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76 Cards in this Set
- Front
- Back
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Pharmacodynamics
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- action of a drug
-drugs bind to receptor and produce a detectable response |
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receptor
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- where drug binds and there's an observable effect from this binding
- most are proteins which initiate events that leads to actions such as tubulin - normally bind endogenous regulatory ligands: NT's and hormones |
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types of drug bonding
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1. covalent
2. electrostatic 3. hydrogen 4. Van Der Waals 5. Hydrophilic |
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covalent bonding
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- strong e- pair from both atoms
- not usually reversible |
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electrostatic bonding
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- common with drugs
- simple opposite charged groups attract drug to receptor |
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hydrogen bonding
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- sharing H bonds between acid and base groups
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Van Der Waals bonding
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- weak attraction between polar and nonpolar molecules
- agonist vs. antagonist |
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hydrophilic bonding
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- interaction of 2 nonpolar substances
- stable, long-lasting |
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types of receptors
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1. cell membrane
2. cytoplasm 3. nucleus 4. authentic receptors |
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saturability
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-finite # of receptors per cell
- eg beta 2 in lungs (vasodil) are saturable and reduce in # |
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specificity
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- drugs have a complimentary structure with specific receptors
- want high specificity to reduce side effects |
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reverse reactions
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- bind to receptor and dissociate in its non-metabolized form
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dose response curve
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want the smallest dose with effect desired in order to minimize side effects
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efficacy
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maximal effect
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potency
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-inherent power of strength related to dose
- fx of drugs affinity for receptor and ADME factors |
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measurements of effect
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1. molecular response
2. cellular response 3. organ response 4. whole animal response |
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molecular response
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- modulation of enzyme activity
- movement of ions across plasma membranes |
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cellular response
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modulation of:
1. secretion of hormone or NT -or- 2. cell motility |
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organ response
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contration/relaxation
- eg erythromycin stim GI motility |
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whole animal response
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- behavior changes
- response can be toxic or lethal |
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studies
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-many done in healthy animals so dose-response different due to:
1. intersubject variation 2. environmental factors 3. disease state - therefore dosage= guideline - eg diabetic animals have low stomach abs and variable GI abs |
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polypharmacy
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many drugs at once
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therapeutic index
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= LD 50/ ED 50
- ED: effective dose - small index requires close monitoring and weighing often because ED close to LD - larger index is safer |
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pharmacokinetics
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disposition and fates of drugs in the body
- Absorption, Distribution, Metabolism, and Excretion |
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rational drug therapy
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- most appropriate therapy is the lowest dose which is effective
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transdermal patches
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take 2-3 days to take effect
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eye drops
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also absorbed systemically
- eg atropine in horses |
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effective dose kinetics
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- reach ED at right location
- interspecies variation - due to difference in ECF compartments, inherent tissue sensitivity at receptors sites and biphasic availability |
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ECF in diff spp
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- horse, dog, cattle= 30%
- cat:25% |
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biphasic availability
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- ruminants
- reach baseline level then the drug comes unbound from food so the level spikes (biphasic spike) |
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plasma monitoring
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-preferable method of determining dose rather than body weight
- expensive method so only used on small TI drugs |
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spp. diff
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- most due to kinetics
- oral absorption may differ between monogastrics and ruminant species, resulting in different plasma levels of a drug at the same dose - eg. stress can shunt blood away from stomach in carnivores, resulting in low oral abs |
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biological membrane passage
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1. drug absorption and distribution (AD): determine receptor site [] (biphasic availability)
2. biotransformation metabolism and excretion: terminate drug action -bio membranes are directly or indirectly important to these processes |
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membrane drug passage
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- Rx move by:
1. passive transfer: most important, Rx diffuses through mem across the [] gradient, lipid soluble rate is directly proportional to the lipid: water coeff 2. specialized transport |
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carrier- mediated transport
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- implies a rapidly reversible interaction b/w components of the mem and the transported substance
- can reach saturation - eg competitive ihibition - active transport: requires E - facilitated diffusion: no E |
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physiochemical factors
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- site- dependent
- lipid soluble: cross skin or the epithelial lining of GI - IM or tissue inj: solubility of minor importance due to peripheral capillary beds - capillary wall: very porous, MW 60,000 KD may be absorbed by passive diffusion |
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ionization of drugs
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- most Rx weak acids or bases in soln as non-ionized and ionized form
- non-ionized (lipid soluble): diffuses across membrane - ionized (water soluble): don't penetrate - salt helps absorption |
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determinants of ionization
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- depends on pKa and pH of environment
1. acid: % ionized= 100/( 1 + antilog (pKa-pH)) 2. base: % ionized= 100/(1+ antilog (pH-pKa) |
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ionization examples
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1. when like in like, mostly non-ionized: eg weak acid pKa 4 in acid of pH , the % ionization is 9%
2. when like is in unlike, most ionized: eg weak base pKa 8 in acid of pH 3 , ionization 99.9% and less than 0.1% non-ionized and available to attach to the receptors |
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ionic trapping
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- influence of pH on a drug
- acidic drug will accumulate on the basic side of the membrane and vice versa - commonly occurs in ruminants, so cannot predict how Rx released |
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IV
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- 100% absorption
- want sterile and pyrogen free - immediate response, control the rate, hyper or hypotonic can only be given IV so use caution - CRI to control pain |
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pyrogens
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degraded bacteria which can cause fever, etc
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single dose vials
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no preservatives
- eg propofol |
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tonicity of inj
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- isotonic= 300M, 0.3% NaCl
- can only give non-isotonic soln IV, not IM or SQ as can damage tissues |
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IM or SQ inj
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- rapid abs when given as aq soln: 30min
- rate det by: 1. vascularity of inj site 2. drug [] in soln, degree of ionization, lipid solubility, area of absorbing surface where the drug administered - lg animal: max 10ml per site to insure abs and prevent abcess |
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altered drug abs
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1. different vehicles
2. acetate, pivilates, Na, K, benzyl alcohol, H2O, HCl 3. addition of other drugs: eg lidocaine and epi prolongs drugs and keeps local 4. pain at inj site 5. not avail in inj form: too unstable or irritating to skin 6. cannot stop after administered |
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chem additives to drugs
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1. acetates: no IV
2. pivilates: Depo- 3. Na and K: IM and IV vehicles, watch w/ heart dz and rate given 4. HCl: usually PO, IV dilute |
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pulmonary abs
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- gaseous anesth abs by diffusing across pulmonary epithelium
- vary in degree of blood solubility which effects: 1. rate of action 2. ease at which depth can be changed 3. recovery |
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percutaneous abs (transdermal)
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- depends on release from drug vehicle and penetrate of keratin layer (stratum corneum)
- abs occurs by passive diffusion: lipid solubility most important feature of the drug - de-epithelialized skin promotes abs: shaving - burns require more moderate dosing as skin abs more |
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percutaneous enhancers and vehicles
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- vehicles: oil in water
- enhancers: trick skin into opening so drug can be abs - DMSO: enhancers, requires cleanliness as will allow anything else (eg dirt) to enter also |
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oral abs
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1. drug must be released from solid dosage form: rate-limiting factor
2. transp across GI mucosal barrier: animals with/ recov from ulcers have dead zones of abs 3. passage through liver: first pass met |
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oral admin
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- dissolution: rate-limiting step that det release of drug from solid dosage form
- enhanced by admin the drug as salt - micronizationL enhances abs by dec the particle size (grisofulvicin) |
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PO horses
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- less info
- gastric pH higher (5.5 vs 3.4) - abs of some dr in the LI - use antibacterials bc antiobiotics destroyed |
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PO dogs, cats, pigs
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- similar to humans in that the rate of stomach emptying is the most important factor controlling dr abs rate
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PO ruminants
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- rumen pH maintained at 5.5- 6.5 due to large vol alkaline saliva (pH 8-8.4)
- weak acids well abs from rumen - weak bases ionically trapped from syst circ, low starting [] due to rumen vol, microflora met - mostly give inj |
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bioavailability of dr
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=F (measure of pharmacokinetics)
- rate and extent to which a dr admin in a particular dosage form enters the syst circ - calc: 1. peak plasma [] 2. time to reach peak [] 3. area under curve (AUC): indicates how long drug stays in animal over 24 hrs |
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stability of dr in GI fluids
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- enz deg : PO in rum
- acid instability: pen GK - complexes: tetracyclines - SI principle site of abs of PO - rate of gastric emptying important det |
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metoclopramide GI
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1. inc gas emptying: given to diabetics
2. improves motility: dr is there a shorter period of time with less abs |
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bioavailability calc
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- IV: 100%/ complete sys abs
- PO calc against IV: F= AUC PO/ AUC IV - % PO, SQ or IM abs |
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Bioavailability and spp
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Decrease in F among spp accounts for a large majority of dosage differences
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Bioequivalency
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- two drugs are BE when the rates and extent of abs of the active ingredient are not significantly different under suitable test conditions
- usually used to compare generic products vs trademarked dr |
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disposition curve
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- graphically defines the decline of the plasma [] of a dr after IV admin
- dist (alpha) phase: attributed to rapid dist into tissues and organs - elim (beta) phase: removal of the dr by biotransformation and excr |
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half life
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- time required for the body to elim 1/2 drug
- knowledge can be used to predict the quantity of a dr remaining in the body |
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factors influencing half life
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- any state that alters either the access of dr to the organs of activity or elim likely causes change
1. maturity: young animals typically lack mature dr met enz 2. dr interactions: eg cimetidine and phenobarb 3. urinary pH 4. spp diff |
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volume dist
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=Vd: vol of fluid (blood, fat, water) that would be required to contain the amount of dr in the body if it were uniformly dist in a []= that in plasma
- amount of tissue to which dr is dist |
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Vd vs HL vs solubility
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- small Vd: high water sol and small HL, not well dist
- large Vd: high lipid sol and large HL |
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body clearance
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- rep total drug clearance
- concept: body as whole acts as dr elim sys - vol of plasma cleared of the dr by various elim processes (liver, kidney) / unit time = ml/min/kg #1 spp diff |
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body clearance vs HL
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- ampicillin and digoxin have the same BC (3.9 ml/min/kg)
- HL ampicillin: 48 min - HL digoxin: 1680 min |
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Vd vs BC vs HL
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Vd: ampicillin 0.27 L/kg and digoxin 9.46L/kg
- drugs with similar BC values: the smaller the Vd, the shorter the HL - relationship: HL directly proportional to Vd |
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plasma protein binding
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- limits dr dist and elim
- reversible process therefore the dr- protein complex serves as a circulation reservoir of potentially active dr - binding occurs to albumin and is expressed as the % dr [] in plasma - only unbound dr fx therefore be careful in dosing low PP animals |
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competition for plasma protein binding
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- drugs can compete for binding sites
- when 2 highly protein bound dr are used concurrently, displacement from binding sites can result in increased free (active) dr - eg fluconazole and seldane - compete for protein binding: overdose of anthistamine - |
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dr- protein complex
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- acid dr bind albumin
- basic dr bind alpha 1 acid pr - don't cross bio mem - inactive |
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drug elim
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- biotransformation: enz alteration of dr
- met changes favor inact and excr - gen become less lipid sol and more polar - polar comp more suitable for carrier-med excr processes - gen pattern usually biphasic - liver, kidney, lungs (DMSO), plasma, intestinal mucosa |
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phase 1 met pattern
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- unmask or introduce polar groups such as OH and COOH
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phase 2 met pattern
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- conjugate the dr to endogenous compounds
-glucuronic acid, acetate, sulfate or aa - conjugates are usually H20 sol and pharmacologically inactive - chem structure predicts met transf |
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acetaminophen (aspirin) toxicity
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-hepatotoxicity, methemoglobinemia
- 52% sulfate, 42% glucouronide, 4% toxic, 2.5% unchanged - glutathione conj - cats: toxic bc cannot met glucuronic acid, antidote: N-acetylcysteine (mucomyst) within 1st 14 hr - humans: not more than 4-5 g/day, do not mix with alcohol |
