L1. Pharmacodynamics 1 - Basic Principles of Pharmacology & Intro to Pharmacodynamics Flashcards
RISK versus BENEFIT assessment - purpose?
knowing HOW a drug achieves its action allows us to predict it’s BENEFICIAL and UNWANTED/HARMFUL effects
Examples of SIGNALING MOLECULES
- NEUROTRANSMITTERS
- AUTOCOIDS
- CYTOKINES
- HORMONES
Key steps in INTERCELLULAR SIGNALLING
e.g.
- specific PROTEINS in cell membranes (MEMBRANE RECEPTORS) recognise specific ligands
- ligand binds REVERSIBLY with receptor
- ligand-receptor binding causes further signaling WITHIN the cell (second messenger systems) and alteration in cell function
e. g. myocardial cell contracts
Key features of MOLECULAR DRUG TARGETS
- most molecular drug targets are PROTEINS
- have a specific CHEMICAL CONFIGURATION or shape that is recognised by the appropriate ligand or drug
State the x5 main locations of MOLECULAR DRUG TARGETS.
- cell membrane receptors (major site)
- cell nucleus receptors
- ion channels
- enzymes
- carrier molecules (transporters)
Outline Drug-receptor activation
e.g.
Membrane receptor
- attachment of drugs (ligands) to receptors
- REVERSIBLE interaction in most cases
Outline the key steps in Second-messenger or signalling systems with example
- receptor is activated
- it sets off a train of events or ‘signals’ that change the FUNCTION of the cell in some way
e. g. smooth muscle cells contract
CESSATION OF LIGAND EFFECTS
key point
- the drug-receptor interaction is REVERSIBLE
- only a few exceptions
- State the two main mechanisms for CESSATION OF LIGAND EFFECTS
- ENZYMATIC DEGRADATION of drug or ligand
e. g. acetylcholine broken down by cholinesterase into choline + acetate - REUPTAKE BACK INTO CELLS FROM WHICH RELEASED
e. g. noradrenaline, serotonin
Serotonin is also known as …
5-HT = 5-hydroxytryptamine
Give an example of how a drug can influence ENZYMATIC DEGRADATION, describe what occurs
e.g.
when acetylcholinesterase is INHIBITED / BLOCKED, then the effects of acetylcholine will be INCREASED / PROLONGED
e.g. muscle contraction
Example of REVERSIBLE acetylcholinesterases
NEOSTIGMINE = cholinesterase inhibitor.
Used to treat conditions such as glaucoma, myasthenia gravis, dementia in Alzheimer’s disease (limited success) e.g. DONEPEZIL
Examples of IRREVERSIBLE acetylcholinesterases
Found in …
- many insecticides (organophosphates)
- nerve agents e.g. sarin, novichok
Give an example of how a drug can affect the REUPTAKE MECHANISM
e.g.
if reuptake transporter is inhibited / blocked, then the neurotransmitter effects will be increased / blocked
e.g. SSRIs & SNRIs act as ANTIDEPRESSANTS by increasing the levels of serotonin & noradrenaline at receptors in certain areas of the brain
Examples of RECEPTOR TYPES & SUBTYPES for different ligands
- HISTAMINE > x2 main subtypes - H1, H2 - ADRENERGIC - Noradrenaline/adrenaline > x2 main subtypes alpha & beta (with subfamilies) - DOPAMINE > x5 subtypes - D1, D2, D3, D4, D5 - SEROTONIN (5-HT) > x7 subtypes - 5-HT1 to 5-HT2 (with subfamilies)
H1 receptors are located in …
H1 receptor antagonists - e.g.
skin, blood vessels, CNS, bronchi
- stimulation –>
itching, vasodilation, nausea, bronchoconstriction
promethazine, cetrizine
- to reverse or prevent itching, vasodilation, nausea & bronchoconstriction
H2 receptors are located in …
H2 receptors antagonist e.g.
parietal cells of stomach
- stimulation –> produce gastric acid
ranitidine
- to reduce gastric acid secretion in treatment of peptic ulcer etc.
5-HT1B & 5-HT1D are located in …
5-HT1B & 5-HT1D receptor agonists
cerebral blood vessels
- stimulation –> produce constriction of blood vessels
sumatriptan
- to prevent dilation of cerebral blood vessels in treatment or prevention of migraine
5-HT3 receptors are located in …
5-HT3 receptors antagonist
stomach & chemoreceptor trigger zone
- stimulation –> produce emesis (vomiting)
ondansetron
- to treat or prevent nausea/emesis during chemotherapy
Selectivity / specificity of drug action
- aim to TARGET a specific sub-type of receptor
- very few drugs are ABSOLUTELY SPECIFIC to one receptor subtypes, therefore explains a lot the unwanted side effects of a drug
- at best they are SELECTIVE
Structure-activity relationships
- even small changes in CHEMICAL STRUCTURE can change receptor selectivity markedly
AFFINITY *
a measure of the STRENGTH OF INTERACTION between the ligand (drug) and receptor
e.g. how easily or readily they BIND TOGETHER
INTRINSIC ACTIVITY (EFFICACY) *
a measure of the ability of the ligand (drug)-receptor interaction to cause a CHANGE IN FUNCTION
e.g. TO PRODUCE AN EFFECT
AGONISTS *
agents with:
- good affinity for the receptor AND
- INTRINSIC ACTIVITY
e. g. the drug-receptor interaction results in a CHANGE IN FUNCTION (muscle cell contracts)
ANTAGONISTS *
> how it works?
agents with:
- good affinity for the receptor
- NO / VERY LITTLE INTRINSIC ACTIVITY
> PREVENTING ACCESS TO THE RECEPTORS for endogenous ligands e.g. block the effect of naturally occuring transmitters or autocoids
COMPETITIVE ANTAGONISM
- competing for a particular receptor type
- the agent with the HIGHEST CONCENTRATION will occupy the receptor
Give an example of COMPETITIVE ANTAGONISM
Naloxone
- an OPIOID ANTAGONIST
- if administered to a patient that has overdosed on an OPIOID AGONIST (morphine, heroin) the naloxone will DISPLACE the opioid by COMPETITIVE ANTAGONISM
- this reverses the respiratory depression
PARTIAL AGONIST +
- a few drugs are partial agonists
- in SMALL CONCENTRATIONS these drugs act as AGONISTS (trigger a response) but their intrinsic activity (efficacy) is less than a full agonist
- there is a CEILING EFFECT
- in HIGHER CONCENTRATIONS they can act as ANTAGONISTS blocking further access to receptors for other agonists or endogenous substances
Example or a PARTIAL AGONIST +
BUPRENORPHINE
- used in opioid analgesic and in opioid dependence
- difficult to overdose due to ceiling effect
INVERSE AGONISTS +
- relatively few drugs are classified as inverse agonists
- binds to the same receptor as an endogenous agonist BUT induces a pharmacological response OPPOSITE to that agonist
Example of an INVERSE AGONISTS
Several anti-histamines
e.g. Loratadine
Outline DOSE-RESPONSE CURVES
- the relationship between the AMOUNT OF DRUG a tissue is exposed to (e.g. its CONCENTRATION AT THE RECEPTOR) and the LEVEL OF RESPONSE that occurs at these receptors
- the response increased as the concentration increases
- there is a PLATEAU EFFECT once we reach a certain concentration
What is a LOG SCALE?
- each unit on x-axis represents a ten-fold increase in dose
Outline LOG DOSE-RESPONSE CURVES
- when the dose (concentration) is put onto a log scale on x-axis there is a definite ‘S-shaped’ curve & a LINEAR RELATIONSHIP between dose & response
Minimal dose (Emin)
- a certain MINIMUM NUMBER OF RECEPTOR SITES must be activated BEFORE a response can occur
- on the ‘S-shaped’ curve as dose (concentration) increases, more receptor sites are activated & a bigger response occurs
> there is no point in under-dosing
Maximal dose (Emax)
- the point when ALL AVAILABLE RECEPTOR SITES HAVE BEEN ACTIVATED
- at this point response is ‘maximal’ - no matter how much the dose increases you cannot get a bigger response
> there is no point in overdosing
TACHYPHYLAXIS
pharmacological term to describe…
some receptors lose responsiveness after repeated exposure to the same concentration (dose) of a particular drug
DESENSITISATION
- a decrease in the response of RECEPTOR-SECOND MESSENGER systems
- associated with chronic exposure to a particular drug
TOLERANCE
e.g. demonstrating how to prevent this
- DESENSITISATION & TACHYPHYLAXIS (together or separately) can contribute to development of tolerance
- need increasing doses of drug to get the same effect
e.g. it is recommended that GTN transdermal patch, used in the prophylaxis of angina, is removed at night
RECEPTOR UP-REGULATION
The number of receptors can be INCREASED in response to strong signals at these receptors.
> generally caused by antagonists
RECEPTOR DOWN-REGULATION
The number of receptors can be DECREASED in response to strong signals at these receptors
> generally caused by agonists
Explain how a drug causes RECEPTOR DOWN-REGULATION using an example
down-regulation of opioid receptors occurs following chronic exposure to OPIOID AGONIST drugs (morphine, codeine)
DEPENDENCE
withdrawal symptoms when drug removed
Explain how drugs can cause RECEPTOR UP-REGULATION
e.g.
chronic use of BETA-ANTAGONIST drugs (beta-blockers e.g. atenolol, bisoprolol, metoprolol) leads to an increased expression of beta-adrenoreceptors
- Give an example of ENZYMATIC DEGRADATION of drug or ligand.
Acetylcholine broken down by cholinesterase into choline + acetate
- Give an example in which REUPTAKE BACK INTO CELLS FROM WHICH RELEASED occurs
noradrenaline, serotonin
Give an example of ENDOGENOUS RECEPTOR DOWN-REGULATION
- when INSULIN levels are continually high in response to high blood glucose levels (T2DM)
- high insulin levels lead to insulin receptors being endocytosed & broken down leading to FAR FEWER RECEPTORS & INSULIN-RESISTANCE (reduced sensitivity to insulin)
Outline why beta-antagonists should not be stopped suddenly?
these drugs should be WITHDRAWN GRADUALLY as abrupt cessation can lead to severe rebound hypertension
