Final Flashcards
(52 cards)
Non-specific physical interactions (not absorbed)
osmotic diuretics= mannitol
antacids- Mg(oh)2 against hyper acidity
laxatives = MGSO4 osmotic laxative
Chelators= EDTA/ Defeoxamine iron poison/ Lead poison
biochemical interactions without receptor
- Inhibition of Enzymes
1.1 NON steroidal anti inflammatory drugs
(AChE)
Meloxicam, aspirin, ibuprofen
1.2 ACE inhibitors
angiotensin converting enzyme inhibition, a hypotensive drug
Enalapril
1.3 Acetylcholine inhibitors
acetylcholine enzyme
Neostigmine
1.4 xanthine oxidase inhibitors, same is inhibited
treatment of gout
Allopurinol
biochemical interactions without receptor
- Damage to DNA
2.1 anticancer drugs cause DNA damage, To treat tumors
Cytabarin
biochemical interactions without receptor
- Transporters
3.1 Proton pump inhibitors.
inhibit the proton K ATpase pump
to treat hyperacidity
Omeprazole
3.2 Diuretics
biochemical interactions without receptor
4.Ion Channels
Local anaesthetics
prevents iron from entering specific channels
Lydicane blocks na+
biochemical interactions with receptors
Ligand gated ion channels
1.1 nicotinic acetylcholine receptors
na channels open letting Na enter. Ap is formed. Ca2+ flows out and repolarization occurs
where: in neuromuscular junction, anatomic ganglia and CNS
Neuromuscular junction 2 alpha, beta, o, e
autonomic ganglia 2 alpha and 3 beta
anatgonist is curare
1.2 Gaba A receptor- gated Chloride Ion Channel
stimulationinhibits muscles due to Cl entering the cell causing hyperpolarization
GABA agonists (Narcotics)
Orthosteric: meaning binding happens on GABA alpha site
Allosteric: meaning binding happens on Benzodiazepine site right next to GABA (Diazepam and Alprazolam)
PROPOFOL ACTS AS BOTH, RAPID SEDATION OCCURS WITHIN SECONDS.
biochemical interactions with receptor
G- Protein coupled receptor
4 receptors linked to adrenaline
b1- heart induceds tachacardia and has a positive endtropic effect
b2- Bronchodilation, Vasodilation (uterus)
a1- Vasoconstriction
a2- sedative
2.1 G alpha-s Coupled receptor (stimulation)
-receptor type: Beta adrenoreceptor
-Ligand: Adrenaline
Beta1: PKA activates Ca2+, stimulates cardiac contractions, positive inotropic, chronotropic, dromotropic. Less effect on kidney
Beta2: cAMP inhibits MLCK(myosin- like chain Kinase) but promotes MLCP
MLCP stops smooth muscle contraction (relaxation)
Agonists Clenbuterol, Terbutaline
2.2G alpha i ( inhibitory)
Limit prod. of cAMP (inhibits AC)
decrease in chronotrophy and Dromotropic
M2 Cholinergic receptors
ligand:acteylcholine
inhibits AC (adenylate cyclase) which inhibits cAMP
slows heart rate and smooth muscle
stimulation leads to bradycardia
Atropine blocks ligation with Ach
Alpha2
ligand: noradrenaline
sedative, antihypertensive effect.
blocks CA2 from entering vesicles. allows influx of K+ ions
Xylazine (agonist for alpha 2 and a sedative
2.3G alpha q receptors
Ligand as conversion of GDP and GTP
activation of phospholipase C (PLC) and conversion of PIP2 and IP3 and DAG
DAG activates protein kinsae C
alpha 1 receptors: vasoconstriction
h1 receptors : histamine
serotonin receptors
Receptor- ACtivated Tyrosine Kinases
contains amino acid Tyrosine
3.1 Insulin receptor substrate
- bind to insulin receptor
-autophosphyrlation
- activation of IP3 K
3.2 JAK/ Janus Kinase Inhibitors
- JAK binds to Cytokine receptors
-2STAT bind and are phosphorylated
1 STAT moves into nucleus and begins to stimulate transcription
stimulates production of IL and IgE
JAK INHIBITORS BIND TO THE CYTOKINE RECEPTOR AND STOP SIGNALLING
Oclacitinib for atopic dermatitis. Mainly on JAK-1 inhibits multiple IL’s against inflammation and IL31 (pruritis)
Intracelluar Nuclear Receptors
must be lipophilic to cross nuclear membrane (steroids or cortisol)
bound to HEAT SHOCK PROTEIN (HSP90)
Slow process meaning slow acting and long lasting action
drug receptor relations
Ligand which binds to recpetor to form a drug- receptor complex
binding is referred to docking the alteration of conformation leads to an effect
strength of binding is known as affinity
Van der Waals forces reversible reactions?
Dissociation constant
“K”
equilibrium state between the rate of association and dissociation
Kd= dissociation constant (Kd=kd/ka)
higher Kd means more ligand is released from the receptor
increasing drug meaning increase of receptors occupied.
Efficacy
the efficiency of a drug acting
the ability of drug binding to receptors
more recptors more efficient
potency and efficacy are different
E max.
Epinephrine is less efficient than morphine
Potency
the impact the drug has on the body
refers to the level of concentration required to reach EC50 on a curve
lower drug concentration needed to reach Ec 50 meaning the drug is more potent. Reaching the same effect with less input.
Fentanyl is more potent than morphine
quantal dose curve
describes the effect of a dose, response curve can be on population
we focus on the effect
ED50: effective dose at 50% of population
LD50: lethal dose at 50% of population
TD50; toxic effects seen at 50% of population
Therapeutic index
is the gap between LD50 and ED50
the higher the gap the more safe the drug is
Remiferentanyl needs *33000 times the initial dose to reach lethal dose
Digoxin only *2
Therapeutic window is the diff between LD50 and TD50 meaning the drug is safe to use within that range
Agonists and Antagonists
receptor is either active or inactive. Ligand may acto on either state
Ligands can either be
Full agonist: favours active state, max response with max affinity
Full antagonist: high affinity but will not activate receptor. no response
Partial agonist: sub max response and only partial activation of the receptor. prevents downregulation of receptors.
Heroin downregulates endorphin receptors. Buprenorphine will stimulate the receptors again but even at max dose they wont achieve the same efficacy anymore.
Drug Tolerance
2 types of tolerance emerge after prolonged use of drugs.
- Pharmacokinetic tolerance: induction of liver enzymes. they get more effective. Phenobarbital to maintain blood plasma.
- pharmacodynamic tolerance (desentization)
opoids and Heroin, inhibits the endorphin receptors.
Downregulation of receptors occurs
3.sequestration, drug being constantly bound to G protein it will break down. loss of adrenaline recptors.G protein activation prevented by beta Arestin.
Drug Toxicity
drug toxicity can be ucaused by genetic predisposition and non selective action, or inappropriate use of drugs
all drugs have an intended (primary) and a secondary (unintended) effects. no drug is entirely specific side effects can be neutral or beneficial. most of the time undesirable.
- AGONISTS
full agonists
- bind the receptor at an active state
Partial agonists
-will try to bind as many active receptors but fail to reach the same effect.
Heptyl and Octyl derivatives
they both compete with each other and the full agonist has reduced efficiency.
Inverse Agonist
- histamine receptors can existeither active or inactive.
histmaine agonist will stimulate active site
antihistamines work as an inverse agonist and pushes the balance of receptors towards an inactive state.
Antagonists
2.1 Non receptor Antagonists
physiological antagonist: histamine inducing anaphylactic shock
chemical anatgonist: counteract agonist. Heparin is an anticoagulant. Protamin is a chemical antagonistas it is strongly positive.
2.2 Receptor Anatagonists
orthosteric binding (same site as agonist)
- reversible (competitive antagonism) Metatomidine and xylazine are reversed by atapazimol
-irreversible( non competitive active site antagonist)
efficacy is largely decrease and small decrease in potency. Ketamine and NMDA receptors.
-Allosteric binding, binds to a different site.
Drug toxicity classification
either on target or off target if receptor based
On target: Primary appropriate effect on the appropriate receptor tisse
Off target: leads to side effects and harmful effect undesired
On target adverse effect:
at intended tissue and receptor but: inappropriate concentration with suboptimal pharmakinetics. happens deliberate or accidental, altered pharmacokinetics, liver and kidney disease
changes in pharmacodynamics:
-drug receptor changes, number, state etc.
intended recptor but different tissue.
-antihistamine diphenhydramine HCl on the H1 receptor. Antagonist used to decrease unwanted symptoms of the histamine release in allergic reactions.. crosses BBB?
Off target:
on the unintended receptor.
Thalidomide - enantiomeric pairs, S-enantiomer was a teratogen (birth deformaties) abnormal development of peripheral vessels. R- enantiomer was a sedative
Testing on pregnant animals before human testing
on the unintended receptor and unintended tissue.
use of the beta blockers
B1 receptor antagonists can also acto on beta 2 receptors - increased contractility affecting SM cells
Harmful Immune and Idiosyncratic Response and
classification of immune mechanism
Drugs are Xenobiotics that the immune system can recognize as foreign material.
immune system has either a hypersensitivity response or autoimmune reaction.
-hypersensitivity type 1-4
type 1 is immediate anaphylactic reactions
type 2 is in response to penicillin or quinidine
type 3 is in response to Cefaclor
type 4 is in response to dermatitis, latex allergy
Idiosyncratic response
-anaphylaxis
-anaphylactoid= pseudo- allergic reaction
Autoimmunity:
Formation of toxic metabolites
lipid peroxidation
- lipid peroxidation initiated by ROS, chain reaction, changes membrane permeability. Defense against Vitamin E, Selenium, GSH excretion.
-generation of ROS molecular oxygen is reduced to superoxide anion. Cytotoxic effect is direct, leads to LPO?
-Modification of Sulfhydryl groups, frees sulfhydryl groups maintain cytoplasmic Ca2+ conc. absence leads to lethal hyperglycemia. inactivationof haem enzymes and increased cell permeability.
-Glutathione deficiency, GSH protects cells from oxidative stress. depletion of GSH leads to drug toxicity, decreased cellular protection. ROS convert GSH to GSSG. replenish with NADPH dependant GSSG reductase.
-Paracetamol, never for Cats. it produces covalent protein derivatives which are highly toxic for liver. antidote is N-acetyl cysteine
