B1 Flashcards
Define pharmacokinetics and pharmacodynamics
Pharmacokinetics :
- what the body does to the drug
- the processes that determine the concentration of a drug within the body over time
- Absorption , Distribution , Metabolism , Excretion ( ADME )
Pharmacodynamics
- what the drugs does to the body
- the actions of drugs on target receptors and tissue.
State the advantages and disadvantages of medicine administered orally
Advantages :
I) Convenient - does not require assistance
II) Cheaper - no need to be sterilised due to gastric juice
III) safer - non invasive
Disadvantages
I) cannot be administered to comatose , nauseous patients
II) some drugs are inactivated by first pass metabolism in liver ***
III) Adsorption of drugs vary widely - rate of gastric emptying , interaction with food , splanchnic blood flow , tablet disintegration & dissolution
State the advantages and disadvantages of medication administered sublingually and give an example of a drug that is administered so
Advantages
I) bypass first pass metabolism in liver as it directly enter the systemic circulation
II) once the desired effect has been reached the drug can be eliminated ( split out )
Disadvantages
I) only lipid soluble & non- irritating drugs can be administered
Example : glyceryl trinitrate
State the advantages and disadvantages of drugs administered rectally and give an example
Advantages
I) certain irritant / unpleasant drugs can be administered via this route
II) suitable for patients w/ recurrent vomiting or children
Disadvantages
I) inconvenient , embarrassing
II) Absorption is slow , irregular & unpredictable
III) Irritant drugs may cause rectal inflammation
Examples : diazepam ( sleeping pill ) , paracetamol
State the advantages and disadvantages of drugs administered transdermally and give example
- forms of ointment / patches
Advantages
- Convenient for patients who are forgetful (elderly) as it may last a longer time
- drugs is administered at constant rate into systemic circulation
- bypasses first pass metabolism
- easily applied
Disadvantages
- only High lipid soluble drugs can be used
- more expensive
- may cause local irritation
Example : glyceryl trinitrate
State the advantages and disadvantages of drugs administered via inhalation & give an example
- Involves votive games and liquids
Advantages
- action is very rapid as it’s is absorbed via the vast surface of the alveoli
- the concentration of drug can be adjusted moment as it is rapidly eliminated via droplet air
Disadvantages
-irritant vapours can cause the airway inflammation and secretion
Example : salbutamol
State the advantages and disadvantages of medications administered via subcutaneous injections
Advantages :
I) completely bypass first pass metabolism
II action of drugs is faster and surer ( vital in emergency )
III) gastric irritation and vomiting is not provoked.
IV) can used on unconscious , uncooperative or vomiting patients
Vi) no interference by food or digestive juices
VII) self injection is possible because deep penetration is not required
Disadvantages I) preparation is costlier due to need for sterilisation II) Method is invasive and painful III) Local tissue injury may occur IV) not to be used in patient in shock
In patients in shock , delivery of drug via subcutaneous or intravenous injection cannot be utilized as (……….j
In patients in shock , delivery of drug via subcutaneous or intravenous injection cannot be utilized as ( during shock , the peripheral vascular it’s is collapses in order to converse blood flow to the vital organs and hence the drug will not be absorbed into the systemic circulation )
State the advantages and disadvantages of administration of drug via intramuscular injection
Advantages :
- irritant drugs can be administered
- action of absorption is faster and surer
- First pass metabolism is bypassed
- gastric irritation & vomiting is not provoked
- can be used in unconscious , uncooperative or vomiting patients
- no interference by food or digestive juices
Disadvantages
- preparation is costlier as sterilisation is required
- deep penetration is required hence self administration is not advisable
- local tissue injury may occur
- chance of contamination / infections
- procedure is invasive and painful
- should be avoided in patients taking anticoagulants medicine to prevent uncontrolled bleeding
State the advantages & disadvantages of a drug administer via IV route
Advantages :
- Bypass the process of absorption in GIT & first pass metabolism
- action of drug is immediate
- greatest reliability and control of the drug reaching the systemic circulation ( 100% bioavailability)
- highly irritant drug can be given ( due to dilution of flow )
- can be administered to unconscious , vomiting patients
- titration of the dose with response is possible
Disadvantages
- costlier as sterilisation is required
- procedure is invasive , painful
- risk of embolism
- risk of toxicity and exposure of vital organs to high concentration of the drug
- should not be used on patients in shock
(……) are widely administered via intravenous route in critically I’ll patients & medical emergencies
(Antibiotics and antineoplastic agents ) are widely administered via intravenous route in critically ill patients & medical emergencies
State and describe the mechanism of drug absorption ( bio-transportation)
1) Passive diffusion
- Rate of diffusion directly proportional to concentration gradient
* **-Highly lipid soluble drugs diffuse rapidly while less lipid soluble diffuse slowly
- examples : ( weakly acidic drugs like phenytoin sodium , phenobarbitone sodium , sodium salicylate ; weakly basic drugs like morphine hydrochloride , amphetamine sulphate & atropine sulphate )
- acidic drugs absorbed better in acidic medium , alkali drugs absorb better in alkaline medium ( acid + alkaline —> ionise —> attract water—> hard to cross biological membranes )
2) Filtration
- dependent on molecular size & weight
- If smaller —> can pass through cell membrane / para cellular space easier
- purely physical process
- rate of diffusion dependent on pressure gradient
- important mechanism for drugs of smaller molecule size : glucose , urea , alcohol
3) active transport
- ex : sympathomimetic amines , transport choline into cholinergic neutrons , absorption of L-dopa from the intestine
4) Facilitated diffusion
Ex : glucose , amino acids in the brain , anti metabolite anti cancer drugs , antiviral drugs , vitamins like thiamine ( B1) , riboflavin ( B2) and B12
5) Pinocytosis ( cell drinking )
- transport across the cell in particulate form by formation of vesicle
- applicable to proteins and big molecules but contributes little to transport of most drugs
Describe some factor affecting drug absorption
1) Physiochemical properties of the drug
- physical state : liquid better than solid
- lipid solubility : higher lipid solubility is more absorbed easily
- ionisation : unionised form is more absorbed easily
- particle size : smaller —> better ( exception m anthelmintics —> larger particle size , not absorbed easily in GIT , produce better effects on gut helminths.
- Disintegration time : time taken for tablet / capsule to break up into smaller pieces
- dissolution time : time taken for particles to go into solution , shorter —> better
2) route of drug administration
3) pH & ionisation
- strongly acidic / basic —>remain ionised —> difficult to be absorbed
- ex :heparin ( acidic ) , aminoglycosides ( basic )
4) presence of food
5) Presence of other drugs -
- Vit C increase absorption of iron , antacids reduce absorption of tetracycline and many other drugs
6) Area of absorbing surface
- in SI , drugs are absorbed better
7) Presence of disease
8) Pharmacogenetic factor
- pernicious anemia —> B12 not absorbed
State & explain the factors affecting bioavailability of a drug ( FPM , enterohepatic recycling & hepatic disease )
1) First pass metabolism
- absorption of a drug administere via oral route : gut wall —> portal vein —> liver —> hepatic vein —> systemic circulation
- during this process some drugs get degraded before they enter the systemic circulation
- result in decreased bioavailability & therapeutic response
- drug should be given in higher dose orally or parental route
- example : propranolol , GTN , L- dopa , morphine
2) Enterohepatic recycling
- Once drug is metabolise in liver —> excreted in bile to intestine in form of glucoronides —> hydrolysed by intestine, bacteria into free drugs —> reabsorbed again and goes to liver
- this prolongs the action of the drugs and increase bioavailability
- example : morphine , doxycycline , oral contraceptives
3) Hepatic disease
- reduces drug metabolism and hence increase bioavailability of drugs that undergo FPM
- example : propranolol , labetalol , morphine , GTN
State & describe the factors affecting the distribution of drugs
1) Lipid solubility
- more lipid soluble —> distribute in all body compartments —> increase in Vd
2) Molecular size
- larger molecule size —: cannot diffuse past biological membranes —> stay in systemic circulation ( plasma)
- decrease in Vd
3) Degree of plasma protein binding
- drugs that bind tightly plasma protein —> stay in plasma —> lower Vd
4) Affinity for different tissue
Ex: lipid soluble drugs —> bind tightly to adipose tissue —> increase Vd
5) Fat lean body mass ratio
- if amount of fat in the body is high , Vd will be high as the drugs are stored within adipose tissue
6 ) Disease like CHF , uraemia , cirrhosis
Explain redistribution using thiopental sodium as an example
- observed within highly lipid soluble drugs ( example : thiopental sodium )
- after administered the drug is distributed to organ w/ higher blood flow ( brain , heart , kidney) which causes general anaesthesia
- then , the drug is redistributed to less vascular but bulkier tissue ( fat , muscle) as it diffuses out of the brain through blood circulation
- this causes the termination of action of drug ( patient become awake )
- hence the action of single dose of thiopental is very short
Describe the physiological barrier to drug distribution
1) Blood brain barrier
- BBB is constituted by the tightly placed endothelial cell of the brain capillaries & astrocytes & glial cells which envelop these capillaries
- only lipid soluble & unionised drugs can cross BBB ( ex : barbiturates )
- pathological state such as meningitis & encephalitis increase permeability of BBB & allow normally impermeable substances to enter the brain ( penicillin G )
2) Placental barrier
- lipid in nature & allows the passage of non polar ( unionised) lipid soluble drugs via passive diffusion
- Active transport for amino acid and glucose & pinocytosis for maternal immunoglobulin also exist
- some transporters also operate in placenta
- not a complete barrier hence drug administration during pregnancy is restricted as the fetus will be exposed to drug
3) Blood test barrier
- limits the effectiveness of chemotherapeutic agents in treating testicular neoplasms
Explain the clinical importance of drugs binding to plasma protein
- Drugs are bound to plasma protein ( example : albumin , alpha 1 glycoprotein) , acidic drugs bind to albumin, alkaline drugs bind to alpha 1 acid glycoproteins
- plasma protein binding favour drug absorption
- It acts as a temporary store for drugs
- Increased plasma protein binding , decreased Vd and delay metabolism of the drugs and hence has longer duration of action
- Highly plasma protein bound drugs are difficult to be removed by hemodialysis and is not available for filtration at the glomeruli hence excretion is also delayed
- In disease states such as anaemia , renal failure and chronic liver disease , plasma protein are low and there will be free form of the drug leading to toxicity and hence the dosage must be reduced.
Drugs are bound in plasma to plasma protein such as (……)
Drugs are bound in plasma to plasma protein such as ( albumin and alpha 1 acid glycoprotein )
- acidic drugs bind to albumin
Basic drug bind to acid glycoproteins
State the sites of biotransformation
1) Liver (major)
2) gut
3) Kidney
4) Lungs
5) Brain
6) Skin
Define the biotransformation
The enzyme-catalysed conversion of drugs to their metabolites
- fundamental role to inactivated and detoxify the drug and make them less lipid soluble —>easily excreted in urine
Describe phase 1 reactions of biotransformation
- non synthetics or functionalization reaction ( opening up )
- Carried out by hepatic microsomal monooxygenase system enzymes ( monooxygenases , cytochrome P450 enzymes , UGT ) which are located on SER of liver , kidney , intestine & lungs
Reactions
I) oxidation
- the most important RXN
- Oxidationr rxns include : hydroxylation , oxygenation & o-dealkylation
-occurs by cytochrome P450 family of enzymes (CYP3A4 , CYP2D6 )
II) hydrolysis
- esters & amides are hydrolysed by variety of enzymes
- ex: cholinesterases & plasma esterases hydrolyse choline esters , local anaesthetics , esmolol
III) reduction
- alcohols , aldehydes , & quinones are reduced
The cytochrome P450 isoenzyme ( ………) is responsible for the metabolism of 50% of all drugs , while ( …… ) metabolises 20% of all drugs
The cytochrome P450 isoenzyme ( CYP3A4) is responsible for the metabolism of 50% of all drugs , while ( CYP2D6) metabolises 20% of all drugs
** Inhibition of CYP3A4 is responsible for the important drug interaction w/ terfenadine , astemizole , and cisapride
Describe enzyme inhibition & enzyme induction
Enzyme inhibition
- One drug can competitively inhibit the metabolism of another if it utilizes the same metabolising enzyme (CYP ) or cofactors
- Inhibition of drug metabolism can lead to toxicity of the object drug
- Fast time course of action compared to enzyme induction
- Ex: Erythromycin , sulfonamides , sodium valproate , isoniazid
Enzyme induction
- drugs which increase the synthesis/ decrease the breakdown of microsomal enzyme
- increase the rate of metabolism of the inducing drug & other drugs —>. loss of therapeutic effect & duration of action
- it may increase the intensity of action of drugs that are activated by its own metabolism ( L dopa —> dopamine , codeine —> morphine
-Induction takes 4-14 days
Example : Rifampicin , phenobarbital
State the consequences of enzyme inhibition & enzyme induction
Enzyme inhibition
- decrease the rate of metabolism of a drugs —>. Leads to longer action of drug , may also precipitate toxicity & cause harmful side effects
Enzyme induction
- Increase rate of metabolism of drugs —> shortening its therapeutic effect
- increase intensity of action of drugs that are activated by metabolism ( L-dopa , dopamine , codeine —> morphine)
- use of enzyme-inducing drugs may interfere w/ the proper dosage of other drugs
- can cause tolerance if the drug induced it’s own metabolism
- precipitation of acute intermittent porphyria
State some examples of enzyme inducers & enzyme inhibitors
Inducers (SCRAP GP)
- Sulfonylureas
- Carbamazepine
- Rifampicin **
- Alcohol
- Phenytoin
- Griseofulvin
Inhibitors ( SICK FACES)
- Sodium valproate ***
- Isoniazid
- Cimetidine
- Ketoconazole
- Fluconazole
- Alcohol binge drinking
- Chloramphenicol
- Erythromycin ***
- Phenobarbital **
List the routes by which a drug can be excreted
1) Kidney (main )
- ex: penicillin , digoxin
2) Hepatobiliary system
: glucoronide- conjugated drugs can undergo EHR
- ex : oral contraceptives , erythromycin , Rifampicin
3) Lungs
- ex: general anaesthetics
4) Saliva & sweat
- ex : lithium , pot , iodine , Rifampicin , heavy metals
5) Milk
- not significant mechanism
- can be toxic to baby
Describe the renal excretion of drugs (GF , TR , TS )
1) Glomerular filtration
- all drugs ( hydrophilic / lipophilic ) which are not highly bound to plasma proteins are filtered
- GF is dependent on renal blood flow , and degree of plasma-protein binding
2) Tubular reabsorption
- occurs via passive diffusion
- depend on lipid solubility & ionisation @ existing urinary pH
- Lipid solubility : the greater the lipid solubility m the greater the reabsorption
- ionisation : the greater the ionisation , the greater the excretion
3) Tubular secretion
- occurs via transporter ( OAT : organic acid transporter , OCT : organic cation transporter
- exogenous substances are more secreted , while endogenous substances are more reabsorbed ( Uric acid)
- active secretion promotes disassociation of drugs from plasma protein —> increase secretion of drug into tubules
- drugs utilising the same transporter (OAT ) compete ( penicillin , probenecid , uric acid )
State the drugs transported by OAT & OCT during tubular secretion in renal excretion of drugs
OAT —> transport anions ( -very charged )
- probeneacid
- penicillin
- uric acid
- drug glucoronides
- sulfates
OCT
- thiazides
- Amiloride
- Triamterene
- Furosemide
- Choline
State the possible outcomes of drug metabolism
1) Conversion of active drug—> inactive metabolite
- ex : ibuprofen , paracetamol ,lidocaine
2) Conversion of inactive drugs —> active metabolite
- ex : L-dopa —> dopamine
3) Conversion of active drug —>active metabolite
- ex: codeine —> morphine
State the sites of biotransformation
1) Liver (major )
2) Gut
3) Kidney
4) Lungs
5) Brain
Describe phase 1 reactions of biotransformation
- non synthetic or functionalization reaction ( opening up )
- carried out by heparin microsomal monooxygenase system enzyme ( monooxygenase , cytochrome P450 enzyme , UGT ) which are located smooth endoplasmic reticulum of liver , kidney , intestine and lungs
Reaction
I)Oxidation
- the most important reaction
- oxidation reaction include : hydroxylation , oxygenation & o-dealkylation
- occurs by cytochrome P450 family of enzyme ( CYP3A4 , CYP2D6 )
II) hydrolysis
- esters & amides are hydrolysed by variety of enzyme
- ex : cholinesterases , plasma enterases hydrolysed choline ester , local anaesthetics , esmolol
III) reduction
- alcohols , aldehydes & quinones are reduced
The cytochrome P450 isoenzyme ( ……………… ) is responsible for the metabolism of 50% of all drugs , while ( …………….. ) metabolized 20% of all drugs
The cytochrome P450 isoenzyme ( CYP3A4) is responsible for the metabolism of 50% of all drugs , while ( CYP2D6 ) metabolized 20% of all drugs
Describe the phase 2 reaction with examples
- synthetic / conjugation reaction occur ( addition )
- conjugation of drug or phase 1 metabolite with an endogenous substrate ( glucoronate , acetate , sulfate , glycine , glutathione
- forms a water soluble , polar , highly ionised metabolite —>easily excreted in urine or bile
Reactions
I) Glucoronide conjugation
- most important
-carried out by UDP glucoronosyl transferase ( UGT)
- compounds with OH or COOH group easily compounded with glucoronate
- glucoronide conjugates can undergo enterohepatic recycling —> extend duration of action
- ex : diazepam , aspirin , chloramphenicol , oral contraceptives , bilirubin
II) acetylation
- carried out by N-acetyl transferase
- ex: sulfonamides , isoniazid , PAS , dapsone , hydralazine , clonazepam , procainamide
III) Methylation
- carried out methyltransferase
- ex : adrenaline , histamine , nicotine acid , methyldopa , captopril , mercaptopurine
IV) Sulfate conjugation
- carried out by sulfotransferase
- on phenolic compounds ( chloramphenicol ) & sterols ( adrenal & sex steroids )
V) Glutathione conjugation
- important in detoxifying episode formed in phase 1
- eg m paracetamol - NAPQI , halothane
- NAPQI -> conjugate with glutathione -> decrease glutathione in body -> increased oxidative stress -> liver failure
VI) Glycine conjugation
- not a major pathway
Describe the enzyme inhibition & enzyme induction
Enzyme inhibition
- One drug can competitively inhibit the metabolism of another if it utilises the same metabolising enzyme ( CYP ) or cofactor
- Inhibition of drug metabolism can lead to toxicity of the object drug
- Fast time course of action compared to enzyme induction
- ex: erythromycin , sulfonamide , chloramphenicol , sodium valproate
Enzyme induction
- drugs which increase the synthesis / decrease the breakdown of microsomal enzyme
- increase the rate of metabolism of the inducing drug & other drugs -> loss of therapeutic effects & duration of action
- it may increase the intensity of action of drugs that are activated by its own metabolism ( L- dopa —> dopamine , codeine -> morphine
- induction takes 4-14 days
- ex: Rifampicin , phenobarbital , phenytoin
State the consequence of enzyme inhibition & enzyme induction
Enzyme inhibition
- decrease the rate of metabolism of drug —> leads to longer action of drugs , may also precipitate toxicity & cause harmful side effects
Enzyme induction
- increase the rate of metabolism of a drug —> shortening its therapeutic effect
- increase intensity of action of drugs that are active by metabolism ( L- dopa -> dopamine , codeine -> morphine
- use of enzyme inducing drugs may interfere with the proper dosage of other drugs
- can cause tolerance if the drugs induce it’s own metabolism
- precipitation of acute intermitten porphyria
State some example of enzyme inducer & enzyme inhibitors
Inducer ( SCRAP GP )
- sulfonylureas
- carbamazepine
- rifampin
- alcohol
- phenytoin
- griseofulvin
- phenobarbital
Inhibitor
- sodium valproate
- erythromycin
Define bioavailability
The rate at which and the extent to which the active concentration of the drug is available at the desired site of action ( or practically speaking in the blood stream )
Describe the term of ‘dentrifies’’
- Therapeutic aid meant for cleaning the teeth with help of toothbrush
- ex : toothpowder , toothpastes
- contain active ( therapeutics) & inactive ingredients ( non therapeutic )
- active ingredients
I) anti-caries agents : fluorides ( sodium fluoride ) , non-fluoride ( xylitol)
II) anti-calculus : tetrapotassium , sodium pyrophosphate , triclosan / copolymer
III) anti-plaque or anti-gingivitis agents : zinc citrate , triclosan
IV) Desensitizing agents : standouts fluoride , potassium nitrate / citrate / chloride
V) Anti halitosis agents : essential oils , chlorine dioxide
Inactive ingredients :
I) Abrasive : chalk (CaCO3)
II) binder : gum Arabic
III) humectants : glycerine
IV) Surfactants / detergents : SLS
V) Buffering agents : sodium bicarbonate
VI) sweetening , flavouring agents : peppermint oil , sorbitol
Describe the term bleaching agents in dental practise
- Peroxide-containing products used for whitening b removal of pigmentation of the teeth ( ex : hydrogen peroxide , carbamide peroxide , sodium perborate )
- for teeth whitening to remobpve intrinsic &extrinsic stains of teeth
- may be administered in clinic or self-administered at home ( in the form of trays , strips , toothpastes , mouthrinse , gels , gums , paint-on products
State the adverse effects of bleaching agents
1) tooth sensitivity
- due to pulpal irritation caused by penetration of peroxide through enamel into pulp
2) alter the hardness of enamel
- calcium & phosphorus content within dental hard tissue altered
3) Affect soft tissues & cause gingival irritation
4) Affect restorative material
Describe the term of disclosing agents in dental practise with example
- substance applied to teeth which reveals the presence of dental plaque which is invisible
Example :
I) erythrosine : red dye , stains plaque area red but may also stain soft tissues
II) fluorescent dye : stains plaque yellow , special light is required to see hence more expensive
III) 2 tone solution : mature plaques are stained blue , new plaques are stained blue
IV) Iodine-containing solutions : not usually preferred ( allergy , unacceptable taste )
In absorption of drugs , a drug with (………. ) pH as the environment will be absorbed better ( …………………………….. )
In excretion of drugs , a drugs with (………… ) pH as the environment will be excreted better (……………… )
The presence of ( ……………. ) contributes to halitosis
The presence of ( volatile sulphur compounds) contributes to halitosis
Describe the term “ obtundents “ used in dental practice ( definition MOA , examples )
- Agents that abolish dentine hypersensitivity and make excavations painless
- used has declined after use of local anaesthesia
Mechanism of action
I) paralysing sensory nerves ( eg . phenol , menthol , thymol , clove oil )
II) precipitate of protein
III) cause destruction of nervous tissue
Phenol - protoplasmic poison ( paralysis nerves j
- initial irritation followed by numbness
Thymol , methol , clove oil , camphor - paralyses sensory nerves - initial irritation followed by numbness
Silver nitrate& Zinc chloride : Astringent - precipitate superficial protein
Paraformaldehyde : Liberates formaldehydes , which precipitate proteins
Describe the term mummifying agents and give some examples
- agents used to harden & dry the soft tissue of the pulp & root canal
- Hardening makes the tissue resistant to infection
- used in combination with other compound in paste form
Examples:
I) Tannic acid : astringents , precipitates proteins & hardens tissue
II) Iodoform
III) Paraformaldehydes
IV) Liquid formaldehyde : irritant , not used alone -> used in combination with zinc oxide , thymol , LA , glycerine
V) Cresol
List the uses of mouthwash
Uses :
1) prevent plaque formation
2) Treat gingivitis , caries & stomatitis
3) Relieve soreness of teeth or gums following flossing & use of denture
4) reduce halitosis
5) Keep oral cavity moist eg in xerostomia
6) treat oral burns , aphthous ulcer , alveolar osteitis
7) Maintain oral hygiene in persons with physical impairment ( old , disabled )
List the composition of mouthwashes
1) Bisguanide : chlorhexidine gluconate
- antimicrobial agents - > treat gingivitis & plaque
2) Essential oils : phenolic compounds h thymol , menthol j
- kill microorganism , scavenge free radicals , slow down maturation of plaque
3) quarternary ammonium compounds : cetylpyrdinium chloride
4) Fluorides
Define the term receptor
- Macromolecular proteins capable of binding with specific functional group of drugs or endogenous substances
- present on cell membrane , cytoplasm
Define the term ligand
-any molecule either an endogenous substances ( like a hormone , autacoid or NT ) or a drug which attaches to a receptor and elicit or blocks a response
Define the term of affinity
- The ability of the ligand ( drug) to get bound to the receptor
Define the intrinsic activity or efficacy
- the ability of the ligand ( drug) to produce actions after combining with the receptor
Define the term of agonist , full agonist , antagonist , and inverse agonist
Agonist :
- a ligand ( drug )that binds to receptor and alters the receptor state resulting in a biological response
- It has high affinity & intrinsic activity ( adrenaline & morphine )
Full agonist
- a drug which can produce a maximum response that the target system is capable of
Partial agonist
- A drug that binds to the receptor but produces sub- maximal response ,
It can acts as antagonist in the presence of agonist . Also known as agonist antagonist
Antagonist :
- A drug which combine with the receptor and prevent binding of agonist to the receptor or blocks its action.
- Has affinity but no intrinsic activity
- Increased concentration of agonist can overcome the blockage & produce maximum effect
Partial agonist
- Adrugs that binds to receptor but produces sub-maximal response
- It can acts as an antagonist in the presence of agonists . Also known as agonist antagonists
Antagonists
- A drug combine with the receptor and prevents binding of agonist to he receptor or blocks its action
- Has affinity but no intrinsic activity
- increased concentration of agonist can overcome the blockage & produce maximum effect
Inverse agonist
- a drug that has full affinity of the receptor but produces effects opposite to that of an agonist
- ex : agonist - benzodiazepines , antagonist - B- carboline
- Flumazenil is a ‘ neutral ‘ antagonist — reverses both the sedating effects of benzodiazepines & the proconvulsant effect of B-carboline
Describe the 4 types of receptor pharmacodynamics with examples
1) Ligand-gated ion channels
- ligand binds to a receptor on an ion channel
- transmits signal across the plasma membrane by increasing the transmembrane conductance of ions (Na+, K+ , Cl-, Ca++ )
- ex : cholinergic nicotinic ( Ach ) , GABAa receptor, Glutamate receptors , 5-HT receptors ( serotonin )
2) G- protein coupled membrane receptors
- binding of molecules to G-protein activates ion channels or other enzymes ( adenylate cyclase , phospholipase C) which then generate second messenger
- secondary messengers : cGMP , cAMP , Ca2+ , IP3-DAG , nitric oxide
- ex : GABAb receptor , a and B adrenoreceptor , Muscarinic acetylcholine receptor , opioid receptor
3) Enzyme-linked receptor / Tyrosine kinase receptor
- ligand bind to receptor -> receptor converts from its inactive monomeric state -> dimeric state in which 2 receptor polypeptides bind non-covalently -> cytoplasmic domains on specific tyrosine residues become phosphorylated -> enzymatic activities activated -> catalysed phosphorylation of substrate proteins
- ex : insulin , atrial natriuretic peptide , epidermal growth factor , cytokine
4) Intracellular ( nuclear receptor )
- binding of ligand to receptor stimulate the transcription of genes by binding to specific DNA sequences
- ex : glucocorticoids , mineralcorticoids , sex steroids , thyroxine , vitamin D
State the characteristics of drug receptor ( location , effector , coupling , examples , response time )
Ligand-gated on channels Location : Membrane Effector : Ion channels Coupling : Direct Examples : Nicotinic , GABAa , Glutamate Time for response : Milliseconds
G- proteins coupled receptor Membrane Channels or enzyme G proteins Muscarinic Adrenergic receptor Second
Enzyme-linked receptor Membrane Enzyme Direct Insulin , growth factor , cytokine Minutes or hours
Nuclear receptor
- Intracellular
- Gene transcription
- Via DNA
- Steroid , thyroid hormone , Vitamin D
- Hours
Describe the physical non receptor mediated mechanism of drug action with example
I) Osmosis
- magnesium sulfate acts as purgative by exerting osmotic effect within the lumen of small intestine
- mannitol ( osmotic diuretics ) changes osmolarity in the nephron
II) Adsoprtion
- Kaolin acts as an anti diarrhoeal agent by adsorbing bacterial toxins
- Methypolysiloxane and simethicone adsorb gases & acts as anti flatulent
III) Astringents - protect mucosa by firming up mucosal surfaces via percipitation by proteins
- example : tannic acid in gum paints
Describe the chemical non receptor mediated mechanism of drug action with examples
I) Chelation
- used removal of heavy metals via excretion via formation of water- soluble compounds
- Dimercaprol ( BAL) chelates mercury , penicillamine chelates copper
II) Neutralization
- antacids act by neutralising gastric hyperacidity
- heparin neutralised clotting factors
Describe non-receptor mediated mechanism of drug action via counterfeit or false incorporation mechanism
- ex: Sulfa drugs ( antibiotics ) & antineoplastic drugs like methotrexate
- sulfa drugs resembles PABA -> gets falsely incorporated into bacterial folic acid synthesis -> hinders growth & development of bacteria
- methotrexate resembles folic acid t-> bind irreversibly to dihydrofolate reductose -> prevent synthesis of folinic acid -> synthesis of purine nucleotides & DNA is hindered -> death to cancer cells
Explain the term potency
- the amount of drug needed to produce a response
- indicated by dose -response ( DRC) on dose axis
- quantity of drug required to produce 50% of the maximal efficacy — (ED50) is used to compare the relative efficacy of drugs within the same class
Explain the term efficacy
- Maximal efficacy is the maximal effect a drug can produce with increasing dose
- it is inflated by the height of the dosage-response ( DRC )
- increasing dosage beyond this does not increase efficacy but only increase adverse effects
Describe the term “ therapeutic index “
- It is ratio of the dose that produces toxicity to the dose that produces a clinically desired / effective response in a population of inidividuals
- Therapeutic index : TD50 or LD50 / ED50
- It is use as a measure of drug safety
- LD50: drug dose that produce a toxic effect in 1/2 population
- ED50 : drug dose that produces a therapeutic responses in 1/2 population
A drug with a therapeutic index (TI) of ( ……….. ) should be used cautiously as patients may experiency toxicity along with therapeutic effect
Ex: ( …………………. )
A drug with TI (…………. ) can be used with ease as they are safe at recommended doses
Ex: ( ……………….. )
A drug with a therapeutic index (TI) of ( <2 ) should be used cautiously as patients may experiency toxicity along with therapeutic effect
Ex: ( digoxin , lithium , warfarin )
A drug with TI ( >2 ) can be used with ease as they are safe at recommended doses
Ex: ( paracetamol , penicillin )
List glucocorticoid based on their duration of action
1) Short acting ( 8-12 hrs )
- hydrocortisone
2) Intermediate acting (12-36hrs)
- prednisone , Prednisolone
3) Long acting ( 36-72hrs )
- dexamethasone , betamethasone
Describe the actions of glucocorticoid
1) Increase blood glucose levels
- Stimulate gluconeogenesis & glucagon deposition in liver
- inhibits glucose uptake & utilisation
- may lead to hyperglycaemia & steroidal diabetes
2) Anti- inflammatory
- inhibits production of phospholipase A2 due to production of lipocortin which is involved in prostaglandin & leukotriene synthesis
3) Lipolysis
- redistribution of fat over neck , face and shoulder ( moon face , buffalo hump , fish mouth )
4) Mineralcorticoid activity
- reabsorb Na & H2O , excrete K+
- can cause hypertension & may lead to congestive heart failure
5) On bone
- antivitamin D action
- increase bone resorption by increasing osteoclast activity , inhibit Ca absorption and increase Ca excretion
- prolong use may lead to osteoporosis and pathological fracture
State the adverse effect of glucocorticoid
1) Hyperglycaemia
2) Immunodiefiency leading to development of infection like oral thrush ( candidiasis )
3) Increased skin fragility & impaired wound healing
4) Osteoporosis due to reduced calcium absorption
5) Acne vulgaris
6 ) Cushing syndrome : moon faces , buffalo hump , abdominal striae , peripheral wasting
7) Proteolysis
List the topical glucocorticoid
1) Hydrocortisone
2) Prednisolone
3) Triamcinolone
4) Dexamethasone
5) Betamethasone
State some ways to minimise hypothalamic- pituitary -adrenal (HPA) axis suppression during long term steroid therapy
I) Slowly withdraw corticosteroids for patients undergoing long term GC therapy (> 2 weeks ) with tapering doses
- allows the adrenal gland function to recover gradually
II) Use of topical steroids is preferred
- oral & IV has higher risk to develop HPA axis suppression
III) Use short acting ( hydrocortisone ) or intermediate-acting GC ( Prednisolone )
IV) Use alternate-day steroid therapy in chronic conditions like bronchial asthma , nephrotic syndrome , SLE
V) Timing of treatment
- single dose at 8AM — matches body circadian rhythms
- if daily dose is high , 2/3 in the morning & 1/3 in the morning
Describe the therapeutics uses of glucocorticoid especially in dental practise
1) For endocrinal uses
I) Acute adrenal insufficiency
- the sudden defective production of corticosteroids eg : abrupt withdrawal of GC in long term steroid therapy ( medical emergency )
- treat with IV hydrocortisone & IV normal saline with 5% glucose to correct fluid & electrolyte imbalance
II) Chronic adrenal insufficiency
- eg :Addison deficiency
- treat with oral hydrocortisone with adequate salt & water
2) For non- endocrinal uses
- mainly used for anti-inflammatory ( eg arthritis ) & immunosuppressant ( eg. Transplants ) effects and also anticancer ( lymphoma & leukaemia )
- dental- related examples :
I) Recurrent aphthous stomatitis / canker sores — repeated formation of benign , non- contagious ulcers
II) Chronic ulcerative stomatitis
III) TMJ pain — intrarticular triamcinolone is used
What are dental implications for patients undergoing glucocorticoid therapy ?
- prophylactic antibiotics should be given prior to dental procedures as GC are immunosuppressant
- wound healing is impaired in pts on long term GC therapy
- In patients on GC therapy , the preferred analgesic is paracetamol
- abrupt stoppage of GC therapy is dangerous after long term treatment as it can cause acute adrenal insufficiency
