6 Drug metabolism and adaptations Flashcards
4 main stages of drug metabolism?
absorption
distribution
metabolism
elimination
phase I metabolism
mainly occurs in liver
Oxidation, reduction and hydrolysis
Expose/add a reactive group
cytochrome P450 dependent oxidation
NADPH and NADPH - P450 reductase important factors
diff isoforms (CYP3A4 & CYP2D6)
phase 2 metabolism
occurs in liver
conjugation w/ polar molecules makes more water soluble
glutathione, glucuronic acid or sulphate enzymes
specific enzymes required + UDPGA
first pass effect and drug example
substance absorbed from ileum lumen extensively metabolised
enter venous blood which drains into HEPATIC PORTAL VEIN moved to liver
eg) 1g paracetamol
how is gout formed from excessive alcohol consumption?
reduced NAD+/NADH
increase lactate, kidneys ability to excrete urine decrease, so uric acid levels which increases crystal formation
alcohol metabolism
90% metabolised
10% excreted
small amount metabolised in liver alcohol oxidised by CYP2E, the rest by alcohol dehydrogenase
then aldehyde dehydrogenase to acetate
alchol>acetaldehyde>acetate
metabolism of paracetamol
therapeutic level 2 tablets 1g, metabolised in phase II
toxic level goes through phase I and II due to saturation
toxic metabolite formed - NAPQI (oxidising agent depletes glutathione)
N-acetyl cysteine - will replenish glutathione
treatment for alcohol dependance
disulfram
cause build up acetaldehyde
causes nausea, vomiting - sickness should deter
what causes fatty liver?
reduced levels of NAD+
increase acetyl CoA, increase in FA and ketone synthesis
effects of increased acetaldehyde
liver enzymes escape into blood (high levels AST/ALT/GGT)
reduced uptake and conjugation of bilirubin causes hyperbilirubinaemia
reduced synthesis of protein
reduced production of urea - hyperammonaemia
what is gestational diabetes?
IN SOME WOMEN, the endocrine pancreas is UNABLE to respond to the increased demand of pregnancy AND is unable to respond to the metabolic demands!
fails to release the increased amounts of insulin required
loss of control of metabolism of blood glucose increase -> diabetes
what changes occurred to meet foetal nutrient demand during pregnancy?
Reducing the maternal utilisation of glucose by switching tissues to fatty acids
delaying disposal of nutrients after meals
releases FAs form storage - first stage of pregnancy
what is metabolic response to exercise?
energy demands of skeletal & cardiac muscle are met by mobilisation of fuel molecules from energy stores
minimal disturbances to homeostasis to keeping the rate of mobilisation equal to the rate of utilisation
glucose supply to brain maintained
end products are removed
Metabolic response to short duration of HIGH intensity exercise (100m
sprint!)
muscle ATP and creatine phosphate used ˜5secs
muscle glycogen mobilised to form G6P
G6P metabolised via glycolysis to form ATP from ADP
under anaerobic conditions - forms lactate and H+ causes fatigue
what does drug metabolism convert
inactive drugs to active form
How are energy demands of skeletal and cardiac muscle met during metabolic response
Mobilise energy stores
How can ketogenic-acidosis occur with alcoholics
High acetyl CoA
Low NAD+
ketone body synthesis
How does damage occur to liver due to acetaldehyde
Acetaldehyde dehydrogenase has a low km and removes acetylaldehyde as it is formed but with excessive drinking acetylaldehyde can accumulate
How does disulfiram work
Aldehyde dehydrogenase inhibitor
If patient drinks alcohol then acetylaldehyde accumulate leading to symptoms of hangover
How does N-acetyl cysteine work
replenish glutathione allowing liver to metabolise the NAPQI
How is acetyl CoA formed during alcohol metabolism
Acetic acid and CoA join to form Acetyl CoA
How is glucose transported to fetus
Active transport GLUT1
How is metformin excreted
Not metabolised and excreted as parent drug
How is the concentration of nutrients in maternal circulation kept high(3)
Reduce maternal use of glucose, mother uses fatty acids and ketones
Delayed disposal of nutrients after meals
Release fatty acids from stores build during 1st half of pregnancy
How much energy can muscle glycogen provide
2 minutes during intensive
60 minutes during low intensity
How much energy does creatine phosphate provide
5 seconds worth during sprint
What activates glycogen phosphorylase
Adrenaline
glucagon
AMP
What are the 2 divisions of pharmacology
Pharmacokinetics
Pharmacodynamics
What are anti-insulin hormones
Hormones that oppose insulin action.
What are issues with metformin
No hypoglycaemia
Lactic acidosis
Weight loss
What are risk factors for gestational diabetes (3)
Maternal age greater than 25
BMI>25
Personal/family history of diabetes
What are some drawbacks of using fatty acids as fuel in exercise
Used only in aerobic conditions
Slow release from adipose
Limited carrying capacity in blood
Limited by carnitine shuttle
What are some examples of enzymes deficiencies affecting drug metabolism
Plasma cholinesterase enzymes
What are some examples of phase 2 reaction in drug metabolism
Glucuronidation
Sulphate conjugation
Glutathione conjugation
What are the 2 functions of drug metabolism
Deactivate drug
Elimination of drug
What are the 2 important placental steroid hormones
Oestrogen
Progesterone
What are the 2 phases of metabolic adaptation during pregnancy
Anabolic
Catabolic
What are the 3 underlying causes of gestational diabetes
Autoantibodies similar to type 1 diabetes
Genetic susceptibility to onset diabetes
Obesity and chronic insulin resistance
What are the 4 general processes in pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
What are the benefits of exercise
Decreased adipose and increased muscle
Increased muscle glycogenesis
Blood pressure falls
What are the clinical implications of gestation diabetes (4)
Increased incidence of miscarriage
Fetal macrosomia (Large body)
Shoulder dystocia
Gestational hypertension and preeclampsia
What are the effects of adrenaline and growth hormone rise in marathon
Adrenaline stimulate glycogenolysis and lipolysis
Growth hormone mobilise fatty acids
What are the energy sources in 100m sprint
Creatine phosphate
Anaerobic production of ATP
What are the energy sources used in 1500m race(3)
Creatine phosphate
Anaerobic glycogen
Aerobic muscle glycogen
What can be used to treat alcoholism
Disulfiram
What can genetic variability cause in P450 activity
Increase or decrease activity of the CYP
What carrier molecule used to alcohol conversion to acetaldehyde
NAD+ converted to NADH+ and H+
What component of alcohol metabolism causes liver damage
Acetaldehyde
What do anti-insulin hormones do
Reduce glucose uptake in adipose/muscle
What do oestrogen and progesterone do the pancreatic Beta cells in pregnancy
Hyperplasia(more cells)
Hypertrophy (bigger cells)
What does drug metabolism do the parent drug molecule
Convert parent drug to polar, lipid Insoluble water soluble derivative
What does increased levels of insulin in mother promote
Anabolic state leading to increased nutrient storage
What does the absorption of a drug depend on
pH of drug
Drug has to non ionised
What effect occurs from glucagon levels rising in a marathon
Stimulate glycogenolysis
Stimulate glucogenogenesis
Stimulate lipolysis
What energy sources are used in a marathon
Muscle glycogen
Liver glycogen
Fatty acids
What enzyme used to convert acetaldehyde to acetic acid
Aldehyde dehydrogenase
What enzyme used to convert alcohol to acetaldehyde
Alcohol dehydrogenase
What factors affect magnitude and nature of metabolic response to exercise(5)
Type of exercise
Intensity
Duration
Physical condition
Nutrition state of individual
What genetic factors can affect drug metabolism
Gene deletions leading to enzyme deficiencies
What goes wrong in paracetamol overdose
High NAPQI
Glutathione depleted
Glutathione used as anti-oxidant
NAPQI covalent bind to hepatic proteins leading to oxidative stress
What hormones changes occur in a marathon (4)
Insulin fall
Glucagon rises
Adrenaline and growth hormone rise
Cortisol rise slowly
What is cytochrome P450
Family of enzymes
What is management for gestational diabetes(3)
Dietary modification
Insulin injection
Regular ultrasound
What is pharmacodynamics
What the drug does to the body
What is pharmacokinetics
What the body does to the drug
What is the abnormal function of pseudocholinesterase enzyme
Drug metabolised in a few hours
What is the co-factor used in glucuronidation
UDPGA
What is the effect of cortisol rising slowly in a marathon
Stimulation of gluconeogenesis and lipolysis
What is the effect of induction of P450 enzymes
Increase metabolism of other drugs
Decrease plasma concentration
What is the effect of inhibition of P450 enzyme
Decrease metabolism
Increase plasma concentration
What is the main site of action for phase 2 drug metabolism
Liver-cystolic enzymes
What is the metabolic response to starvation
Tissue switch from glucose to fatty acid/ketones
Brain uses ketones
What is the most common anti-insulin hormones
Corticotropin releasing hormone
What is the normal metabolism of paracetamol
NAPQI made in phase 1
NAPQI conjugated with glutathione
What is the pathway for alcohol metabolism
Alcohol to acetaldehyde using alcohol dehydrogenase
Acetaldehyde to acetic acid using aldehyde dehydrogenase
What is the polarity of a parent drug
Lipid soluble
What is treatment of Paracetamol overdose
N-acetyl cysteine
What occurs in catabolic phase in pregnancy
Maternal metabolism adapts to accommodate growing foetus
What occurs in anabolic phase in pregnancy
Increase maternal fat stores
Small increase insulin sensitivity
What occurs in body due to anti-insulin after meal
Transient hyperglycaemia
What occurs in phase 1 of drug metabolism (3)
Convert lipophilic drug to polar molecule
Oxidation, reduction, hydrolysis
Add or expose reactive groups on drugs
Where is the main site of action for phase 1 drug metabolism
Liver
Microsomes on endoplasmic reticulum of hepatocytes
Why cannot most drugs be excreted by kidney
Most drugs lipid soluble instead of water soluble
Why do lipids accumulate in liver due to liver damage
Reduced Protein synthesis
Less lipoprotein synthesis
Lipids produced in liver cannot be transported from the liver hence accumulate
Why is NAPQI bad
Depletes Glutathione which acts as a anti-oxidant
Why may alcoholics have fatty liver
High acetyl CoA
Low NAD+
Fatty acid synthesis
Fatty acids converted to Triacylglycerol
Triacylglycerol cannot be transported to liver hence contribute to fatty liver
Why may alcoholics have gout
NAD+ decreased due to alcohol to acetaldehyde
NAD+ needed for metabolism of lactate to pyruvate
Increased lactate means kidney cannot excrete uric acid hence urate accumulates and forms uric acid crystals
Why might alcoholics have hypoglycaemia
NAD+ needed for fatty acid oxidation and metabolism of glycerol
Liver cells cannot use lactate and glycerol hence gluconeogenesis not activated
Why must ATP be rapidly resythesised in exercise
ATP stores are limited in muscle
Only last 2 seconds during sprint
