Pharmacology basics Flashcards
What are aliphatic compounds?
Contain carbon chain with functional groups attached
What do all aromatic compounds contain?
Benzene ring
How does barbituric acid become active?
Addition of phenyl group = anticonvulsant
Addition of alkyl group = hypnotic
What happens if O2 is substituted for Sulfur in Barbituric acid?
Increases solubility allowing drug to cross BBB
How are volatiles divided?
- Ethers (Iso/Sevo/Desflurane)
- Halogenated hydrocarbons (Halothane, Chloroform)
How is a halogenated hydrocarbons potency & stability increased?
Potency: Chloride/bromide
Stability: Fluoride
What are the compounds found in local anaesthetics?
Aromatic group
Amine group
Intermediate chain
What are the 2 main functional groups in LA?
Ester
Amide
Which anaesthetics are esters?
Procaine
Tetracaine
Which LA are amides?
Lidocaine
Bupivacaine
What does the type of linkage in an LA determine?
Speed of metabolism
Esters = Fast, by plasma esterase
Amides = Slowly, in liver
What increases the potency/duration of a LA?
- Increased lipid solubility
- Protein binding (inc amide side chain or add groups)
What makes a molecule an acid or a base?
- Acid = Molecule that donates protons
- Base = Molecule that accepts protons
What is the role of the functional group of a drug?
Affects whether drug is an acid or base
What happens to Midazolam at physiological pH?
- Contains amine group
- Amine group incorporated into benzodiazepine ring
- Renders drug non-ionised, lipid soluble
- Able to cross BBB
What happens to Thiopental in a pH of 10 and pH 7.4?
- 10: Ionised and water soluble
- 7: Non-ionised lipid soluble molecule able to cross BBB
What are the properties of ionic compounds?
- Electron transfer
- High melting & boiling points
- Soluble in water
- Conduct electricity
What elements tend to form covalent bonds?
Non-metallic e.g oxygen
What affects the polarity of a molecule?
The electro-negativity
Why is Desflurane metabolised slower than Isoflurane?
- Desflurane has higher electro-negativity
- Results in stronger bonds
What are the 3 types of attraction between molecules?
- Van der Waals forces: Weakest
- Dipole-Dipole: Attraction between polar molecules
- Hydrogen bonding: Strongest, H+ bonded to strongly electronegative atom
How does intermolecular attraction affect GA?
- GA acts by disrupting molecular associations due to VdW/Hydrogen bonds within lipid membranes
- Includes the H+ bonds in OH & NH groups formed within neurotransmitters receptors
- Also formation of H+ bonds e.g aromatic rings & volatiles
What are most types of bonds between drug and receptor?
Ionic
How do bonds work on acetylcholine?
- +vely charged ammonium ion forms ionic bond with -ve receptor
- VdW force between CH3 group on ach & receptor reinforces stability
- H+ bond
How is a covalent bond broken?
1) Homolytic fission: Each element takes 1 electron to form a free radical (Needs UV or high temp)
2) Heterolytic fission: 1 element takes both electrons so 2 oppositely charged ions formed
What makes molecules water soluble?
- Ability of compound to disrupt normal attraction between H2O molecules (due to Hydrogen bonding)
- Functional groups in a drug can provide regions that can polarise their electron cloud allowing interaction
What is pKa?
- The pH at which the conc of the proton donor form is equal to that of the proton acceptor form
- Indication of how readily a functional group gives up/accepts a proton to become ionized
What do the nitrogen atoms on neuromuscular blocking agents do?
- Reduces lipid solubility
- Increases water solubility
What are the cell surface receptors and what is their function
- G protein coupled: Hormones, neuropeptides, neurotransmitters
- Ligand gated: synaptic transmission (Cys-Loop receptors, Glutamate recepts, P2X recepts, CNG channels, TRP)
What are the intracellular receptors and what is their function
- Steroid receptors: Steroids, Thyroxine, Vit D, Retinoic acid
What are the enzyme-linked receptors and what is their function
- Tyrosine Kinase: Peptide GF, GH, Cytokines, Prolactin
- Tyrosine Phosphatase: Unknown
- Serine Kinase: Transforming GF B
- Guanylate Cyclase: ANP
How do G-Protein Coupled receptors work?
- 7 transmembrane domains coupled to intracellular heterotrimeric G Protein complex
- Activated by ligand binding
- Induces conformational change leading to dissociation of G protein
- Reduces receptor-ligand affinity results in agonist release
- Alters conc of 2nd messenger molecule or produces a change in membrane potential
- Modulate funciton of downstream proteins to produce cellular response
- Intrinsic GTPase activity allows returning to resting state
How do ion channels work?
- From aqueous channel in lipid bilayer allowing charged particles to pass
- 2 types: Voltage-gated & ligand-gated
How do voltage-gated ion channels work?
- Open/close in response to changes in voltage across membrane
- Alpha subunit forms channel pore
- Confers both ion selectivity & sensitivity
- Other subunits stabilise & modulate function
- At normal MP channels are closed
- When membrane depolarised channels have conformational change allowing them to open
How do ligand-gated ion channels work?
- Open in presence of extracellular ligands
- Inotropic: Binding site & transmembrane ion channel integral to 1 protein. Binding alters activity- rapid synaptic transmission
- Metabotropic: Transmitter binding site & effector are separate. Coupled via G-protein which alters activity- slower onset
What does the Cys-Loop receptor family include?
- Nicotinic Ach receptors (Excitatory)
- Inotropic serotonin (5-HT3) (Excitatory)
- GABA A (Inhibitory)
- Glycine (Inhibitory)
Each receptor has 5 homologous subunits - 4 transmembrane segments & extracellular N-terminus for neurotransmitter binding
How do Tyrosine Kinase receptors work?
- Molecule binds
- Kinase activity stimulated
- Tyrosines are phosphorylated
- Intracellular proteins bind to phospho-tyrosine docking sites
What receptors are linked to cytoplasmic enzymes?
- TNF
- Cytokines
- Integrins
- IL-1 receptors
Important in post-op inflammation, immune response, allergies, pain & tissue repair
What is constitutive activity?
- GPCRs able to spontaneously become active without agonist/ligand attachment
What are drug receptor binding sites described as?
- Orthosteric: Endogenous activators bind
- Allosteric: Modulatory sites distinct from the active site
What are allosteric functions?
- Drugs binding at multiple distinct binding sites distant from agonist binding sites
- Causes changes altering receptor function
What is signal amplification?
- Usually receptors coupled to enzymes
- Binding initiates cascade of intracellular responses eg activation of second messenger molecules
What is signal dampening?
- Limits physiological response to drug
- Receptors undergo desensitisation via downregulated expression, receptor internalisation by endocytosis or receptor phosphorylation
- ## Seen as tachyphylaxis or tolerance
