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What is pharmacodynamics?
How drugs work in our bodies
What is pharmacokinetics?
Fate of drug in body
What are the four steps of pharmacokinetics?
- 1) Absorption
- 2) Diffusion
- 3) Metabolism
- 4) excretion
What types of molecules are utilized in the body?
What is the largest size molecule that can enter systemic circulation?
What is a drug?
Small, organic molecules that interact with body
What are the two mechanisms of drug action?
- 1) chemical rxns with body ingredients
- 2) receptor - effector concept
What are some chemical rxns and their function? (mads)
- Methenamine: release formaldehyde for UTI
- Antacids: gastric acid neutralization
- Disinfectants: destroy membranes
- Some anesthetics
What are drug receptors?
molecular sites where drugs bind and have their effect
What are the 7 common drug receptors?
- Intracellular receptors
- Transport proteins
- Ion channels
- Ligand gated channels
- nucleic acids
What are five common characteristics of receptors?
- Smaller than 45kD
- often reversible
- up-regulation or down-regulation (no stimulation = up-regulation)
What is the rule for drug clearance?
once the drug is removed from body, the reaction will stop
What is the one main exception to the drug clearance rule?
Corticosteroids: they alter genes and can last for weeks after clearance
What are the four irreversible specific drug-receptor interactions?
- 1) electrostatic interaction
- 2) hydrogen bonding
- 3) hydrophobic interactions
- 4) Van der Waals forces
What is the one reversible specific drug-receptor interactions?s
What are the five basic receptor-effector receptors (mechanisms)?
- 1) intracellular
- 2) Tyrosine kinase (Allosteric)
- 3) cytokine
- 4) ion channel (ligated)
- 5) G-protein (Gs or Gi)
Name the 6 intracellular receptors that affect gene expression?
- Sex steroids
- Vitamin D
- Thyroid hormones
- P450 inducers
What drugs utilize tyrosine kinase receptors?
- Epidermal growth factor
- platelet-derived growth factor
What are three common tyrosine kinase inhibitors? (-nibs)
What is a common cytokine receptor mechanism?
What are three ligand gated receptor channels and their effects?
- Nicotinic/ACh →sodium
- Glutamate →Sodium & Calcium
What happens to sensitization after agonists are in contact with G-proteins over a long period of time?
What G protein forms cAMP? Inhibits cAMP?
- Activates = Gs
- Inhibits = Gi
What converts ATP to cAMP?
What is the effect of phosphorylation on Ca and K channels?
Drugs that stimulate cAMP and their receptors?
- Epinephrine (β1andβ2)
- Norepinephrine (β1andβ2)
- Isoproterenol (β1andβ2)
- Dopamine (DA1)
- Dobutamine (β1)
- Histamine (H2)
Drugs that inhibit cAMP and their formation?
- Norepinephrine (α2)
- Dopamine (D2)
- Clonidine (α2)
- Acetylcholine (M2)
- Morphine (μ, κ, δ)
- Serotonin (5-HT1)
What is the polyphosphoinositide signalling pathway? Functions of products?
- Gq - activate Phospholipase C - hydrolyze PIP2 - IP3 & DAG created
- IP3 = Ca released from intracellular stores
- DAD = stimulate PK-C
What drugs stimulate the Gq pathway? Receptors?
- Acetylcholine: M1 & M3
- NE & Epi: Alpha 1
- Phenylephrine: Aplha 1
- Serotonin: 5-HT1c
Review of the cGMP/NO pathways?
- Guanylyl cyclase stimulation = cGMP
- cGMP = vascular relaxation
- NO histamine or M receptors stimulated in vascular endothelium = Calcium increase = calbinding activation = NO synthase activation = arginine conversion to NO & Citruline
- NO = paracrine effect via diffusion = vasodilation
Is NO a Paracrine or Autocrine?
What is the effect of sildenafil (viagra) on NO and why?
Maintains NO effect by inhibitin phosphodiesterase V that would inhibit cGMP
What muscarinic receptors is activated by Ach to produce NO?
What three second messenger systems will affect gene expression?
- Guanylate cyclase
- Adenylate cyclase
- Phospholipase C
What is an agonist?
induce a receptor
What is an antagonist?
T/F Antagonists have a biological effect like Agonists?
F, agonists are the only ones that have a biological effect (except for sympathetic tone areas)
What are three common agonists and their antagonists?
- Acetylcholine - AtropineEpi alpha-1 - PhentolamineEpi Beta-1&2 - PropranololHistamine H1 - Diphenhydramine (Benadryl)Histamine H2 - Cimetidine
If you have 1% of Beta receptors on the surface, which is greater: binding or effect?
Binding, b/c of so many that are not being activated
What is affinity?
propensity of a drug to bind to a receptor (agonist and antagonist)
What is potency?
dose required to produce an effect (agonist and antagonist)
What is efficacy?
biological response (agonist only)
What are the four types of antagonists?
- functional (physiological)
What is a competitive antagonist and its effect on the graph?
- What? binds to receptors and requires more agonist to overcome
- Graph change? shift to right, Emax stays the same
What is non-competitive antagonism and changes on graph?
- What? allosteric binding so agonist cannot bind to receptors
- Graph? downward shift as Emax drops
What is functional antagonism?
antagonist acting through different mechanism to counteract agonist effect
What is chemical antaonism?
antagonist interacts directly with agonist and inactivates it
What is a partial agonist and when does it function?
- What? can act as a competitive antagonist
- Function? with full agonist
What happens to efficacy with a inverse agonist?
Efficacy (Effect) decreases
What type of agonist do you want to use to inhibit a constituitive receptor?
- inverse agonist* If binding occurs the reaction will be decreased
What are three common inverse agonists?
-Graded DR curves
-Quantal DR curves
- Graded: one system
- Quantal: population (Y or N)
Therapeutic Ration formulas for Adults and animals?
- Adults: TR = TD50/ED50
- Animals: TR = LD50/ED50
What is the formula for margin of safety?
* formed from area of overlap b/t two curves
Two most common outcomes of chronic drug use?
What are the three drug tolerances and their definitions?
- Pharmacokinetic tolerance: drug not as effective because it is removed more rapidly
- Pharmacodynamic tolerance: lessened effect due to less receptors, etc...
- Tachyphylaxis: tolerance occurs quickly (common with amines b/c of pool depletion)
Two drugs that can cause tachyphylaxis?
Acetaminophen & Tyramine
Name the four mechanisms of tolerance and their definitions?
- desensitization: channel inactivation or phosphorylation inactivation
- down regulation: ligand induced endocytosis
- physiologic tolerance: two drugs with effects that counterbalance
- competitive tolerance: antagonist with an agonist
What drug can cause desensitization?
Are drugs more selective or specific?
What are two drug selectivities?
Name the five methods of increased drug activity?
- Chemically induced
- Surgically induced
- Deficiency in degrading enzymes
- Competition for binding
- Physiologic synergism
How does halothane increase activity?
- * increases catecholamine sensitivity
How does succinylcholine have increased activity?
- Deficient degrading enzyme
- ** no cholinesterase
How does Primaquine have increased activity?
- Deficient degrading enzyme
- ** no G6P Dehydrogenase
Why do you have to decrease warfarin in patients that take phenytoin
- Competition for binding sites
- ** phenytoin will displace warfarin from albumin so more is available which would increase bleeding
Name three types of physiologic synergism?
- Additive or summation: the effect of the combination is the sum of the two individual effects (e.g. NSAIDs)
- Synergism: the effect of the combination is larger than the sum of the two individual effects (e.g. antihypertensive agents,)
- Potentiation: one drug that does not have a specific effect increases the effect of another drug (e.g. cholinesterase inhibitors, GABA - benzodiazepines)
Which three drugs can have several responses?
- CNS depressants
What is an overextension reaction?
The reaction had more toxic effects, even utilizing the same receptor-effector system, than expected
What type of immune response is anaphylactic shock?
What are three characteristics of drugs that create hypersensitivity reactions?
- Bind macromolecules
- highly charged
- long half-life
What is the common percent of the placebo effect?
What organ do aminoglycosides toxify?
kidney & ear
What organ do Acetaminophens toxify?
Toxic effects of Chloramphenicols?
Toxic effects of Tetracycline?
teeth and bone
Why are thalomide, methotrexate, phenytoin and warfarin dangerous?
They are teratogenic
Idiosyncrasy of succinylcholine?
Idiosyncrasy of Isoniazid?
fast and slow acetylation
Idiosyncrasy of primaquine?
Idiosyncrasy of barbituate?
induced porphyria w/ abnormal heme synthesis
What is a type I rxn to a drug?
drug binds to IgE that has bound to the Fc region of an antibody
3 examples of Type I hypersensitivity?
What drug is administered to resolve a type 1 hypesensitivity rxn?
epinephrine 0.5 ml of 1:1000 solution
What is a Type II hypersensitivity Rxn?
Autoimmune syndromes induced by drugs (IgM or IgG binding causing complement)
What is a Type III hypersensitivity Rxn? Drugs that resolve?
- Rxn mediated by immune complexes
- Drugs: corticosterois (Sulfonamides, thiuracil, penicillin, anticonvulsants, iodides)
What is a type IV hypersensitivity Rxn?
- Cell mediated or delayed
- * often occurs with topical drugs (poison ivy)