Advantages: convenient

  • Disadvantages: absorption


Routes of drug administration: receptor level; drug receptor interactions)

1. Oral

  • Advantages: convenient

  • Disadvantages: absorption

    digestion


Routes of drug administration: receptor level; drug receptor interactions)

1. Oral

  • Advantages: convenient

  • Disadvantages: absorption

    digestion

    compliance


Routes of drug administration: receptor level; drug receptor interactions)

1. Oral

  • Advantages: convenient

  • Disadvantages: absorption

    digestion

    compliance

    1st pass effect


2. Sublingual receptor level; drug receptor interactions)


2. Sublingual receptor level; drug receptor interactions)

  • rapid effect


3. Cutaneous - local receptor level; drug receptor interactions)

- systemic


3. Cutaneous - local receptor level; drug receptor interactions)

- systemic

Steady rate of absorption


3. Cutaneous - local receptor level; drug receptor interactions)

- systemic

Steady rate of absorption

Avoids 1st pass effect


4. Intravenous - bolus receptor level; drug receptor interactions)

- steady infusion


4. Intravenous - bolus receptor level; drug receptor interactions)

- steady infusion

- Rapid


4. Intravenous - bolus receptor level; drug receptor interactions)

- steady infusion

- Rapid

- Avoids problems of absorption


4. Intravenous - bolus receptor level; drug receptor interactions)

- steady infusion

- Rapid

- Avoids problems of absorption

  • requires clinical expertise


4. Intravenous - bolus receptor level; drug receptor interactions)

- steady infusion

- Rapid

- Avoids problems of absorption

  • requires clinical expertise

  • E.G. anaesthetics, chemotherapeutic agents


5. Nasal receptor level; drug receptor interactions)


5. Nasal receptor level; drug receptor interactions)

Convenient

Rapid effect


5. Nasal receptor level; drug receptor interactions)

Convenient

Rapid effect

E.G: ADH, GnRH, calcitonin





7. Rectal. For patients who are: vomiting excessively; in receptor level; drug receptor interactions)status epilepticus; unconscious.


8. Others….. receptor level; drug receptor interactions)

Eye drops

Intramuscular

Intraperitoneal


  • A receptor level; drug receptor interactions) D M E

  • Absorption:


  • A D M E receptor level; drug receptor interactions)

  • Absorption:

    Stomach plasma tissues



  • Most important factor = receptor level; drug receptor interactions)lipid solubility

  • The best absorbed drugs are lipid soluble (hydrophobic; lipophilic),


  • Most important factor = receptor level; drug receptor interactions)lipid solubility

  • The best absorbed drugs are lipid soluble (hydrophobic; lipophilic),

  • …and are not electrically charged.


  • Most important factor = receptor level; drug receptor interactions)lipid solubility

  • The best absorbed drugs are lipid soluble (hydrophobic; lipophilic),

  • …and are not electrically charged.

  • WHY?




  • A simple example…. receptor level; drug receptor interactions)

  • A weak acid such as acetyl salicylic acid HA likes to give away its H (this is the definition of an acid)


HA H+ + A- receptor level; drug receptor interactions)

weak hydrogen base

acid ion


HA H+ + A- receptor level; drug receptor interactions)

weak hydrogen base

acid ion

Acetyl salicylic H+ ion Acetyl Salicylate

acid


HA H receptor level; drug receptor interactions)+ + A-

weak hydrogen base

acid ion

Acetyl salicylic H+ ion Acetyl salicylate

acid

Uncharged(charged) charged


  • HA H+ + A- receptor level; drug receptor interactions)

    weak hydrogen base

    acid ion

    Uncharged (charged) charged

  • In an acid environment (e.g. the stomach) the uncharged form will predominate.


  • HA H+ + A- receptor level; drug receptor interactions)

    weak hydrogen base

    acid ion

    Uncharged (charged) charged

  • In an acid environment (e.g. the stomach) the uncharged form will predominate.

  • In a more alkaline environment (e.g. the small intestine) there will be more of the charged form.


A receptor level; drug receptor interactions)DME


A receptor level; drug receptor interactions)DME

  • Acidic drugs are best absorbed in an acid environment (e.g. the stomach).

    • E.g aspirin, phenytoin.


  • Alkaline receptor level; drug receptor interactions) (or “basic”) drugs are best absorbed from a more alkaline environment (e.g. the small intestine).


  • Alkaline receptor level; drug receptor interactions) (or “basic”) drugs are best absorbed from a more alkaline environment (e.g. the small intestine).

    • E.g. chloroquine, amphetamine.




  • Some other factors affecting drug absorption: receptor level; drug receptor interactions)

    • Food will ↓ [drug], ↓ gastric emptying, so will induce variability into absorption.

    • can be preferable to take drugs on an empty stomach








  • How do drugs enter / exit cells? receptor level; drug receptor interactions)

  • Usually by diffusion.

  • Occasionally drugs can be transported

    • E.g. extrusion of anti-cancer drug molecules from cells by p-glycoprotein


  • How do drugs enter / exit cells? receptor level; drug receptor interactions)

  • Usually by diffusion.

  • Occasionally drugs can be transported

    • E.g. extrusion of anti-cancer drug molecules from cells by p-glycoprotein

    • P-glycoprotein is coded for by themdr (multidrug resistance gene).


A d me
A receptor level; drug receptor interactions)DME

  • Distribution.


  • Main compartments: receptor level; drug receptor interactions)

  • Plasma (5% of body weight)


  • Main compartments: receptor level; drug receptor interactions)

  • Plasma (5% of body weight)

  • Interstitial fluid (16%)


  • Main compartments: receptor level; drug receptor interactions)

  • Plasma (5% of body weight)

  • Interstitial fluid (16%)

  • Intracellular fluid (35%)


  • Main compartments: receptor level; drug receptor interactions)

  • Plasma (5% of body weight)

  • Interstitial fluid (16%)

  • Intracellular fluid (35%)

  • Fat (20%)


  • Also: Specific organs / systems: receptor level; drug receptor interactions)

  • Liver and kidney

  • These organs are key organs in the metabolism and excretion of drugs respectively. Therefore they have a high capacity to concentrate drugs


  • Also: Specific organs / systems: receptor level; drug receptor interactions)

  • Liver and kidney

  • These organs are key organs in the metabolism and excretion of drugs respectively. Therefore they have a high capacity to concentrate drugs

  • - Muscle, bones, CNS.


Factors Affecting Drug Distribution: receptor level; drug receptor interactions)

  • Plasma protein binding


Factors Affecting Drug Distribution: receptor level; drug receptor interactions)

  • Plasma protein binding:

    a) bioavailability

    Drug Plasma Body tissues


Drug Drug-protein receptor level; drug receptor interactions)

+ Plasma protein complex

Body tissues




Factors Affecting Drug Distribution: receptor level; drug receptor interactions)

  • Plasma protein binding:

    b) bioactivity

    Ideally:

Receptor

Drug molecule


Activated receptor receptor level; drug receptor interactions)

Receptor

Drug molecule


Activated receptor receptor level; drug receptor interactions)

Receptor

Drug molecule

Response


….but if the drug molecule is protein-bound, then it receptor level; drug receptor interactions)cannot bind to the receptor.


Only the free form of the drug is biologically active receptor level; drug receptor interactions)


Only the free form of the drug is biologically active receptor level; drug receptor interactions)

  • protein-bound drug is too large to penetrate endothelium, so stays in circulation


Only the free form of the drug is biologically active receptor level; drug receptor interactions)

  • protein-bound drug is too large to penetrate endothelium, so stays in circulation

  • Protein-bound drug cannot bind to receptors.






  • Displacement the fraction of unbound drug:from binding site by other drugs

    • E.g aspirin, sodium valproate, sulphonamides.


  • Example: the fraction of unbound drug:

    A NIDDM patient on tolbutamide is given sulphonamide antibiotics for an infected leg ulcer; the patient later collapses in a coma - why?



  • Because the sulphonamides the fraction of unbound drug:displace the tolbutamide from plasma albumin.

  • This leads to increased plasma concentrations of free tolbutamide, causing the patient to go into a hypoglycaemic coma.


  • Drugs can the fraction of unbound drug:compete for binding sites on the plasma proteins…


Drugs can the fraction of unbound drug:compete for binding sites on the plasma proteins…

…with the result that Drug A can displace

Drug B,  increased concentrations of

free Drug B.






  • After this need be displaced to displacement by Z:

    96% 4%

    protein-bound free Drug X

    Drug X


  • After this need be displaced to displacement by Z:

    96% 4%

    protein-bound free Drug X

    Drug X =Doubled!


Factors Affecting Drug Distribution (cont’d) this need be displaced to

  • Regional blood flow to an area of the body

    • Reduced blood flow to peripheries e.g. diabetics

    • Enhanced blood flow to well perfused organs e.g. liver, heart


  • Lipid solubility of the drug this need be displaced to

    • Affects ability to cross membranes such as:

    • blood/brain barrier e.g. gentamicin only penetrates inflamed meninges


  • Lipid solubility of the drug this need be displaced to

    • Affects ability to cross membranes such as:

    • blood/brain barrier e.g. gentamicin only penetrates inflamed meninges

    • GI tract e.g. vancomycin cannot be given orally except for infections of the GI tract as it is not absorbed


  • Lipid solubility of the drug this need be displaced to

    • Affects ability to cross membranes such as:

    • blood/brain barrier e.g. gentamicin only penetrates inflamed meninges

    • GI tract e.g. vancomycin cannot be given orally except for infections of the GI tract as it is not absorbed

    • Highly water soluble drugs such as gentamicin are mainly confined to body water


Factors Affecting Drug Distribution (cont’d) this need be displaced to

  • Disease

    • Liver disease can cause low plasma protein levels and affects protein binding


Factors Affecting Drug Distribution (cont’d) this need be displaced to

  • Disease

    • Liver disease can cause low plasma protein levels and affects protein binding

    • Renal disease causes high blood urea levels which also affect protein binding


  • The Blood Brain Barrier this need be displaced to

    Proposed by Ehrlich - intravenously injected dye did not enter the CNS


E.g. “large” drug molecules such as penicillin will not this need be displaced to  CNS

(unless some damage has occured to the BBB - eg during an infection).


  • Conversely – small this need be displaced to lipophilic molecules e.g. general anaesthetics can easily cross into the tissues.





  • Four key aspects of the BBB: this need be displaced to

  • Tight endothelial junctions in CNS capillaries – no pores between cells.

  • MDR transporter in endothelial cells


  • Four key aspects of the BBB: this need be displaced to

  • Tight endothelial junctions in CNS capillaries – no pores between cells.

  • MDR transporter in endothelial cells

  • Capillaries surrounded by glial cells (astrocytes); these constitute a lipid barrier


  • Four key aspects of the BBB: this need be displaced to

  • Tight endothelial junctions in CNS capillaries – no pores between cells.

  • MDR transporter in endothelial cells

  • Capillaries surrounded by glial cells (astrocytes); these constitute a lipid barrier

  • Low protein concentration in ECF


  • Other "barriers“ this need be displaced to

  • Many drugs can pass across the placenta into the fetal circulation, placing the embryo / fetus at risk;


  • Other "barriers“ this need be displaced to

  • Many drugs can pass across the placenta into the fetal circulation, placing the embryo / fetus at risk;

  • similarly so with drugs  breast milk during lactation.


  • Volume of Distribution this need be displaced to

  • The volume of distribution of a drug reflects the amount left in the blood plasma after the drug has been absorbed and distributed.


  • Volume of Distribution this need be displaced to

  • The volume of distribution of a drug reflects the amount left in the blood plasma after the drug has been absorbed and distributed.

  • Drugs are distributed unevenly between various body fluids and tissues according to their physical and chemical properties.


  • When a drug has a this need be displaced to LOW volume of distribution, this suggests it is confined mainly to the blood stream and body water.


  • When a drug has a this need be displaced to HIGH volume of distribution, this suggests it is distributed widely to the tissues.


Vd this need be displaced to = X

Cp


Vd this need be displaced to = X

Cp

Where:

X = total amount of drug in body

Cp = plasma concentration of drug


E.G. gentamicin has very good water solubility (= this need be displaced to hydrophilic) and is mainly confined to body water.

It therefore has a small volume of distribution.

For example:

Vd = X/Cp


E.G. gentamicin has very good water solubility (= this need be displaced to hydrophilic) and is mainly confined to body water.

It therefore has a small volume of distribution.

For example:

Vd = X/Cp

= 150mg = 3.75L

40mg/L



If very little drug remains in blood steam (e.g. a this need be displaced to lipophilic drug), it has a large volume of distribution.

For example:

Vd = X/Cp = 150mg = 30L

5mg/L


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