What does the term ‘pharmacology’ mean?
Study of molecular signals regulating physiological processes.
What are the different types of extracellular signals (based on distance of action)?
- Autocrine
- Paracrine
- Endocrine
What is autocrine signalling?
- Cells respond to signalling molecules they produce and release themselves.
- Typically act over microns.
- Shares many paracrine signalling molecules, e.g. Cytokines and growth factors.
What is paracrine signalling?
- Act on neighbouring cells - molecules released into extracellular environment and induce changes in receptor cells.
- Uses signals such as:
- Neurotransmitters
- Local chemical mediators
What is the function of neurotransmitters?
- Mediate signalling between neurons over synapses (20 nm distance, msecs transmission velocity).
- Electrochemical system as enables chemical signal conversion/coupling with electrical signals.
- Signalling can be:
- Excitatory - increases firing rate post-synaptically
- Inhibitory - decreases firing rate post-synaptically
What are the major groups of neurotransmitters?
- Amino acids
- glutamate
- glycine
- GABA
- Monoamines
- adrenaline
- noradrenaline
- dopamine
- serotonin
- (Neuro)peptides
- Acetylcholine
Name examples of inhibitory neurotransmitters.
- GABA
- Glycine
- Dopamine
Name examples of excitatory neurotransmitters.
- Acetylcholine
- Adrenaline
- Noradrenaline
- Dopamine
- Serotonin
- Glutamate
When are local chemical mediators used in signalling?
Local injury results in local signalling response - paracrine: rapid, focused and integrated.
Give examples of local chemical mediators.
- Cytokines (interleukins, chemokines, interferons, histamine)
- Eicosanoids (prostaglandins, leukotrienes)
- Others: nitric oxide, neuropeptides, platelet-activating factor
Give examples of therapeutic applications of pharmaceutical derivates of NTs.
- Propranolol antagonises adrenaline/noradrenaline: treatment of hypertension, thyrotoxicosis, etc.
- Dopamine precursors + agents to inhibit breakdown: treatment of parkinsonism
Give examples of therapeutic applications of pharmaceutical derivates of local chemical mediators.
- Inflammation: steroids are potent blockers of inflammatory signal of local mediators.
- Moderate pain: non-steroidal anti-inflammatories (NSAIDs) block local mediator pain signal.
What is endocrine signalling?
- Glands produce hormone signalling molecules - typically act over long distances/throughout whole body via bloodstream.
- Molecules are highly potent - picomolar to nanomolar range, with timescale of action ranging from seconds to months.
- Recipient cells need to express receptors.
Give examples of the therapeutic applications of exogenous endocrine analogues.
- Adrenaline i.v. Use in A&E
- Insulin derivates for blood sugar control in diabetes
- Steroid use as anti-inflammatories
- Steroids in contraception
What are the major types of hormones?
- Catecholamines
- adrenaline
- noradrenaline
- dopamine
- Peptides and proteins
- insulin
- atrial natriuretic peptide (ANP)
- oxytocin
- Steroids
- testosterone
- progesterone
What are catecholamine hormones, what is their mode of action and what is their plasma 1/2 life?
- Tyrosine derivatives
- Hydrophilic, receptors in PM
- Mode of action (msec-sec)
- Change in membrane potential
- Trigger synthesis of cytosolic second messengers
- Plasma 1/2 life = seconds
What are peptide/protein hormones, what is their mode of action and what is their plasma 1/2 life?
- Short to long chain of amino acids.
- Hydrophilic, receptors in PM
- Mode of action (min-hrs):
- Trigger synthesis of cytosolic 2nd messengers
- Trigger protein kinase activity
- Plasma 1/2 life = minutes
What are steroid hormones, what is their mode of action and what is their plasma 1/2 life?
- Derived from cholesterol lipid.
- Lipophilic, intracellular receptors (cytosolic or nuclear)
- Mode of action (hrs-days):
- Receptor-hormone complex controls transcription and stability of mRNA.
- Plasma 1/2 life = hours
What are the main types of drug targets, and what is the main exception?
- RITE: ~ Receptors ~ Ion channels ~ Transporters ~ Enzymes - In chemotherapy/antibiotics, drug target is often a structural protein or DNA.
What are the different types of receptors targeted by signalling molecules?
- KING: ~ Kinase-linked ~ Ion channels (ligand-gated) - ionotropic Rs ~ Nuclear/intracellular ~ G-protein coupled - metabotropic Rs
What is the MOA of kinase-linked receptors and give examples?
- Act via protein phosphorylation - causes signalling cascade of molecular switches - regulation of gene transcription.
- Takes hours.
- Mediate signals from a wide variety of protein molecules.
- E.g. Cytokinesis receptors
What is the MOA of ionotropic receptors and give examples?
- Ligand (e.g. ACh) binding causes ion channel protein to open, allows transmembrane movement of ions - ion currents and voltage change modulates AP generation in neurones and contraction in muscles.
- Coupled to Ca2+ signalling.
- Acts in milliseconds.
- E.g. Nicotinic ACh R.
What is the MOA of nuclear/intracellular receptors and give examples?
- Lipid-soluble ligand (steroids, thyroid hormone, vitD) binds to intracellular receptor and complex migrates to nucleus - binds to a gene TF - activates/inactivates gene(s).
- Takes hours.
- E.g. Oestrogen R.
What is the MOA of metabotropic receptors and give examples?
- 3 major types: Gs, Gi, Gq - activate different intracellular signalling routes via 2nd messengers, e.g. Ca2+ release, protein phosphorylation. Or allow ion channel to open - change in excitability.
- Act in seconds.
- E.g. Muscarinic ACh R.
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Pharmacokinetics64
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Ion Transporter In Cell Physiology21
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Pharmacodynamics26
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Membrane Potential24
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The ANS17
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Adrenergic Synapses And Drugs14
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Cholinergic Synapses And Drugs8
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Hypertension And The Sympathetic NS9
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The Thyroid Gland & Thyrotoxicosis7
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Signalling Molecules24
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GPCRs25
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Calcium21
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Action Potentials19
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Action Potentials 2 - Myelin10
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Synaptic Transmission16
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Pharmacodynamics 2 - Partial Agonists & Antagonists22
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Asthma14
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The ANS (new)9
