Introduction to Pharmacology
Pharmacology = branch of medicine concerned with the uses, effects and modes of action of drugs on living tissues
A drug is a substance which modifies the activity of living tissue. Interfere with either normal or abnormal physiology.
Physiology is the science of how living tissues function. Abnormal physiology aka pathophysiology. Pharmacology and physiology are inter-related
Pharmacology covers many areas of research inc pharmacokinetics/drug metabolism, biochemical pharmacology, molecular pharmacology, chemotherapy and systems pharmacology
Systems pharmacology eg neuropharmacology, cardiovascular pharmacology, gastrointestinal pharmacology, immunopharmacology and respiratory pharmacology
Therapeutics = study of the use of pharmacological agents in disease states
There are many different types of therapy and they are typically administered following a medical diagnosis. Many produce adverse effects and not all therapies are always effective
Pathology = the study of how the body goes wrong in disease states
Pathology is also the study of cause and effects of disease/injury. Incorporates a huge breadth of biology research areas and medical practices
Agonists
An agonist is a drug (or natural body substance) that directly causes a measurable response. The response can be excitatory or inhibitory depending on the receptor activated.
Agonist affinity is defined as the binding to its receptor. Efficacy is the ability of the agonist to activate the receptor and elicit a response. Efficacy can be graded - the response isn’t usually all or nothing.
Full agonists produce a maximal response whereas partial agonists only produce a sub-maximal response.
As concentration of agonist eg acetylcholine is increased the response also increases and a sigmoidal concentration-response curve can be generated using a semi-log scale. This can be used to find the EC50 value
EC50 value = concentration of drug at 50% maximum effective concentration. The lower the value, the more potent the drug.
Antagonists
Antagonism can be pharmacological (most popular/common), chemical or physiological.
Pharmacological antagonism = when drugs counteract each other by acting on the same receptor type.
Chemical antagonism = when one drug antagonises the action of another by chemically combining with it.
Physiological antagonism = when two drugs counteract each other by producing opposing effects on different receptors.
An antagonist typically has much higher affinity for the receptor than the agonist does.
Competitive antagonism is where drugs compete to bind to the same receptor. Increasing agonist concentrations can compete out the antagonist, restoring tissue responses but the EC50 value increases. The antagonism is described as being surmountable.
Key features of competitive antagonism include the antagonist concentration-response curve shifting right and a linear relationship between agonist and antagonist concentrations. Binding studies prove competition.
Occupancy = proportion of receptors to which the receptor is bound
Irreversible-competitive antagonism is where the bond between the antagonist and receptor is so strong that increasing agonist concentration doesn’t displace the antagonist, typically due to covalent bonding. An anti-coagulant drug with a half life of 18 hours was withdrawn in the EU as its affinity is so high that it can’t be competed out.
Non-competitive antagonists act at sites other than the agonist binding site.
Hyoscine = antagonist of acetylcholine so reduces muscle contraction. Used in medications for IBS.
Morphine - opioid receptor agonist which causes acetylcholine reduction. Very good pain relief but causes constipation due to lack of bowel movements.
Early pharmacology
Synthetic chemistry was very important in furthering pharmacology as it meant new drugs could be synthesised from a chemical background rather than just a natural background eg anaesthetics and new antimicrobials.
William Blair Bell discovered that breast cancer could be treated using lead colloidal mixtures. Paul Ehrlich discovered that arsenical compounds could treat syphilis. Both of these treatments are toxic to our body cells but more so to the cancer cells or microbes causing the disease. Many antimicrobial and anti-cancer treatments still work on this basis today.
Toxicology
Toxicology is the study of the toxic effects of drugs and environmental hazards. This idea dates back to Paracelsus in the 1400s.
Some drugs have a narrow or even non-existent margin between desired therapeutic effects and undesired toxic effects. We ideally want the therapeutic range to be wide in case of slight error in dosing. However it is not always possible to use a drug with a wide therapeutic range so doctors may need to decide whether the benefits outweigh the risks.
There are two different forms of drug toxicity: iatrogenicity and teratogenicity. Iatrogenicity is the capacity to produce disease from the side effects or inappropriate prescribing of drugs, such as the anti-malarial drug mefloquine which is associated with profound suicidal thoughts. Teratogenicity is the capacity to produce abnormalities in the unborn foetus/child eg thalidomide (prescribed for severe morning sickness in late 50s) caused phocomelia.
More on thalidomide:
Thalidomide is a racemic mix of the R and S isomers. The R form has sedative properties which meant it could be used against nausea. The S form is teratogenic as it binds to enzymes involved in limb development of unborn foetus.
Companies tried to manufacture the R form on its own but when metabolised the liver converted the 100% R form back into a racemic mix. Thalidomide caused many tragedies but made regulations of testing much stricter.
Botulism
Cause: canned/bottled foods that haven’t been properly sterilised
Bacteria: Clostridium botulinum
Toxin: botulinum
symptoms: muscle paralysis, respiratory failure, death
However, many toxins are being re-utilised as drugs at very small doses. Botulinum as a therapeutic treats:
facial wrinkles (type A botulinum, temporary treatment)
severe underarm sweating
cervical dystonia = neurological, severe neck and shoulder muscle contractions
blepharospasm - uncontrollable blinking
strabismus = misaligned eyes
Studying drugs
3 different methods: in vivo, ex vivo and high throughput screening.
Ex vivo uses tissue samples rather than cells as the 3D structure means the samples are closer to physiological relevance. If the observed properties are good, the drug may then be tested in animals.
High throughput screening is the method of choice for most drug companies. Thousands of compounds are screened each day. Cell lines which are sometimes genetically modified are used to screen drugs and observe their pharmacological properties
Drug targets include ion channels (verapamil which blocks cardiac calcium ion channels) , enzymes (ibuprofen =COX inhibitor), transporter/carrier proteins (prozac inhibits 5-HT uptake) and receptors (salbutamol and cimetidine).
Pharmacology = branch of medicine concerned with the uses, effects and modes of action of drugs on living tissues
A drug is a substance which modifies the activity of living tissue. Interfere with either normal or abnormal physiology.
Physiology is the science of how living tissues function. Abnormal physiology aka pathophysiology. Pharmacology and physiology are inter-related
Pharmacology covers many areas of research inc pharmacokinetics/drug metabolism, biochemical pharmacology, molecular pharmacology, chemotherapy and systems pharmacology
Systems pharmacology eg neuropharmacology, cardiovascular pharmacology, gastrointestinal pharmacology, immunopharmacology and respiratory pharmacology
Therapeutics = study of the use of pharmacological agents in disease states
There are many different types of therapy and they are typically administered following a medical diagnosis. Many produce adverse effects and not all therapies are always effective
Pathology = the study of how the body goes wrong in disease states
Pathology is also the study of cause and effects of disease/injury. Incorporates a huge breadth of biology research areas and medical practices
Agonists
An agonist is a drug (or natural body substance) that directly causes a measurable response. The response can be excitatory or inhibitory depending on the receptor activated.
Agonist affinity is defined as the binding to its receptor. Efficacy is the ability of the agonist to activate the receptor and elicit a response. Efficacy can be graded - the response isn’t usually all or nothing.
Full agonists produce a maximal response whereas partial agonists only produce a sub-maximal response.
As concentration of agonist eg acetylcholine is increased the response also increases and a sigmoidal concentration-response curve can be generated using a semi-log scale. This can be used to find the EC50 value
EC50 value = concentration of drug at 50% maximum effective concentration. The lower the value, the more potent the drug.
Antagonists
Antagonism can be pharmacological (most popular/common), chemical or physiological.
Pharmacological antagonism = when drugs counteract each other by acting on the same receptor type.
Chemical antagonism = when one drug antagonises the action of another by chemically combining with it.
Physiological antagonism = when two drugs counteract each other by producing opposing effects on different receptors.
An antagonist typically has much higher affinity for the receptor than the agonist does.
Competitive antagonism is where drugs compete to bind to the same receptor. Increasing agonist concentrations can compete out the antagonist, restoring tissue responses but the EC50 value increases. The antagonism is described as being surmountable.
Key features of competitive antagonism include the antagonist concentration-response curve shifting right and a linear relationship between agonist and antagonist concentrations. Binding studies prove competition.
Occupancy = proportion of receptors to which the receptor is bound
Irreversible-competitive antagonism is where the bond between the antagonist and receptor is so strong that increasing agonist concentration doesn’t displace the antagonist, typically due to covalent bonding. An anti-coagulant drug with a half life of 18 hours was withdrawn in the EU as its affinity is so high that it can’t be competed out.
Non-competitive antagonists act at sites other than the agonist binding site.
Hyoscine = antagonist of acetylcholine so reduces muscle contraction. Used in medications for IBS.
Morphine - opioid receptor agonist which causes acetylcholine reduction. Very good pain relief but causes constipation due to lack of bowel movements.
Early pharmacology
Synthetic chemistry was very important in furthering pharmacology as it meant new drugs could be synthesised from a chemical background rather than just a natural background eg anaesthetics and new antimicrobials.
William Blair Bell discovered that breast cancer could be treated using lead colloidal mixtures. Paul Ehrlich discovered that arsenical compounds could treat syphilis. Both of these treatments are toxic to our body cells but more so to the cancer cells or microbes causing the disease. Many antimicrobial and anti-cancer treatments still work on this basis today.
Toxicology
Toxicology is the study of the toxic effects of drugs and environmental hazards. This idea dates back to Paracelsus in the 1400s.
Some drugs have a narrow or even non-existent margin between desired therapeutic effects and undesired toxic effects. We ideally want the therapeutic range to be wide in case of slight error in dosing. However it is not always possible to use a drug with a wide therapeutic range so doctors may need to decide whether the benefits outweigh the risks.
There are two different forms of drug toxicity: iatrogenicity and teratogenicity. Iatrogenicity is the capacity to produce disease from the side effects or inappropriate prescribing of drugs, such as the anti-malarial drug mefloquine which is associated with profound suicidal thoughts. Teratogenicity is the capacity to produce abnormalities in the unborn foetus/child eg thalidomide (prescribed for severe morning sickness in late 50s) caused phocomelia.
More on thalidomide:
Thalidomide is a racemic mix of the R and S isomers. The R form has sedative properties which meant it could be used against nausea. The S form is teratogenic as it binds to enzymes involved in limb development of unborn foetus.
Companies tried to manufacture the R form on its own but when metabolised the liver converted the 100% R form back into a racemic mix. Thalidomide caused many tragedies but made regulations of testing much stricter.
Botulism
Cause: canned/bottled foods that haven’t been properly sterilised
Bacteria: Clostridium botulinum
Toxin: botulinum
symptoms: muscle paralysis, respiratory failure, death
However, many toxins are being re-utilised as drugs at very small doses. Botulinum as a therapeutic treats:
facial wrinkles (type A botulinum, temporary treatment)
severe underarm sweating
cervical dystonia = neurological, severe neck and shoulder muscle contractions
blepharospasm - uncontrollable blinking
strabismus = misaligned eyes
Studying drugs
3 different methods: in vivo, ex vivo and high throughput screening.
Ex vivo uses tissue samples rather than cells as the 3D structure means the samples are closer to physiological relevance. If the observed properties are good, the drug may then be tested in animals.
High throughput screening is the method of choice for most drug companies. Thousands of compounds are screened each day. Cell lines which are sometimes genetically modified are used to screen drugs and observe their pharmacological properties
Drug targets include ion channels (verapamil which blocks cardiac calcium ion channels) , enzymes (ibuprofen =COX inhibitor), transporter/carrier proteins (prozac inhibits 5-HT uptake) and receptors (salbutamol and cimetidine).
