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

  • 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


  • Pharmacodynamics – what the drug does to the body (esp. at receptor level; drug receptor interactions)

  • Benefit:risk ratio – the therapeutic index.

  • Drug overdose and poisoning.

  • Drug dependence and abuse

  • An introduction to the pharmacology of the autonomic nervous system


  • Pharmacodynamics – what the drug does to the body (esp. at receptor level; drug receptor interactions)

  • the therapeutic index.

  • Drug overdose and poisoning.

  • Drug dependence and abuse

  • An introduction to the pharmacology of the autonomic nervous system


  • Pharmacodynamics – what the drug does to the body (esp. at receptor level; drug receptor interactions)

  • Benefit:risk ratio – the therapeutic index.

  • Drug overdose and poisoning.

  • Drug dependence and abuse

  • An introduction to the pharmacology of the autonomic nervous system


  • Pharmacodynamics – what the drug does to the body (esp. at receptor level; drug receptor interactions)

  • Benefit:risk ratio – the therapeutic index.

  • Drug overdose and poisoning.

  • Drug dependence and abuse

  • An introduction to the pharmacology of the autonomic nervous system


  • Pharmacodynamics – what the drug does to the body (esp. at receptor level; drug receptor interactions)

  • Benefit:risk ratio – the therapeutic index.

  • Drug overdose and poisoning.

  • Drug dependence and abuse

  • An introduction to the pharmacology of the autonomic nervous system


Recommended Books

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


Pharmacology

  • – the science of drugs


Pharmacology

  • – the science of drugs

  • - the interaction of drugs with living tissues


Routes of drug administration:

1.Oral


Routes of drug administration:

1.Oral

  • Advantages: convenient


Routes of drug administration:

1.Oral

  • Advantages: convenient

  • Disadvantages: absorption


Routes of drug administration:

1.Oral

  • Advantages: convenient

  • Disadvantages: absorption

    digestion


Routes of drug administration:

1.Oral

  • Advantages: convenient

  • Disadvantages: absorption

    digestion

    compliance


Routes of drug administration:

1.Oral

  • Advantages: convenient

  • Disadvantages: absorption

    digestion

    compliance

    1st pass effect


2.Sublingual


2.Sublingual

  • rapid effect


3.Cutaneous- local

-systemic


3.Cutaneous- local

-systemic

Steady rate of absorption


3.Cutaneous- local

-systemic

Steady rate of absorption

Avoids 1st pass effect


4. Intravenous-bolus

-steady infusion


4. Intravenous-bolus

-steady infusion

- Rapid


4. Intravenous-bolus

-steady infusion

- Rapid

- Avoids problems of absorption


4. Intravenous-bolus

-steady infusion

- Rapid

- Avoids problems of absorption

  • requires clinical expertise


4. Intravenous-bolus

-steady infusion

- Rapid

- Avoids problems of absorption

  • requires clinical expertise

  • E.G. anaesthetics, chemotherapeutic agents


5. Nasal


5. Nasal

Convenient

Rapid effect


5. Nasal

Convenient

Rapid effect

E.G: ADH, GnRH, calcitonin


  • Intrathecal - into the sub-arachnoid space.


  • Intrathecal - into the sub-arachnoid space.

    - Requires clinical expertise


  • Intrathecal - into the sub-arachnoid space.

    - Requires clinical expertise

  • E.G: anti-cancer drugs, local anaesthetics, antibiotics


7. Rectal. For patients who are: vomiting excessively; in status epilepticus; unconscious.


8. Others…..

Eye drops

Intramuscular

Intraperitoneal


  • A D M E

  • Absorption:


  • A D M E

  • Absorption:

    Stomach plasma tissues


  • Most important factor = lipid solubility


  • Most important factor = lipid solubility

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


  • Most important factor = lipid solubility

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

  • …and are not electrically charged.


  • Most important factor = lipid solubility

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

  • …and are not electrically charged.

  • WHY?


  • However, most drugs are not lipids; most are partly hydrophilic, and partly hydrophobic.


  • However, most drugs are not lipids; most are partly hydrophilic, and partly hydrophobic.

  • In addition, drugs are often not pH neutral, but are weak acids or weak alkalis.


  • A simple example….

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


HAH++A-

weak hydrogen base

acid ion


HAH++A-

weak hydrogen base

acid ion

Acetyl salicylic H+ ionAcetyl Salicylate

acid


HAH++A-

weak hydrogen base

acid ion

Acetyl salicylic H+ ionAcetyl salicylate

acid

Uncharged(charged)charged


  • HAH++A-

    weak hydrogen base

    acid ion

    Uncharged(charged)charged

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


  • HAH++A-

    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.


ADME


ADME

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

    • E.g aspirin, phenytoin.


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


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

    • E.g. chloroquine, amphetamine.


  • Some drugs are always charged so have to be given IV.

  • E.g. suxamethonium, tubocurarine


  • Some other factors affecting drug absorption:

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


  • Some other factors affecting drug absorption:

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

    • can be preferable to take drugs on an empty stomach


  • Some other factors affecting drug absorption:

    • Drugs: can decrease gastric emptying


  • Some other factors affecting drug absorption:

    • Drugs: can decrease gastric emptying

      e.g. atropine, amphetamine, morphine.


  • Some other factors affecting drug absorption:

    • Gut motility:

    • will  tablet dissolution,  blood flow.


  • Some other factors affecting drug absorption:

    • Gut motility:

    • will  tablet dissolution,  blood flow.

    • but excessive motility (eg diarrhoea) will hinder absorption.


  • How do drugs enter / exit cells?


  • How do drugs enter / exit cells?

  • Usually by diffusion.


  • How do drugs enter / exit cells?

  • 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?

  • 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).


ADME

  • Distribution.


  • Main compartments:

  • Plasma (5% of body weight)


  • Main compartments:

  • Plasma (5% of body weight)

  • Interstitial fluid (16%)


  • Main compartments:

  • Plasma (5% of body weight)

  • Interstitial fluid (16%)

  • Intracellular fluid (35%)


  • Main compartments:

  • Plasma (5% of body weight)

  • Interstitial fluid (16%)

  • Intracellular fluid (35%)

  • Fat (20%)


  • Also: Specific organs / systems:

  • 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:

  • 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:

  • Plasma protein binding


Factors Affecting Drug Distribution:

  • Plasma protein binding:

    a) bioavailability

    Drug Plasma Body tissues


Drug Drug-protein

+ Plasma protein complex

Body tissues


  • The major blood proteins are:

    globulins (a, b, g)


  • The major blood proteins are:

    globulins (a, b, g)

    and albumin


Factors Affecting Drug Distribution:

  • Plasma protein binding:

    b) bioactivity

    Ideally:

Receptor

Drug molecule


Activated receptor

Receptor

Drug molecule


Activated receptor

Receptor

Drug molecule

Response


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


Only the free form of the drug is biologically active


Only the free form of the drug is biologically active

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


Only the free form of the drug is biologically active

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

  • Protein-bound drug cannot bind to receptors.


  • Factors which can affect plasma protein binding and increase the fraction of unbound drug:


  • Factors which can affect plasma protein binding and increase the fraction of unbound drug:

  • Renal impairment causing a rise in plasma urea


  • Low plasma albumin levels (<20-25g/L)

    • E.g. chronic liver disease, malnutrition


  • Late pregnancy


  • Displacement from binding site by other drugs

    • E.g aspirin, sodium valproate, sulphonamides.


  • Example:

    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 displace the tolbutamide from plasma albumin.


  • Because the sulphonamides 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 compete for binding sites on the plasma proteins…


Drugs can compete for binding sites on the plasma proteins…

…with the result that Drug A can displace

Drug B,  increased concentrations of

free Drug B.


  • A similar situation occurs with the sulphonamide sulfisoxazole which can displace the haemoglobin metabolite bilirubin from plasma proteins.


  • A similar situation occurs with the sulphonamide sulfisoxazole which can displace the haemoglobin metabolite bilirubin from plasma proteins.

  • Bilirubin is toxic, particularly so to newborns who can develop kernicterus as a result.


  • Note that, if a drug is e.g. 98% protein bound, only 2% of this need be displaced to double the plasma concentration of free drug.


  • Note that, if a drug is e.g. 98% protein bound, only 2% of this need be displaced to double the plasma concentration of free drug.

    Thus for Drug X:

    Before displacement by Drug Z:

    98% 2%

    protein-bound free Drug X

    Drug X


  • After displacement by Z:

    96% 4%

    protein-boundfree Drug X

    Drug X


  • After displacement by Z:

    96% 4%

    protein-boundfree Drug X

    Drug X=Doubled!


Factors Affecting Drug Distribution (cont’d)

  • 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

    • Affects ability to cross membranes such as:

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


  • Lipid solubility of the drug

    • 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

    • 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)

  • Disease

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


Factors Affecting Drug Distribution (cont’d)

  • 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

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


E.g. “large” drug molecules such as penicillin will not  CNS

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


  • Conversely – small lipophilic molecules e.g. general anaesthetics can easily cross into the tissues.


  • Conversely – anaesthetics are usually small lipophilic molecules which can easily cross into the tissues.

  • Note: the BBB is not fully developed in neonates.


  • Four key aspects of the BBB:


  • Four key aspects of the BBB:

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


  • Four key aspects of the BBB:

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

  • MDR transporter in endothelial cells


  • Four key aspects of the BBB:

  • 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:

  • 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“

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


  • Other "barriers“

  • 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

  • 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

  • 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 LOW volume of distribution, this suggests it is confined mainly to the blood stream and body water.


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


Vd = X

Cp


Vd = X

Cp

Where:

X = total amount of drug in body

Cp = plasma concentration of drug


E.G. gentamicin has very good water solubility (=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 (=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 lipophilic drug), it has a large volume of distribution.


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

For example:

Vd= X/Cp=150mg=30L

5mg/L


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