Pharmacology lectures Flashcards
Specificity
specifity is the effect of a drug upon one individual pharmacological action.
Disassociation constant
disassociation constant is the concentration when half the drug binds to the receptor to form the drug receptor complex.
What is the central compartment?
Liver, kidneys and plasma, Areas that are highly perfused.
What is the peripheral compartment?
Muscle. Areas that are poorly perfused.
Affinity
Affinity is the strength of the covalent bonds between the drug and the receptor measured by the disassociation konstant Kc
Non specific binding
Non specific bidning is when drugs use plasma gobulins to produce an effect.
Potency
potentcy is the dosage of a drug needed to produce an effect at a given intensity.
Ec50
effective concentration/ec50 is the concentration of a drug needed to produce half the maximum effect.
Gs protein
Stimulates adenyl cyclase enzyme for cAMP formation
Gq protein
Activates phoshpolipase C which increases production of IP3 to release intracellular calcium and DMG for protein kinase activation to influence protein synthesis
Gi/Go protein
Inhibits adenyl cyclase enzyme to prevent cAMP formation
Action of tyrosine kinase
Tyrosine kinase autophosphorylates tyrosine residues on intracellular domain. It can then recruit G proteins to control gene expression.
Cytoplasmic receptors
in the cyptoplasm there are homodimers and the ligand is endocrine
Nuclear receptors
in the nucelus it is heterodimers and the ligand is usuallly a lipid
Trachphylaxis
trachyphylaxis is the usual timecourse of a drug in the formaiton of the complex and the time taken for the drug to leave the tissue. usually greater dosage can just be given.
Time course
Time taken for drug to bind to receptor and be removed from tissue
Ammonia hydroxide
Antipyretic for itching by lowering pH
Effect of alcohol
Increases fluidity of cells
St John’s wort
Anti depressant
Milk thistle
Treatment for liver dysfunction
Agonist treatment for opioid addiction
Methadone- analgesic which treats withdrawal symptoms
Antagonist treatment for opioids
Naltrexone- creates negative donitioning by preventing possitive effect
MAP kinase pathway
Ligand binding causes dimerisation. Kinase enzymes is activated and phosphorylates amino acid residues present on intracellular catalyctic domain. This activates the intracellular catalyctic domain. The GTPase Ras protein is activated which subsequently activates Map kinase kinase kinase through the use of a guanine exchange factor to substitute GDP for GTP. This then allows the activated map kinase kinase kinase to activate downstream map kinase kinase through the hydrolysis of ATP –ADP. Activated map kinase kinase activates downstream map kinase through ATP hydrolysis –> ADP which allows it to alter gene expression of proteins.
GTP
GTPase is activated by the binding of GTP caused by guanine exchange factors. GTPase is inactivated by GTPase regulatory proteins. GTPase regulatory proteins inhibit GTPase in response to GTP hydrolysis
GTP
GTPase is activated by the binding of GTP caused by guanine exchange factors. GTPase is inactivated by GTPase regulatory proteins. GTPase regulatory proteins inhibit GTPase in response to GTP hydrolysis
Most common G protein receptor
Rhodopsin family
Least common G protein receptor
metabatorpic glutamate
Kinase linked receptor
consists of dimers linked through dimerisation via ligand binding which use direct coupling to link intracellular to extracellular domain to induce the effector kinase proteins. Kinase autophosphorylates tyrosine residues on the catalyctic domain/ associated enzyme to activate itself following dimerisation triggered by ligand binding. regulate gene transcription and control cell growth. Structure consists of two transmembrane helix linked by ligand. EG,.
Recoetors from fastest to slowest
Ligand gated > G protein > Kinase > Nucelar
Intracellular receptor
They use DNA to connect the intracellular domain and extracellular domain to induce gene transcription. There are two types:
cytoplasmic- forms homodimer interactions and triggered by ligand binding, translocate to the nucleus. Ligands are typically endocrine
nuclear- forms heterdoimer interactions with
It is a monomeric structure with receptor domain for ligand seperate from the DNA binding domain
Absorption
Accumulation of drugs in compartment
First pass metabolism
Metabolising drugs in liver to make them more polar and easier to exccrete in the kdineys as urine
Vd
Volume distribution is the theoretical volume of a drug uniformly distirubted in the body to reach the same Cp( drug blood plasma conc).
High Vd
A high volume distribution is more likely if the drug can travel across compartments, such as morphine. This requires a higher volume because it has a greater pharmacological effect.
Low Vd
A low volume distribution is more liekly if the drug is limited to the plasma compartment, such as heparin. Therefore a lower volume is required because it has a greater pharmacological effect.
Treatment for NSAIDS
Misoprosol, prostaglandin mimetic which decreases gastric acid secretion
Helicobacter pylori action
it releases urease an enzyme which breaks down urea into NH3 and H2CO3. This disrupts the stomach lining and leads to ulcer formation.
Action of proton pump inhibitors
Proton pump inhibitors in low pH in the gastric acid are converted into sulphenamides and use ATPase to irreverisbly inhibit the pump.
Action of proton pump inhibitors
Proton pump inhibitors in low pH in the gastric acid are converted into sulphenamides and use ATPase to irreverisbly inhibit the pump.
Drug exposure on graph
Area under the curve reveals drug exposure
How can Cmax be increased?
Increase rate constant
What food reduces drug absorption?
Grapefruit juice reduces elimination of drug and lead to greater absorption of drugs such as cyclosporine and lead to toxicity
What food increases drug absorption/effect?
High fibre foods adsorb to bile, which means it forms a thin film. This prevents it from elimiating drugs and leads to toxicity,
Therapeutic dose
Therapeutic dose regimen is a process used to determine the optimal dose of medication to administer to a patient. This is due to the high variance in patient response to drug vs the actual Cp variance (c
What is a zero order reaction?
Conc has no effect on rate of reaction
What is a first order reaction?
If conc of reactant doubles, rate of reaction will double. Rate increases by the same amount that conc changes
What is a second order reaction
If conc of reaction changes, rate of reaction will square.
What is rate constant?
K is a proportionality constant which links rate of reaction and concentration of reactants. Rate constant increases with temperature
Half life remains the same
First order reaction
Half life increases each time
Second order reaction
Half life decreases each time
Zero order reaction
Anabolism
Synthesis of compounds
Catabolism
Breakdown of compounds
High prothrombin time
Indicator of early liver damage because liver produces clotting factors involved in the extrinsic pathway
Increase in aspartate aminotransferase and alanine aminotransferase
Liver damage caused by drugs, hepatitis, alcohol. Both are synthesised and stored mainly in the liver. Aspartate aminotransferase is released from cells when there is damage in the body
Role of alanine aminotransferase
Transamination between alanine and 2-oxoglutarate to form glutamate and pyruvate
What are pericytes?
Cells located in the walls of capillaries which regulate blood flow. In the CNS, it is important for blood vessel formation
What regulates proliferation of hepatocytes?
Hepatic stellate cells located in the space of Disse. They are liver pericytes which produce ECM, regulate blood flow and cytokines in the liver
What is responsible for liver cirrhosis?
Quiescent Hepatic Stellate cells which form activated myofibroblasts which respond to injury or inflammatory mediators to produce connective tissue.
What is the microcirculation of the liver?
Sinusoidal capillaries
What is the hepatic microsomal enzyme system?
Enzymes in the endoplasmic reticulum of hepatocytes which are fragments of the ER involved in synthesis of protein and metabolism. Includes cytochrome P450 which is an oxygen substrate and NADPH H cytochrome C reductase for electron transfer. They can be induced by drugs
What is phase 1 metabolism?
Occurs in perivenous end of liver by cytochrome P450. This is a biological catalyst which binds to the drug and causes oxidation, hydrolysis, hydroxylation and deamination. This converts the drug into a polar inactive or active metabolite.
What is phase 2 metabolism?
Occurs in perivenous end of liver in the hepatocyte cyptoplasm. There is conjugation of the drug by hepatocytes which adding group such as sulfate to make the drug more water soluble polar and less reactive metabolite to be more easily excreted in bile or urine.
What phase 2 metabolism is least likely to be secreted in bile?
Amino acid conjugation
What is the most common Phase 2 metabolism?
Glucoronidation which is the only phase 2 to occur in liver microsomal enzyme system. It is secreted in bile and released in urine. Conversion is low in neonates so the antibiotic chloramphenicol can have serious side effect.
Periportal region?
High oxygen region with the hepatic protal vein and hepatic artery. Site of o2 uptake, glucose delivery, gluconeogenesis, fatty acid oxidation, urea synthesis.
Perivenous region?
Low oxygen region near the central vein. Site of glucose uptake, bile acid synthesis, glycolysis, ketogenesis and lipogenesis. Drug metabolism phase 1 and phase 2 (conjugation) occur here
What is phase 2 metabolism?
Occurs in perivenous end of liver where there is conjugation of the drug into a polar active metabolite which occurs in the hepatocyte cyptoplasm
What is bioavailability?
Amount of drug left available to enter general circulation.
How is apirin metabolised?
How is aspirin metabolised?
Aspirinis hydrolysed in phase 1 metabolism to salicyclic acid and is conjugated in phase 2 metabolism via glucoridination to salicyl acyl glucorinide and salicyl phenolic glucorinide and excreted in urine
Where does sulfation phase 2 metabolism occur?
Periportal region of liver in high oxgen
How can Phase 1 metabolism be induced?
Increasing plasma drug concentration by decreasing plasma drug concentration such as ethanol and steroids and rifampicin.
How can Phase 1 metabolism be inhibited?
Decreasing plasma drug concentration by ketaconazole (antibiotic) and terfenadine
What is the implication of a longer t 1/2?
Drug has a longer residence in the body following dose so more time is needed to acclimate it to a steady therapeutic level.
What is C0?
Intial concentration
What is CCt?
How to determine drug absorption?
Region of graph before the Cmax which is the highest point.
How to determine drug elimination?
Region of graph after Cmax
How to determine drug exposure?
Area under the curve. Longer exposure time means drug has been there longer.
What affects drug absorption?
Stronger acidic or alkaline drugs are more difficult to absorb and are protein bound so have a lower Vd and greater pharmacological effect. Lipid soluble drugs ar emore easy to absorb. THe closer it is to neutral, the more easier it is to absorb.
What is Kabs?
Absorption/Transfer of drug to central compartment. The slower it is, the longer the duration of action
What happens when Kabs ends at Cmax?
The Cp (plasma conc) decreases at the same rate of T 1/2.
What is therapeutic dose?
Determine the optimal conc/dose s due to the high variance in patient response to drug vs the actual Cp variance (conc of drug in plasma).
What is elimination of drug in simple compartment model?
First order kinetics
What is the two compartment model?
Drug enters peripheral compartment(tissue) before central compartment for oral drugs.
How do IV drugs enter circulaton?
DRUG ENTERS CENTRAL COMPARTMENT BEFORE PERIPHERAL- therefore it bypasses first pass metabolism
What is the fast phase?
Transfer of drug between central and peripheral compartments from plasma to tissues
What is the slow phase?
We can use slow phase t 1/2 to determine rate of excretion
What is non linear kinetic?
At high conc, drug is zero order and at low conc, drug is first order
What is saturation kinetics?
Enzymatic reactions where maximum rate of reaction occurs when there is 100% enzyme saturation. It has non linear kinetics where rate of reaction increases with higher conc at lower dose in first order. Beyond this, it will be zero order clearance where at higher dose, increasing enzyme has no effect on clearance.
What are the implications of saturation?
There is a limitation of enzymes produced, so there is a limit for metabolism and clearnace. This means after a certain dose beyond Vmax, Cp will continue to increase. Duration of action is dependent on dose. Dose and Cp are not proprotional. This makes it difficult to administer
hat are the implications of saturation?
Duration of action is dependent on dose. Dose and Cp are not proprotional. This causes non-linear kinetics. The maximum rate of metabolism sets a limit for drug clearance where after a certain point, Cp can continue to increase. This makes it difficult to administer
