Pharmacology

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Drug distribution

most drugs are distributed by diffusion – drug state must allow this - for some it is active transport

• small molecules diffuse more rapidly than large

• pH affects nature & absorption of drugs e.g. acid drugs are absorbed better in acidic medium & base drugs in base medium

• cell membranes are mainly lipid (fatty) materials – only lipid-like (lipophilic) substances cross easily & rapidly

• most drugs act on receptors (usually protein)

• factors such as the chemical nature of the drug & route of administration will determine distribution of the drug

• drugs may be distributed to different areas & fluid compartments e.g. particular receptors, cell membranes, tissues, intracellular fluid, vascular, intercellular fluid, extracellular 

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Pharmacodynamics

  • Pharmacodynamics describes the action of a drug (qualitatively and quantitatively)

  • mechanism by which drugs have effect on body at molecular, cellular, tissue & system levels

  • is what the drug does to body for therapeutic action to happen

  • drugs usually act on physiological processes

  • disease is usually an alteration to normal physiological function

  • drug therapy aimed at reversing/modifying changes to regain homeostasis 

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Pharmacokinetics

means the movement of drugs inside the body
this includes absorption, distribution, metabolism &

i.e. what the body does to a drug

A knowledge of both pharmacodynamics and pharmacokinetics is essential to understand what drugs do, and how they do it 

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Drug absorption

most drugs are given orally
in most routes absorption has to happen for the

drug to access body compartments

exceptions are some of the parenteral routes

drugs have to cross membranes to gain access sometimes several

chemical nature of drug determines how absorption occurs 

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Drug distribution

most drugs are distributed by diffusion drug state must allow this - for some it is active transport

small molecules diffuse more rapidly than large

pH affects nature & absorption of drugs e.g. acid drugs are absorbed better in acidic medium & base drugs in base medium

cell membranes are mainly lipid (fatty) materials only lipid-like (lipophilic) substances cross easily & rapidly

most drugs act on receptors (usually protein)

factors such as the chemical nature of the drug & route of administration will determine distribution of the drug

drugs may be distributed to different areas & fluid compartments e.g. particular receptors, cell membranes, tissues, intracellular fluid, vascular, intercellular fluid, extracellular 

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Protein binding

after absorption drug enters circulation – and may bind to proteins

entry into tissues is required
‘free’ drugs enter tissues – protein bound drugs don’t

as drugs leave bloodstream more protein bound is released

if protein levels are low then too much of the ‘free’ drug may be available to the body

drugs can ‘compete’ for protein binding sites 

  • The distribution of a drug throughout the body depends on blood flow. capillary permeability and degree of protein binding.

  • Blood flows to skeletal muscle is at a faster rate but travels slower to the liver, kidney or brain.

  • Drugs bind to plasma proteins (usually albumin) to ease their passage around the body.

  • This helps to maintain blood levels of free drug (unbound and available to target cells) by releasing bound drug at the levels of free drug fall due to metabolism and excretion.

    • Example-Warfarin is 98% bound to protein = 2% active. If albumin levels are low, the amount of active drug (unbound) increases 

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Protein binding

after absorption drug enters circulation – and may bind to proteins

entry into tissues is required
‘free’ drugs enter tissues – protein bound drugs don’t

as drugs leave bloodstream more protein bound is released

if protein levels are low then too much of the ‘free’ drug may be available to the body

drugs can ‘compete’ for protein binding sites 

  • The distribution of a drug throughout the body depends on blood flow. capillary permeability and degree of protein binding.

  • Blood flows to skeletal muscle is at a faster rate but travels slower to the liver, kidney or brain.

  • Drugs bind to plasma proteins (usually albumin) to ease their passage around the body.

  • This helps to maintain blood levels of free drug (unbound and available to target cells) by releasing bound drug at the levels of free drug fall due to metabolism and excretion.

    • Example-Warfarin is 98% bound to protein = 2% active. If albumin levels are low, the amount of active drug (unbound) increases 

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Agonist : Antagonist

when a drug stimulates the receptor it is known as an agonist

when it blocks a receptor it is known as an antagonist 

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Drug metabolism

processes in the body metabolise drugs

this means drugs will be altered to increase their excretion from the body

this often involves enzymes

if a drug is present over prolonged periods amount of enzyme increases & speed of drug metabolism increases 

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The liver & ‘first pass metabolism’

mostsubstancesthatareabsorbed fromGI tract are taken up by the portal system this includes drugs

the substances are taken to the liver to be processed /stored or metabolised

some drugs are metabolised so well in the liver that they cannot be given orally GTN (96% destroyed in liver) 

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Hepatic Portal system

Small intestine absorbs products of digestion 

Nutrient molecules travel in hepatic portal vein to liver

Liver monitors blood content

Blood enters generic circulation by way of hapatic vein 

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Blood –brain barrier

cerebral capillaries are different from those in body

  • endothelial cells of cerebral capillaries are close together

  • this, along with connective tissue cells of the CNS form a barrier between blood & brain - many molecules are prevented from travelling to brain tissue

  • only some substances can ‘actively’ cross the barrier - this has advantages & disadvantages

    1. Other barriers

      • placental most drugs cross this barrier and may cause congenital malformation

      • testicular protects spermatogenesis from blood borne chemicals currently little is understood about this barrier. 

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Drug half life

is the time taken for the concentration of a drug to decrease by a half

if blood concentration of drug X is 1000mcg/l at a certain time , then after four hours it is 500mcg/l, the drugs half life is 4 hours another 4 hours on and it will be 250mcg/l

half life is used in calculating when repeat doses should be given 

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Bioavailability

  1. is the proportion of the drug that reaches the circulation.

    intravenous drugs have a bioavailability of 100%.

  2. a swallowed drug has only a proportion of this. Oral administration is however probably the most common route of administration. 

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Steady state

there comes a point when the amount of drug going in is the same as the amount of drug getting taken out.

the intention is to achieve steady state concentrations

half life of 48hrs would take 2 weeks

half life of 2 hours would take less than a day

  • a loading dose can help to achieve this in drugs with longer half lives

  • for all drugs there is a minimum effective concentration (mec) and a maximum safe concentration (msc) 

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Therapeutic index

Is the ratio of dose that produces toxicity: to dose which produces clinically desired or effective response

Provides a measure of the drugs safety.

Large index (ratio) - wide margin to reach toxic levels.

Small index (ratio) - toxic levels quickly reached.

Individual patient variation more likely in drugs with smaller index, as effective & toxic plasma concentrations are similar.

E.g. Penicillin large index, warfarin - small index, so warfarin toxicity is regularly monitored. 

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Receptor theory

  1. Certain tissues contain structures called receptors that determine & pick up presence of specific drugs & initiate or inhibit an action - can be blocked by presence of another drug or chemical. 

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Antimetabolites

these drugs closely resemble substances required for cell metabolism / nutrition. 

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Enzyme inhibitors

these drugs interfere with action of body enzymes therefore preventing certain chemical reactions / processes from occurring 

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Action on cell membranes

these drugs interfere with chemical activity of cell membrane & prevent function. 

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Replacement of deficiencies

here drugs replace a dietary factor or hormone that is essential for normal function. 

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Cytotoxic effect

Used to kill bacteria or malignant cells without undue harm to other cells. Interference with cell activity may occur & multiplication stopped. Various cytotoxic drugs have differing specific effects / actions. 

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Total body clearance

Achieved by combination of action by the liver & kidney(s).

Liver assists clearing by metabolising and/or excreting drugs through bile. Drugs can therefore be excreted in faeces or reabsorbed within liver to be excreted via the kidney.

In certain instances lungs are the main organs of elimination (e.g. inhaled anaesthetic gases). 

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Drug excretion

drugs can leave body in saliva, sweat, tears & breath - excretion of alcohol by lungs is the reason breath testing detects alcohol levels

  • majority of drugs are excreted unchanged or as metabolites in urine or bile

  • patients with kidney or liver problems need careful consideration in drug therapy & often have reduced dosages 

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