Pharmacology

Pharmacokinetics

Objectives - understand

1. Pharmacokinetics and pharmacodynamics

2. Different routes of administration of

medications (advantages and disadvantages)

3. Terms: ‘First pass metabolism’, absorption,

bioavailability, drug distribution .

4. Drug interaction with proteins, drug

metabolism, elimination, half-life

What is pharmacology?

Includes:

1.Origins, chemical structure, preparation,

administration, actions, metabolism,

excretion

2.Therapeutics: application of action of drugs

and other measures in the treatment of

disease

Pharmacology • Pharmacology is the study of the action and use

of drugs

• Medical pharmacology is the science of chemicals (drugs) that interact with the human body

• Drugs are chemical substances which, by interacting with biological systems, are able to change them in some way, or:

• A substance, applied to a living system, with the intent of bringing about a change

Pharmacokinetics

• Refers to the processes concerned with the distribution of drugs in the body and their:

– Absorption

– Excretion

– Metabolism

• Therefore it is it is concerned with the way in which the concentration of a drug varies as per the site of its action and how this is affected by the of administration

Pharmacokinetics Drug at site of administration

Drug in blood

Drug in tissueMetabolismMetabolites in tissue

Drugs and/or metabolites inUrine/faeces/bile

Absorption

Elimination

PharmacokineticsAbsorption

Blood Stream

Protein bound

Distribution

Tissue BoundMetabolism

Metabolites Elimination

Route of administration

1. Oral

2. Sublingual

3. Rectal

4. Intravascular

5. Intramuscular

6. Subcutaneous

Oral • By mouth

– Common route of administration

• Complicated pathway

• Some of drug is absorbed:

– Stomach

– Duodenum

– Small intestine

• Via the small intestine, it goes via the hepatic portal vein to the liver before the systemic circulation

Oral

Liver

Rest of body

First pass metabolism

First pass metabolism • All drugs absorbed in the gut go via the liver

to reach the systemic circulation

– In the liver

• Some of the drug is metabolised

• Therefore not all reaches systemic circulation

• E.g. 90% of nitroglycerine is cleared in a single pass

through the liver

First pass metabolism

Sublingual route – under tongue

• Delivers the drug direct to the bloodstream

– Not via the liver and liver metabolism

• E.g. Glyceryl trinitrate

Rectal

• 50% of blood bypasses the portal circulation

and liver metabolism

• Avoids stomach and acids/enzymes in GIT

• Useful if the drug causes vomiting when taken

orally.

• E.g. Diazepam (antiepileptic drug)

Intravenous injectionAdvantages

• For days not absorbed

orally

• Avoids GIT; 1st pass

metabolism of liver

• Rapid effect

• Maximal degree of control

over circulating levels of

drugs

Disadvantages

• Drugs cannot be recalled

once injected

• Site of injection can be

infected with bacteria

• Adverse reaction because of

a too rapid delivery of high

concentration of drug to

blood and tissues (infusion

rate must be controlled)

Intramuscular injection

• Must be aqueous preparation or specialised

‘depot’ preparation (suspension in ethylene

glycol or peanut oil)

– Aqueous suspension

• Absorbed quickly

– Depot suspension

• Absorbed slowly

• E.g. Haloperidol – anti-schitzophrenic drug

Intramuscular injection

Subcutaneous injection

Advantage

• Minimises risk

• E.g. Heparin, insulin

Disadvantage

• Slower rate of absorption

compared with i.v.

Subcutaneous injection

Other routes of administration

• Inhalation

• Intranasal

• Topical (ointment/creams)

• Transdermal (patches)

• Intrathecal (into spinal canal)

Absorption of drugs• Drugs absorbed from gut by

– Diffusion (across GIT wall into blood)

– Active transport (via carrier proteins in plasma membrane; active process)

• pH (acid/alkaline environment) influences drug absorption

• Physical factors influencing absorption– Blood flow through the absorption site

– Total surface area available for drug absorption

– Contact time at absorption site (e.g. Poor absorption with diarrhoea)

– Presence of food in stomach• Dilutes drug

• Slows stomach emptying

Bioavailability

• Fraction of the administered drug that

reaches the systemic circulation

• E.g. If 100mg of drug is administered and

70mg of drug is absorbed unchanged:

• Bioavailability is 70%

Bioavailability

Bioavailability

Bioavailability – affecting factors• 1st pass metabolism

• Solubility of drugs– If hydrophilic: poorly absorbed because can’t cross

lipid bilayer of plasma membrane

– Highly hydrophobic: poorly absorbed because insoluble in aqueous body fluids

– Drugs need to be hydrophobic, but have some solubility in aqueous solution

• Chemical instability– Penicillin: unstable because of pH in stomach

– Insulin: may be destroyed by GIT enzymes – injected

• Nature of drug formulation

Drug distribution

• Drug distribution refers to the movement of

the drug to/from the blood and various

tissues of the body (e.g. Fat, muscle, brain)

and the relative proportion of the drug in the

tissues

• This depends on blood flow;

– Brain, liver, kidney>skeletal muscle>adipose tissue

– Capillary structure

– Drug structure(hydrophilic/phobic)

– Binding of drugs to blood plasma protein

Endothelial fenestrations

Blood brain barrier

Drugs and blood plasma proteins• Main influence of plasma proteins on drugs is in their distribution

• The most important plasma proteins are

– Albumin, acid-glycoprotein, β-globulin

• Once a drug is absorbed into the circulation, it can become protein-bound

• This plasma protein binding can be rapidly reversible and is non-specific

– Many drugs can bind to one protein

• But the plasma proteins are not the target tissue and drugs that are

bound to them cannot bring about a physiological effect, however:

• Drug/protein binding can form a reservoir of the drug

– Only free (unbound) drug is available to the tissues to exert a

therapeutic effect.

Effect of protein binding on drug action?

• If protein binding does occur, the behaviour of

the drug can be influenced:

1. Extensive protein binding reduced available free

(unbound) drug; therefore more drug has to be

administered to get therapeutic effect

2. Elimination of a highly bound drug may be

delayed

• If the free drug is low, the total drug

elimination/excretion is delayed

– E.g. This is the reason for the prolonged effect of digoxin

Effect of protein binding on drug action?

• 3 – Low plasma concentration may result

in old age

• Can get reduced plasma protein concentration

with liver disease (made there), or chronic

renal failure causing xs protein loss in urine

– Increased free drug; decreased bound drug

– Increased free drug; reduced drug dose needed

Effect of protein binding on drug action?

• 4 – different drugs can compete for the

binding sites on plasma proteins, leading to

interactions

– E.g. Warfarin (anticoagulant) is highly bound and

even a small change in binding will greatly effect

the amount of free drug

– Therefore if there is administration with (e.g.)

aspirin, the aspirin displaces the warfarin causing

an increase in free anticoagulant

Volume of distribution:

water compartments

Drug metabolism 1

• Metabolism is the enzymic conversion of one compound into another– Mostly occurs in the liver, but also in gut wall, lung

and blood plasma

• Generally, the metabolism of a drug converts in into a more water soluble compound with more polarity – This is important as it can only be excreted in urine an

bile

– Few drugs are excreted without being metabolised

• Generally, as drug is metabolised, its therapeutic effect decreases

Drug metabolism –2• Liver hepatocytes have all the necessary

enzymes for the metabolism of drugs

– Main enzyme involved in drug metabolism belong

to the cytochrome P450 group.

• These are a large family of related compounds housed

in the smooth endoplasmic reticulum of the cell

– Metabolism is often divided into phase 1 and

phase 2

• Some drugs just need to undergo either phase 1 or 2

• More often need phase 1, then phase 2

Drug metabolism 3• Phase 1 metabolism can be reduction or

hydrolysis of a drug, but is usually oxidation

• Oxidation is catalysed by cytochrome P450

– One electron removed

• Drug is now oxidised; but even after phase 1

metabolism it can still be chemically active

Drug metabolism pathways

Drug metabolism - 4• Phase 2 metabolism involves conjugation

– an ionised group is attached to the drug• Groups included glutathione, methyl or acetyl groups

– Usually occurs in hepatocyte cytoplasm

• The attachment of the ionised group makes the drug more water soluble– Facilitates excretion

– Decreases pharmacological activity

• E.g. Aspirin– Phase 1 undergoes hydrolysis to salicylic acid

– Phase 2 is conjugated with either glycine or glucuronic acid

• Forming a range of metabolites that can be excreted

Drug metabolism - 5• Some drugs are administered in inactive form, or prodrug,

e.g. Enalapril– It’s metabolite is pharmacologically active

• Enalaprilat – antihypertensive

• Some drug metabolites can be toxic– E.g. Those produced from paracetamol phase 1 metabolism

– These are detoxed by phase 2 conjugation with glutathione

• In overdose situations, where the dose of paracetamol is high, not enough glutathione is available to detox the metabolites– accumulates causing toxicity – hepatitis

– As a solution, compounds are administered to boost levels of glutathione so that phase 2 can take place; thus paracetamol is metabolised fully and reduces the risk of liver damage

Drug metabolism - 6• Affecting factors

– Age: reduced numbers of hepatocytes and

enzymic activity

– Diseases that reduce blood flow to liver (heart

failure/shock) reduce its metabolic activity

– Genetic deficiency – re one enzyme

– Other drugs and diet etc that reduce liver function

• E.g. Grapefruit juice and St john’s Wort

– Inhibit cytochrome P450

• Smoking and brussel sprouts

– Increase P450 activity

Elimination and half life - (t½) • The duration of the drug in the body is called its half-life (t½)

• The t½ is the period of time for the concentration/amount of a drug in the body to be reduced by half

• Usually the t½ is used in reference to its plasma concentration

• The drug may not be in the plasma; if it leaves:– may be in another body fluid compartment (intracellular fluid)

– Destroyed in plasma

• The removal of a drug from the plasma– Clearance

• The distribution of a drug in various body tissues– Volume of distribution

• The clearance and volume of distribution are important in determining the t½

Half life

Half life

Volume of distribution - THC

Maintenance of therapeutic dose

Single dose

Maintenance of therapeutic dose

Single dose

Maintenance of therapeutic dose

Multiple doses

Elimination • Elimination is the process by which the drug (and its

metabolites) is eliminated fro the body without further chemical change

• Most drugs are metabolised prior to excretion– Some drugs (e.g. Aminoglycoside antibiotics) are polar

compounds (hydrophilic) and are excreted by the kidneys without being metabolised first

• The kidneys are the major excretory organs and excrete water soluble drugs

• The biliary system contributes to excretion if the drug is secreted in bile and then is not reabsorbed from the GIT

• There are small contributions from:– Intestines, saliva, sweat, breast milk and lungs

• Excretion via breast milk may not be of importance to the mother, but may be to the suckling child

Renal excretion

• Excretion of the drug via the kidneys uses 3

processes, all of which occur in the nephron

– Glomerular filtration

– Tubular secretion

– Tubular reabsorption

Urinary system

Urinary system

Glomerular filtration

Glomerular filtration

• The drug goes to the kidney via the blood

• From the glomerulus it passes into the

glomerular (Bowman’s) capsule as part of the

filtrate

• Large drugs, e.g. Heparin, or those bound to

plasma proteins, cannot be filtered and

therefore cannot be excreted

Tubular resorption

• Drugs and their metabolites enter the filtrate

in the nephron, but some may be resorbed

• Resorption occurs as diffusion (not active)

• Occurs because water is resorbed by osmosis

– The majority of water that enters the nephron is

resorbed back in to the blood (to maintain body

fluid volume) and the drug follows it by diffusion

Urine pH - 1

• Urine pH has a great influence on how fast a

drug is excreted

• This can be manipulated in a clinical situation

to control the excretion of certain drugs from

the body

Urine pH- 2• Most drugs are either weak acids or bases (alkaline)

– In alkaline urine, acidic drugs are more readily ionised

– In acidic urine, alkaline drugs are more readily ionised

• Ionised substances are more polar and so are dissolved and excreted more readily

• This is important in situations like blood poisoning; drug must be excreted rapidly from the body

– One strategy is to alter urine pH to increase excretion

– E.g. Aspirin poisoning: making the urine more alkaline with sodium bicarbonate increases the ionisation of salicylic acid (aspirin metabolite) and increases it excretion from the body

Tubular secretion - 1• Most drugs don’t enter the nephron via the

glomerular filtrate, but by tubular secretion

– Active process: drugs are carried against their

diffusion gradient, from the capillary network into

the tubular filtrate

• Tubular secretion involves 2 carrier systems:

– Basic (alkaline) carriers: transport basic drugs

(amiloride, dopamine, histamine)

– Acidic carriers: transport acidic drugs (frusemide,

penicillin, indomethacin)

Tubular secretion - 2

• Tubular secretion can have a big impact on

the speed that a drug is eliminated from the

body; e.g. Penicillin is readily secreted into the

tubular filtrate and rapidly excreted in urine

• If the therapeutic effect needs to be

prolonged/maintained, agents can be

administered that block tubular secretion,

thus slowing the excretion of the drug

Biliary tree

Biliary secretion

• Drugs and metabolites that are secreted in

bile are transported across the biliary

epithelium against their concentration

gradient (active)

– Affecting factors

• Blood concentration: if high, bile content will be high

• If drugs with similar physiochemical properties are

present together, they can compete for the transport

mechanisms

Biliary secretion

• Drugs that are more likely to be excreted into

bile have a molecular weight of >300g/mol

– Smaller, only in negligible amounts

– Both bipolar and lipophilic are excreted

– Conjugation (especially with glucuronic acid) leads

to biliary excretion