Pharmacology Cameron McCloskey Flashcards
What is the difference between pharmacodynamics and pharmacokinetics?
- Pharmacodynamics - what the drug does to the body
- Pharmacokinetics - what the body does to the drug
Drugs which act on receptors can be either _________ or ______________
Agonists
Antagonists
What is affinity?
The strength at which a ligand will bind to its receptor
What is efficacy?
The ability of an agonist to evoke a cellular response
What is EC50?
The concentration of agonist that elicits half maximal response
This is the Michaelis-Menten constant
What is competitive antagonism?
The antagonist and agonist compete for the same binding site
What is non-competitive antagonism?
The agonist binds to the orthosteric site and the antagonist bings to a separate allosteric site
Activation cannot occur when the antagonist is bound
What is potency?
amount of drug required to produce a desired effect
How do competitive antagonists affect the concentration response curve?
Competitive antagonists cause a parallel rightward shift of the agonist concentration response curve with no depression of the maximal respons
How do non-competitive antagonists affect the concentration response curve?
Non-competitive antagonists depress the slope and maximum of the concentration response curve, but do not cause a rightward shift
Label A, B and C on the concentration response graph
What is the therapeutic window?
Any concentration of drug between the minimum effective concentration (MEC) and maximum tolerated concentration (MTC)
How is the therapuetic ratio calculated?
TR - MTC/MEC
minimum effective concentration (MEC) and maximum tolerated concentration (MTC)
Drugs with ____ therapeutic ratios (or index) are unsafe
Low
When a drug is given by IV, how is the initial concentration calculated?
C0 = D/Vd
- D - dose (mg)
- Vd = volume of body plasma
The drop in concentration of a drug in the body over time depends on what?
The rate of removal or elimination (Kel)
What is first order kinetics?
Most drugs express this
It is when the rate of elimination is directly proportional to drug concentration
Drug elimination = drug concentration
What is “clearance”?
This is the volume of plasma filtered clear of the drug in unit time
How is rate of elimination calculated?
Rate = Cl x Cp
- Cl - clearance
- Cp - plasma concentration
Rate of elimination is measured in l/hr
At a stead state the rate of drug administration will equal what?
The rate of elimination
(drug concentration remains constant)
Changing the rate of drug administration does not change the time to reach a steady state, it will change what instead?
It will change the concentration of the steady state
How many half lives does it take to reach a steady state?
5
What is a loading dose?
An initially higher administered dose given at the beginning f treatment.
It accelerates the time at which a steady state can be reached and when plasma concentration becomes adequate
How does a larger Vd affect half life?
It increases it
Equal relationship
How can half life be shortened?
If Cl is increase
Opposite relationship
What is zero order kinetics?
This describes drugs that are eliminated at a constant rate, regardless of their concentration
An increase in drug concentration will have no effect on the rate of elimination
(at very low concentrations some drugs may initially function at first order kinetics because concentration is the limiting factor)
What is the reason for some drugs functioning at zero order kinetics?
The enzyme that breaks them down has a Km that is lower than the concentration of the drug in the body
What is a ganglion?
A group of cells at which a synpase is present
Why is the sympathetic innervation of the adrenal gland unusual?
It is innervated by a preganglionic neurone
Acetylcholine is released
The adrenal gland acts as the postganglionic neurone, by releasing adrenaline
Where does the sympathetic outflow originate?
The sympathetic chain (thoracolumbar outflow)
Between the levels of T1 and L2
Where does parasympathetic outflow originate?
- Cranial nerves III, VII, IX and X
- Cranio-sacral outflow
- Thoraco-lumbar outflow
- Sacral spinal nerves
How is noradrenaline cleared from the synaptic cleft?
It is reabsorbed
How is acetylcholine cleared from the synaptic cleft?
Broken down and re-synthesised
Describe how action potentials are sent via the sympathetic system
- The action potential causes volatge gated calcium ion channels to open allowing for calcium influx into the preganglionic neurone
- Acetylcholine is released into the synaptic cleft
- Acetylcholine bins to receptors (nicotinic) on the postsynaptic neurone and ligand gated ions channels open
- The postsynaptic neurone becomes depolarised and calcium ions enter via voltage gated ion channels
- Noradrenaline is released at the effector site
- Noradrenaline activates G-protein coupled adrenoceptors
How is transmission of an action potential different in the parasympathetic system when compared with the sympathetic system?
- Acetylcholine is released at effector sites
- Acetylcholine activates muscarinic acetylcholine receptors on the target cell instead of nicotinic receptors - this is a slower process
Which is faster, ligand gated ion channels or G-protein coupled?
Ligand gated channels
What is G-protein?
Guanine nucleotide binding protein
It is a peripheral membrane protein with 3 subunits, alpha, beta and gamma
It contains a binding site for GTP/GDP
- Heterotrimeric G proteins (peripheral proteins) conduct signals from membrane receptors (integral proteins) to regulatory proteins localized to various cellular compartments
Describe how G-proteins function
- When the receptor is bound, the G-proteins couples with the receptor
- GDP dissociates from the G-protein (bound in inactive state) and will bind to the alpha subunit
- The alpha subunit then combines with the effector altering its activity
- The receptor and effector are not linked so the signal can still be exerted even after the agonist dissociates
- The signal stops when the alpha subunit hydrolyses GTP releasing energy to rembine to subunits and cause dissociation from the effector
What are nicotinic acetylcholine receptors constructed of?
Up to 5 different glycoprotein subunits
They form a transmembrane channel that allows conduction of cations
What are the peripheral variants of nicotinic receptors?
- Skeletal ((α1)2βγε)
- Ganglionic (α3β4)
What are the CNS variants of nicotinic receptors?
- α4β2
- α7
Describe cholinergic transmission
- Uptake of choline via transporter
- ACh synthesisedvia choline acetyltransferase (CAT) – choline combines with acetyl CoA provided by mitochondria
- ACh packaged into vesicles
- Depolarization by action potential – must be present for exocytosis
- Ca2+ influx through voltage-activated Ca2+ channels – must occur for exocytosis
- Ca2+- induced release of ACh (exocytosis)
- Activation of ACh receptors (nicotinic or muscarinic) causing cellular response
- Degradation of ACh to choline and acetate by acetylcholinesterase (AChE) – terminates transmission
- Reuptake and reuse of choline
Which two receptors can ACh activate?
- Nicotinic (ligand gated receptors)
- Muscarinic (G-protein coupled receptors)
What are the individual roles of muscarinic receptors M1, M2 and M3?
- M1 – signals to specific G-protein (Gq) which stimulates phospholipase C which causes increased acid secretion in the stomach.
- M2 – signal to specific G-protein (Gi) which stimulates inhibition of adenylyl cyclase which opens K+ channel causing decreased heart rate.
- M3 – signals to specific G-protein (Gq) which stimulates phospholipase C production which causes increased secretion of saliva or contraction of visceral smooth muscle.
Describe noradrenergic transmission
- Synthesis of NA (multiple steps) – L-Tyrosine is converted through a variety of steps to noradrenaline
- Storage of NA by transporter (concentrates) – into vesicles
- Depolarization by action potential
- Ca2+ influx through voltage-activated Ca2+ channels
- Ca2+-induced release of NA - exocytosis
- Activation of adrenoceptor (receptors for noradrenaline) subtypes causing cellular response (tissue dependent)
- Reuptake of NA by transporters uptake 1 (U1) or uptake 2 (U2)
- Metabolism of NA by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
What are the different G-protein coupled adrenoceptor subtypes and their functions at sympathetic neuroeffector junctions?
- B1 – stimulates through Gs stimulating adenylyl cyclase increasing heart rate and force
- B2 – stimulates through Gs stimulating adenylyl cyclase causing relaxation bronchial and vascular
- a1 – stimulates through Gq stimulating phospholipase C causing contraction of vascular smooth muscle
- a2 – stimulates through Gi stimulating inhibition of adenylyl cyclase causing inhibition of NA
What are pre-synaptic autoreceptors and give an example?
- Pre-synaptic auto-receptors are either muscarinic or G-protein coupled (based on type of synapse)
- Instead of being present exclusively on the post synaptic neurone, they also occur on the pre-synaptic neurone
- This leads to the control of further neurotransmitter release by means of a negative feedback loop.
- When stimulated, the pre-synaptic muscarinic receptor for acetylcholine, causes the reduction of calcium influx into the pre-synaptic terminal through calcium channels.
What is a prodrug?
An inactive precursor of a drug
How many phases are there in drug metabolism?
2
What is the purpose of the drug phases that result in a metabolised drug?
To increase polarity and add functional groups increasing chance of excretion
Where may drugs be excreted from the body?
- Bile
- Sweat
- Breast milk
- Urine
What is the name of the family of proteins in the liver responsible for metabolism of drugs
Cytochrome P450 monooxygenases
Which two components make up the elimination step of a drug?
- Metabolism
- Excretion
What is the pKa of a drug?
The pH at which 50% of the drug is ionised and 50% is not
What is Vd?
The theoretical volume necessary to contain the total amount of drug at the same concentration that it is observed in the blood plasma
dissociation equilibrium constant Ka has ——— with the affinity of the ligand
opposite relationship
when curve is on a logarithmic x-axis it will form
signmoidal curve
HIll-langmenuir equation describe relation between
ligand concertation and proportion of receptors occupied
in the theory receptors of ‘two state” modals the binding of A+B is governs by ——- and the trnasition of AR to active AR* is governs by —-
Affinity افانادي and efficacy افاكسي
another defiance for potency ?
its the expression of the activity of a drug, in terms of the concentration or amount needed to produce an effect such as EC50
Note : it does not require 100% of the receptors in the tissue to be occupied
is acetylcholine an antagonist or agonist ?
its an agonist which bind to nicotinic acetylcholine receptor ion channel, imitate a confirmational change in receptor causing the ion channels to open allowing Na+ to rapidly flow into the cell and begin biological response, to stimulate sympathetic reaction
the lower the EC50 the higher the potency True or Flas?
The lower the EC50, the less the concentration of a drug is required to produce 50% of maximum effect and the higher the potency.
Pharmacokinetic antagonism
The ‘antagonist’ reduces the concentration of the active drug at its site of action (e.g., phenobarbitone increases hepatic metabolism of the anticoagulant drug warfarin)
Chemical antagonism
the antagonist combines in solution directly with the chemical being antagonised
(e.g., chelating agents, used to treat lead poisoning, bind to heavy metals and form a less toxic chelate).
Physiological antagonism
Two agonists that produce opposing physiological actions and cancel each other out. Each drug acts through its own receptors
(e.g., adrenaline relaxes bronchial smooth muscle reducing the bronchoconstriction of histamine)
What do ligand gated ion channels consist of?
A
Separate glycoprotein subunits forming a central, ion conducting channel
What do Ligand-gated ion channels allow?
Rapid change in the permeability of membrane to certain ions
They can rapidly alter membrane potential
How G protein coupled receptors (GPCRs) turns off
- ⍺ subunit acts as an enzyme - hydrolyses GTP to GDP and Pi (signal is now off)
- ⍺ subunit recombines with β𝛾 subunit
How drugs act at enzymes
- Can affect synaptic transmission - speed up, slow down or block transmission
- Affect the receptors’ affinity
How drugs act at receptor sites
After attachment to a receptor site the drug will either initiate act as agonist or prevent a response by acting as antagonist
Kinase-linked receptors
- involved in growth and metabolism.
- Hydrophilic protein mediators
- Hour timescale
- Example - insulin
Nuclear receptors
- They are bound by steroid hormones or chemically similar analogues. That is because the steroids can cross the plasma membrane (because they are lipophilic)
- activate these receptors leading to changes in gene transcription.
- The time course for these actions are hours (or longer) compared to ligand-gated ion channels or G-protein coupled receptors.
Where is the enteric nervous system?
The enteric nervous system (ENS) is a web of sensory neurons, motor neurons, and interneurons embedded in the wall of the gastrointesinal system, stretching from the lower third of the esophagus right through to the rectum.
⍺ subunit is only signalling unit in G couple receptor True /False
False
⍺ subunit and β𝛾 dimer are both signaling units
What are the Factors which influence drug disposition ?
(((ADME )))
Absorption
Process by which a drug enters the body from its site of administration
Distribution
Process by which drug leaves circulation and enters tissues perfused by blood
Metabolism
Process by which tissue enzymes catalyse chemical conversion of a drug to a more polar form that is more readily excreted from the body
Excretion
Process that removes the drug from the body
Absorption
Distribution
Metabolism
Excretion
What does the degree of ionisation in drug absorption depend on?
pKa of the drug and the local pH
Henderson Hasselbalch equation?
What type of substance is it if Ka is large?
pH-pKa= log (A-/AH) = acid
Strong acid
What does henderson hasellbalch equation help you determine?
Determine how active a drug may be in the body
Volume of distribution? (Vd)
Equation for setting up an IV?
Vd= dose/plasma concentration
Volume of distribution : is the theoretical volume necessary to contain the total amount of an administered drug at the same concentration that is observed in the blood plasma
What is MEC?
Minimum effective concentration
What is MTC?
Maximum tolerated concentration
What does it mean if the TR of a drug is very high?
The higher the TA the safer the drug
When is concentration of steady state ( Css) reached?
Approx 5 half lives
Why is a loading dose used?
and what type of drugs is used for
Employed to decrease time to steady state for drugs with a long half-life
What is half-life dependant on?
Vd and Cl
What does drug metabolism do?
Convert drugs to more polar metabolites not readily absorbed in renal tubules, facilitating excretion
How many phases of drug metabolism and describe each phase ?
Phase 1
- Oxidation, reduction and hydrolysis
- Makes a drug more polar, adds a chemically reactive group permitting conjugation
- phase1- occur in the RHS of liver
- Phase 2 Occur in the LHS
- During Phase 2
- Conjugation (Glucuronidation, is a conjugation reaction)
Glucuronidation, a conjugation reaction
-Adds an endogenous compound increasing polarity
3 basic processes involved in renal excretion of drugs and drugs metabolites involved?
- Glomerular filtration
- Active tubular secretion
- Passive reabsorption
What is depolarisation?
What is hyperpolarisation?
The membrane potential becomes less negative (or even positive)
The membrane potential becomes more negative
Ion channels responsible for action potentials in neurones?
A
Voltage activated Na channels = depolarizing
Voltage activated K channels = Hyperpolarizing
Which direction does Na flow in sodium channels?
A
Inwardly
the driving force is Vm-Ena
Which way does K flow in potassium channels?
A
Outwardly (when positive)
The driving force is Vm-Ek
What does an absolute refractory period mean?
No stimulus, however strong, can elicit a second AP
Oligodendrocytes?
A
Produce myelinated cells in CNS (Shwann cells do it in PNS)
GI motility is increased in sympathetic response. True or false?
A
False
Decreased and sphincters are constricted
What activates G protein coupled receptors? (adrenorecptors) sympathetic
A
ACh activates the G protein coupled muscarnic acetylcholine receptors in target cell membrane
Noradrenaline
What do ligand gated ion channels consist of?
A
Separate glycoprotein subunits forming a central, ion conducting channel
Types of G protein coupled muscarinic ACh receptor subtypes at parasympathetic neuroeffector junctions?
M1-Gq= stimulates phospholipase C= increased stomach acid secretion
M2-Gi = Inhibition of adenylyl cyclase, opening of K+ channels- decreased HR
M3- Gq = stimulates phospholipase C= Increased saliva secretion and bronchoconstriction
Types of G protein coupled muscarinic ACh receptor subtypes at sympathetic neuroeffector junctions?
B1- Gs = Stimulation of adenylyl cyclase = increased HR and force
B2- Gs = Stimulation of adenylyl cyclase- relaxation of bronchial and vascular smooth muscle
A1- Gq = Stimulation of phospholipase C = Contraction of vascular smooth muscle
A2-Gi = Inhibition of adenylyl cyclase = Inhibition of NA release
What is atropine?
Competitive antagonist of muscarinic ACh receptors , does not block nicotinic ACh recpetors THUS blockade of parasympathetic division
- Used to reverse bradycardia post MI and in AChE poisoning
Absorption and elimination occur simultaneously
True/False
TRUE
Which of the following routes has the fastest method of drug delivery into the systemic circulation
Intravenous
-fluid-directly-into-a-vein-
Which of the following anti-cancer drugs is most associated with drug-induced paraesthesia?
vincristine
Side effects of vincristine to warn patients about include peripheral neuropathy, constipation and hair loss. One of the initial symptoms of peripheral neuropathy includes a foot drop, tingling numbness, pain and hypersensitivity to cold, which begins distally and progresses proximally. Vincristine is never given intrathecally (into the spinal canal) for this reason
It is defined as the risk of poor outcomes in the intervention group divided by the risk of poor outcomes in the control group
The relative risk ratio
Doubling the concentration of the reagents quadruples the reaction rate. This definition of
Second order kinetics is where doubling the concentration of the reagents quadruples the reaction rate
wht is inoisised molecules
they are molecules with positive or negative (GAIN ELECTRON)charge. THUS ONLY unionised molecules can pass through the membrane
How does the beta- 1 adrenoceptor mediate its intracellular effects?
The Beta-1 adrenoceptor is a G-protein coupled receptor, and does indeed activate adenylyl cyclase via the Gs G protein
A new drug designed to control symptoms of schizophrenia undergoes clinical trials. 400 patients are recruited and 100 patients are randomised to receive the drug. During the six-month period, 10 of these patients relapse. In the control group, there are 300 patients who are given a placebo. In this group 40 relapse. What is the relative risk of having a relapse whilst taking the drug?
Relative risk is calculated by (Experimental event rate/Control event rate). 0.133 is the control event rate.
ans : 0.75
Kinase linked receptors
- The leptin receptor is a kinase-linked receptor.
- All histamine and adrenergic receptors are GPCRs, as well as the GABA-B receptor
- It is important to note that GABA-A receptor is a ligand-gated ion channel.
How does the HER2 receptor transmit its signal intracellularly?
Through dimerization and tyrosine autophosphorylation
inverse agonists
produce an effect opposite to that of an agonist. They bind to the same receptors at the same site as an agonist
Prostaglandin receptors 2 bind to
Receptor 1 EP1 causing
EP2
EP3
EP4
- Activation of EP1 receptors causes contraction of smooth muscle in bronchi and the gut.
- Activation of EP2 receptors causes relaxation of smooth muscle in bronchi, the gut and blood vessels as well as stimulation of intestinal fluid secretion.
3. Activation of EP3 receptors causes inhibition of gastric acid secretion, increased gastric mucus secretion, contraction of intestinal and uterine smooth muscle, inhibition of lipolysis and inhibition of autonomic neurotransmitter release.
4. Activation of EP4 receptors causes contraction of bronchial smooth muscle and vasodilatation.
what is NSAIDs ?
its also called Ibuprofen
this is a non-selective COX inhibitor so inhibits the activity of COX-1 and COX-2. Inhibition of COX-2 decreases prostaglandin synthesis (via the arachidonic acid pathway) which in turn will decrease inflammation, pain, fever, and swelling
the precursor to prostaglandins
Arachidonic acid
The majority of cytokine action is mediated by which type of cell signalling?
paracrine signalling
A 25 year old patient with tonic clonic seizures gets pregnant while on the oral contraceptive pill. what drugs are she most likely to be taking?
the ones which are Cytochrome P450 enzyme inducer
- One of the known side effects of Carbamazepine is P450 enzyme induction. This case it has led to increased metabolism of the oral contraceptive leading to subcontraceptive levels
What type of receptor is a nicotinic acetylcholine receptor?
Ligand-gated ion channel
What type of receptor is a muscarinic acetylcholine receptor?
G-protein coupled receptors
What type of receptors are alpha and beta adrenoceptors?
G-protein coupled receptors
What type of receptor are mineralocorticoid and glucocorticoid receptors?
intracellular nuclear receptor
What type of receptor is the GABA-A receptor?
Ligand-gated ion channel
What type of receptor is the GABA-B receptor?
G-protein coupled receptors
How do alpha-1 adrenergic receptors mediate their intracellular effect?
They are G protein coupled receptors which activate phospholipase C enzymes via Gq proteins
Why does aspirin have a greater anti-platelet effect than other NSAIDs?
Irreversible inhibition of COX with platelets unable to synthesise new proteins
Prostaglandin E2 receptor 1
Activation of which Prostaglandin E2 receptor causes contraction of smooth muscle in bronchi and the gut?
Prostaglandin E2 receptor 1
What are the effects of platelet activating factor?
It is a potent vasodilator, bronchoconstrictor and chemotaxin and also increases vascular permeability.
What type of receptor is a prostanoid receptor?
G-protein-coupled receptor
What reaction does cyclooxygenase (COX)catalyse?
Conversion of arachidonic acid into endoperoxidase
What effect do NSAIDs have on the stomach?
They inhibit prostaglandins, leading to increased gastric acid secretion (increasing risk of stomach ulcers)
What drug should you co-prescribe with aspirin in patients at risk of gastric ulceration?
Omeprazole
What are cautions/contra-indications of ibuprofen?
Active bleeding Gastro-intestinal ulceration History of gastro-intestinal bleeding/perforation Severe heart failure
How is alkalinisation of urine beneficial during salicylate poisoning?
Decreases salicylate reabsorption in the renal tubular cells
What happen when agonist bind to A subtype of GABA receptor
GABA is ligate gate ion channel it work by allowing Cl- to go into the cell decreeing the chance of generating action potential
Drug A produce same response as drug B but drug B require more concentration what does this indicate
Drug B has lower potency than drug A since E50 is higher than drug A
- the curve is shift to the right in B case
In the presence of propranolol, a higher concentration of epinephrine is
required to elicit full anti-asthmatic actjvity. Propranolol has no effect on
asthma symptoms. Which is correct regarding these medications?
Epinephrine is an agonist propranolol is competitive antagonist
Which of the following up-regulates postsynaptic a1-adrenergic receptors?
A. Daily use of amphetamine that causes release of norepinephrine
B. A disease that causes an increase in the activity of norepinephrine neurons
C. Daily use of phenylephrine, an alpha 1 receptor agonist
D. Daily use of prazosin, an alpha 1 receptor antagonis
D you don’t want all receptors to be saturated.
Different between pharmodynamic and pharmacokimetics
- What the drug is doing to the body
- what the body is doing to the drug (drug distribution)
G protein coupled receptors structure ?
It consist of receptor domain ( intracellular domain) connect to G protein e.g Gq Gi
Gq activation
ligand bid to receptor domain casing GDP to pop out of G protein and GTP to bind in
- Gq move along cell memebrane bound to phospholipase C which break down PIP2 into diacyloglycerol and inositol trisphosphate.
- these components will activate protein kinase C that increase Ca2+ intracellular
- this could eventually stimulate the cell generate action potential
Gs stimulatory protein.
similarly Gs+GTP will move along cell membrane to activate adenylate cyclase
- ATP is convert to cyclic AMP by adenylate cyclase
- CAMP ACTIVATE protein kinase A
Gi inhibitory
Gi+ GTP adenylate cyclase
thus decrease phosphorylation of particular proteins
Tyrosine kinase receptor e.g insulin
When ligand bind two monomers combine
tyrosines cross phosphorylate each other each trigger separate cellular responses
Type of extra cellular receptors and intra cellular receptors
- Ligand gate ion channels , GPCR and tyrosine receptors are for Hydrophilic , large , polar and charged drugs.
- intracellular are for hydrophobic, small and uncharged drugs they take time e.g nucleus receptors
Tachyphylaxis
Tolearance
-
Is rapid response to large initial does of drug
- is chronic responses to repeated exposure of drug
Increase potency lead to
The strong the bond the more affinity the more potent the drug is the Low EC50
high EC50 mean the curve is shift to the right thus low the affinity
High efficiency
High drug receptor interaction ( how many receptors are bound) and high intrinsic activity
efficiency = Vmax not potent
Therapeutic index
TD50 / ED50 is the concentration of drug to produce toxic effect divide by the desire effect
the larger the therapeutic index the safer the drug
Different between full and partial agonist
Both cause cellular response but partial produce lower Vmax
What does competitive agonist does to the drug efficacy
Affinity/ potent decrease as curve is shift tie the right but Vmax stay the same
this increase EC50
What does non-competitive agonist does to the drug efficacy ?
It decrease VMAX BUT affinity and potent stays the same
Steady state
Is the concentration at which the dosing rate is equivalent to the elimination rate
dosage rate is the rate at which we delivering drug
What does the time to reach the steady state depend on
Is heavily depend upon the T½ which is about 4 to 5 half life’s therefore its where dosing rate is equal to elimination rate
- it’s not only half life it’s also depend on infusion rate as it increase SS will increase
Maintenance does
is the does that we give to the patient to maintain steady state concentration
Loading does
Is dose to reach steady state quickly
amd from there we can give maintain doses
Loading does is haven’t depend upon …….
Volume of distribution
- high it mean its require high loading does because of decrease in plasma contraction of the drug
- Low it mean it require low loading does because increase plasma concentration of the drug
Want to do if the clearance is reduce due to renal dysfunction or hepatic
Lower the maintenance does
this can be done by
- reduce dose
- change the dosing interval to be less frequent c
A 55-year-old woman is brought to the emergency department
because of seizures. She has a history of renal disease and
currently undergoes dialysis. She receives an intravenous
infusion of antiseizure Drug. What will happen in according to the half life and drug distribution in plasma
Both will increase
Two definiations of clearance
- The rate of elimination of particular drug over the plasma concentration of the drug.
- define as the volume of plasma clearance of drug per unit of time
What happen to clearance during renal dysfunction ¿
Cl will decrease and drug will accumulate
what is the difference between first order kinetic and second order kinteic ?
- happen to most drugs which is the drug concentration ( amount of drug given to patient ) is directly proportional to the rate of elimination and form exponentail curve. Half life is constant
- only to number of drugs aspirin , ethanol and phenytoin T½ is variable but rate of elimination so constant and is independent of concentration of drug given.
- See the summery table in the notes
The fraction of the drug that is eliminated per unit time is constant, this principle is related to which type of elimination kinetics?
Zero order kinetic
- which one represent first and zero order kinetic
- The rate of elimination for these drugs is independent of concentration of the drug give
- The amount of drug given to a patient is directly proportional to the rate of elimination
- zero
- first
What is the most common way of excretion of drug ?
Through urine
other excretion bath ways are
- gall bladder (Bile )
- lungs
- Git
- Breast milk
- other hair / skin
Factors which effect excretion by kidneys ? 3 paths
- Filtration
- secretion
- reabsorption
What do filtration depends on ? 2
- GFR if it decreases blood plasma concentration increases thus less filtration
- protein binding e.g albumin heavy protein bind lead to less filtration , low protein binding most of drug will be excreted thus less will be used by cells e.g cirrhosis of liver .
What do secretion depends on ?
- Drug pass into Arterioles around glomerulus then to peri tubular capillary then to tubular cells then into the lumen of the tubular to be excreted.
- solubility of the drug polar vs non polar
What do reapportion depends on ?
This happen in the DCT
- drugs moves along the concentration gradient
- drug require to have non polar character
- drugs will become more Polaris and llipophobic by the liver
What is trapping in urine
Decrease reabsorption increase increase urinary secretion.
How do we prevent weak acid reabsoption
Using sodium bicarbonate (HCO3-)
this will decrease the concentration protons alkalinize urine thus shift the reaction to right
How to prevent weak base reabsorption
Using ammonium chloride (CL- ) to acidify urine thus increase proton concentration this will shift reaction to left
Drugs can also work to inhibit tubular secretion of certain drugs such as
Probenecid prevent penicillin secretion this increase its concentration in drug
Excretion happen thr shedding of epitheluim True / false ?
false other 3 ways
What is phase I bio transformation ? 3 in the liver
- Oxidation adding O-
- Reduction adding H
- Hydrolytic reaction adding OH
What is phase II transformation
conjugation reactions
- methyl
- acetyl
- sulfa
- glutathione
- glucuronate
Which drugs are CYP450 inhibitors
- Azoles
- erythromycin
- ritonavir
- omeprazole
Which drugs are CYP450 inducers
- Rifampin
- Phenytoin
- PHB
- carbamazepine
What are the three mechanism of drug metabolism by the liver
- Toxic substance convert to non toxic
- prodrug is converted into active drug
- most commonly active drug is converted into an inactive metabolite that easily excreted
all drugs had to go through both phases of metabolism True / False
False
Enzymes of phase 1
Inside hepatocytes there are smooth endoplasmic reticulum and mitochondria
they contain heme containing enzymes called. CYP450 system
in this system there are two type of families which catalase most of the drugs
CYP3A4
CYP2D6
what two type of metabolism that can be done by CYP2D6 polymorphism
CYP2D6 in most cases convert active drug into inactive drug this can happen
- rapid metabolism this decrease amount of active drug present in the serum thus decreasing the therapeutic effect
- slow metabolism increase concentration of active drug in serum lead to increase toxicity
Liver diseases could increases the side effects of a drug True/ Flase
True
Molecule with high molecular weight and extensively bound to albumin will have ———- volume of distribution
Low
A 40-year-old male patient (70 kg) was recently diagnosed with infection involving methicillinresistant S. aureus. He received 2000 mg of Vancomycin dose. The peak plasma concentration of Vancomycin was 28.5 mg/L. The apparent volume of distribution is
1L/kg
Levodopa is a drug very commonly used to treat Parkinson’s disease that acts by being converted to dopamine in the brain. Which property should it have in order to being able to cross the BBB?
Hydrophobic
other require transporters
What is the formula to determine Vd of a drug
Vd = F x dose / C
Factors that effect blood flow ?
- Organs with an increase blood flow brain , kidney and liver
- organs with decrease blood flow skin , adipose tissue
- clinical correlation e.g shock which decrease blood flow thus lower distribution of drug
Factors effect distribution of drug 5
- blood flow
- capillaries permeability
- albumin binding
- solubility
- volume of distribution
Albumin binding and how it effect volume of distribution
Drug whcih strongly bound will have low free drugs low distribution and more concentrated in the plasma
low protein bound will have free drug increase distribution and concentrated in ICF and interstitial fluid
What is solubility of drug
The ability of drug to cross into interstitial fluid and tissue this effect by
a. Small nonpolar ( uncharged) hydrophobic drugs will have high distribution and high solubility
b. Large polar hydrophilic drug still have high distribution but poor solubility
c. Drugs bound to albumin strongly will have poor solubility due to charge and large size and very little distribution
Difference volume distribution
- Low volume distribution this
will be due to either plasma protein binding drug , large polar hydrophilic drugs , low blood flow and poor capillary permeability warfarin
- medium volume distribution
- High volume of distribution due to either free drug , small non polar hydrophobic head large amount of drug flow and increase capillary permeability e.g cholroquine
in G G-protein Signaling is terminated by agonist dissociation from the G-protein-coupled receptor
True/ False
False
Signalling only terminated by the hydrolysis NOT the agonist discussion (the action may persist WITHOUT the presence of an agonist)
Choose that gives the type of neurotransmitter released in that part of the ANS?
1. Sympathetic preganglionic neurones
2. parasymathtic post-ganglionic neurones
3. Parasympathetic pre-ganglionic neurones
4. sympathetic post-ganglionic neurones
- Everything pre-ganglionic in the ANS uses acetylcholine
- Acetylcholine is used in the post-ganglionic parasympathetic division
- acetylcholine
- noradrnaline
How Varenicline act as partial agonist
As a partial agonist, varenicline has a lower intrinsic activity than the full agonist nicotine, meaning that it produces a weaker activation of the receptor than nicotine does.
When varenicline binds to the α4β2 nAChR, it can cause a partial activation of the receptor, which leads to a release of dopamine in the reward pathway of the brain. This can help reduce the craving and withdrawal symptoms associated with smoking cessation.
An exmaples of G proteins Beta 1 and 2 angoinst
Isoprenaline and salbutamol
How does the binding of a drug to proteins in various tissues of the body affect its apparent volume of distribution?
It decreases the volume of distribution.” Tissue protein binding can reduce the amount of free drug available to distribute to other tissues
For drugs of equal potency, a drug with a high Vd will generally require a higher dose than a drug with low Vd. True / False
True becasue less of it will be remain for the site of action because most of it went into the tissues.
Bioavailability
The amount of drug that is absorbed into the body after administration
factors can affect the bioavailability of a drug?
a) The route of administration
b) The dosage form
c) The presence of food in the stomach
microsomal enzymes (for metabolism)
Hepatic drug-metabolising enzymes (microsomal enzymes) are embedded in the smooth endoplasmic reticulum of the liver hepatocytes.
what casues the drug to have Sub-therapeutic
Effects
in regrard their pharmokientic
if the rate of absorption is slower than the rate of elimination, the drug may not reach therapeutic concentrations in the bloodstream, and the efficacy of the drug may be reduced.
what casues the drug to have Therapeutic
Effects
in regrard their pharmokientic
If both absorption and elimination are occurring simultaneously
what casues the drug to have Toxic
Effects
if the rate of absorption is faster than the rate of elimination, the drug may accumulate in the body and lead to toxicity.
What is the relationship between clearance (CL), volume of distribution (Vd), and elimination half-life (t1/2) of a drug?
Clearance (CL) and volume of distribution (Vd) are independent of each other, but both determine the elimination half-life (t1/2) of a drug.
Patient has COPD and is to be administered IV theophylline.
Recommended [Drug]plasma is 10-20 mg/L.
CL for theophylline is 3L/hour.
Upper plasma limit is recommended for this patient
what is dosage rate
Dosage Rate = [Drug]PlasmaSS x CL /
F (IV=1)
60 mg/hour would need to administered (20mg/L X 3L/hour)
give an example of non-adrenergic and non-cholinergic (NANC) transmission
adenosine triphosphate (ATP) and neuropeptide Y (NPY) from sympathetic fibres
nitric oxide (NO) and vasoactive intestinal peptide (VIP) from parasympathetic fibres
preganglionic fibres, both sympathetic and parasympathetic are **myelinated **and are termed motor B-fibres. They give a **white appearance. **
By contrast, postganglionic fibres are largely unmyelinated and appear grey and are termed motor C-fibres
True
Overview of Neurochemical Transmission in the ANS
- Uptake of precursor
- Synthesis of transmitter (T), or intermediate
- Storage of transmitter (T), or intermediate #
- Depolarization by action potential #
- Ca2+ entry via voltage-activated Ca2+ channels#
- Ca2+- induced release of transmitter (exocytosis) #
- Receptor activation #
- Enzyme-mediated inactivation of transmitter (cholinergic), # or
- Reuptake of transmitter (adrenergic) #
Every step is a drug target, often of clinical significance (#)
Cocaine
mechanism of action in ANS
- it increase noradernaline in synaptic cleft lead to increase adrenorepcetor stimulation.
- this causes vasoconstraction aplpha 1 receptors and arrthymia by stimulating beata 1 reeptors
Amphetamine
mechanism of action in ANS
- Also cause increase adrenorepceptor stimulation lead to aplpha 1 and Beta 1 stimulation.
Prazosin
mechanism of action in ANS
its slective apha 1 antagoinst vasodialtor and anti-hyeprtensive
Atenolol
mechanism of action in ANS
selecctive beta 1 anatagoisnt anti anginal and anti-hypertenisve
Atenolol
mechanism of action in ANS
selecctive beta 1 anatagoisnt anti anginal and anti-hypertenisve
Salbutamol
selcctive B2broncodilator antagoisnt broncodilator
Atropine
competotve muscarinic antagoisnt ACh block all muscarinic receptors with equall affinity
Used to reverse bradycardia following MI and in anticholinesterase poisoning
Which cells in the CNS maintains homeostasis and Blood-Brain-Barrier?
Astrocytes
