ASCI 366 Veterinary Pharmacology

pharmacokintetics

1. absorption

2. distribution

3. metabolism

4. elimination

pharmacotherapeutics

study of medicines used to treat diseases

* effective dose

amt of drug that produces desired effect

ED50

* lethal dose

amt of drug that produces death

LD50

- multiple of ED50

- want to be large #

* therapeutic index

aka margin of index

tells how much greater lethal dose is compared to effective dose

LD50/ED50

-greater # = safer

therapeutic range

drug concentration that produces the desired effects w/ no sign of toxicity

variables affecting therapeutic range

- rate of entry

- pharmacokinetic

- pre existing disease

- obesity

- unique physio

- overall health

* obesity

- dosage measured based on lean body fat --> obese = more fat (larger mass but does not take into account lean body mass --> overdose)

- affects metabolism --> absorbs fat soluble drugs (fat depot)

3 major factors of therapeutic range

- ROA

- dose

- dose interval --> determined by rate of elimination (half life)

bodily fluid compartments

1. intercellular fluids

2. interstitial fluids

3. extracellular fluids

extracellular fluids

interstitial fluids + plasma

* plasma membrane

- lipophilic

- hydrophobic

- polar/ionized (positively charged) --> cant pass

membrane transport

- passive diffusion

- assisted transport

- endocrytosis

passive transport

- electrical gradient --> particles move towards LOWER charge

- chem gradient --> particles move from HIGH to LOW concentration

assisted transport

- facilitated diffusion

- active transport

endocrytosis

active transport in which cell transport molecules into cells w/o passing though memb --> engulfs

- usually large molecules

1. pinocytosis --> liquid

2. phagocytosis --> solid

fick's law

describes mvmt of substances/molecules down concentration gradient

- moves from HIGH to LOW concentration --> can use loading dose

- fast diffusion

1. thin surface

2. large SA

3. branched

4. porous

osmotic pressure

pressure req to stop water from diffusing through the barrier by osmosis

osmosis

solvent travel from HIGH to LOW solvent concentration

- LOW to HIGH solute --> want to dilute

- HIGH free water to LOW free water

hydrostatic pressure

pressure of water in body

- same as blood pressure in plasma --> capillaries act as holes to release water

- moves from HIGH to LOW pressure

oncotic pressure

amt of plasma protein

- low --> water leaves

- high --> water enters

* absorption

mvmt of drug from site of administration to blood stream

- increases dose to increase absorption

* bioavailability

fraction of drug administered that enters systemic circulation

- key determinant of onset of action

- mostly referring to oral

- not necessarily synonymous w/ absorption (rare)

- low bioavail may not be overcome by increasing dose

- degradation prior to arrival @ site of action

- 1st pass effect

factors of bioavailability

- blood supply to area

- SA of absorption

- mech of absorption

- drug dosage

factors of absorption

- ROA

- food/fluid given w/ drug

- dosage formulation

- status of absorptive surface

- rate of blood flow to SI

- acidity of stomach

- GI motility

pka <2

strong acid

- completely ionize/dissociate in water = cant pass memb

* 7 > pka > 2

weak acid

- partial ionized in water

- won't ionize in strong acid (stomach) --> absorbed

- ionize in weak acid (SI) --> ion trapping

- nothing happens if add to weak base

- uncharged = lipid soluble

10 > pka > 7

weak base

- uncharged = lipid soluble

pka > 10

strong base

Ka

[H][A]/[HA]

pka

-logKa

log(HA/A)

pka-pH

external ROA

- oral

- sublingual

- buccal

- rectal

factors of oral absorption

- digestive enzymes --> denatures

- stomach acid --> denatures

-GI motility --> affects rate

- food --> buffer = decrease/alter rate

ion trapping

alters elimination of substance

- trapped in blood & cant pass through memb = inactive

- change pH of urine & trap in urine for excretion

- ionized

* 1st pass effect

1. hepatic

2. respiratory

- inactivates & eliminated & recycled

EX: 20% 1st pass effect = 20% drug removed, 80% bioavail

* hepatic 1st pass effect

GI absorption to portal circulation ( bw digestive & liver)

- drug goes here first then drained to liver --> inactivation & eliminated

- liver enzymes detoxify

liver disease compromises ability to inactive substance = unable to remove --> give less drug

distribution

mvmt of drug through blood

* factors of distribution

- membrane permeability

- tissue perfusion

- protein binding

- depot storage

- volume of distribution

tissue perfusion

organs that get more blood get more drug

protein binding

protein bond = inactive --> difficult to distribute to other parts of body

- stuck to plasma

less protein (albumin) --> less concentration of blood

depot storage

lipophilic --> stored in blood

- fat soluble drugs absorbed in fat 1st --> takes longer to take affect & recover

calcium binding --> accumulates in bone & teeth

* volume of distribution (VD)

amt of drug in plasma (L)

- compares proportion of drug in blood vs body

- large VD = more in body than blood --> reacts fast ( reaches target fast)

- lipophilic = high VD

- protein bound = low VD

- MOA

dose/concentration @ time 0

use of VD

- determine loading dose

- achieve therapeutic concentration rapidly

* loading dose

VD x desired therapeutic range

metabolism

aka biotransformation --> hepatic 1st pass effect

- functions

1. inactivation

2. activation

3. toxification

- 4 rxns

1. oxidation

2. reduction

3. hydrolysis

4. conjugation

* metabolism phase I

blood comes to liver & hepatics transform

- drug undergoes reactions and becomes metabolites (polar & hydrophilic)

- oxidation, reduction (by NADPH), hydrolysis by hepatic enzymes: cytochrome P# (CYTP#) --> CYTP450 are oxidases

* metabolism phase II

conjugation: liver conjoins metabolite to substance

- metabolite acted upon by enzymes in liver ( glucuronide, sulfate, acetate)

- highly polar --> excreted

* toxicity

- overdose --> wrong ROA, impared metabolism

phase II rxns leads to toxicity

- conjugation --> toxic metabolites

-hepatoxic

drug interaction

- altered absorp.

- competitive binding of plasma proteins

- altered excretion

- altered metabolism

enterohepatic recirculation

some conjugates excreted in bile

- bacteria in SI act upon conjugates --> deconjugates = reabsorbed & active drug form

- when taken orally --> prolonged elimination & half life

* elimination

excretion/removal from body through liver & kidney

- rate of elimination: amt of drug eliminated (mg/hr)

rate of elim not equal rate of clearance

* steady state

blood concentration constant

- rate intake (maintenance dose) = rate of elim

dose rate = clearance (L/hr) x plasma drug conc(desired blood) (mg/L)

rate of clearance

vol of blood cleared of substance per unit of time (L/hr)

- rate of elim w/ respect to conc of drug in fluid

- does not tell how much drug is removed

- blood clearance = plasma clearance

- usually constant fraction of elim per unit of time

CL = dose rate / plasma drug conc (mg/L)

graph --> plasma drug conc vs time

- plateau = CL

clearance

most important

1. renal (kidney --> urine)

2. hepatic (liver)

- often synonymous w/ total clearance

- used to determine dosage

- used to determine maintenance dose rate (MDR)

factors of clearance

- how much blood going to kidney/liver

- how much drug in blood going to kidney/liver

- how much blood removed

hepatic clearance

- drug administered orally

- may be most significant --> 1st pass effect

- sequence

1. transport across GI

2. portal transport to liver

3. enter systematic circulation --> drug may be affected by metabolism

- enterohepatic recirculation

* renal clearance

- BP influences --> dehydrated = low BP = less renal clearance

- water soluble drugs cleared more efficiently

- Fick's law

rate excreted (RE) =urinary conc x urine production

plasma conc x clearance rate = urinary conc x urine flow

clearance rate (l/hr) = urinary conc (Mg/L) x urine flow (L/hr) / plasma conc (mg/L)

-3 kinds

1. glomerular flitration

2. tubular secreation

3. tubular reabsorption

glomerular filtration

substance cleared by GFR: kidneys filter fluid and waste products out of the blood into the urine

- non specific

- correlates w/ creatinine (waste) concenration

- about 120 ml/min

- protein binding very important

- determined by capillary blood pressure --> measure of how well your kidneys are cleaning blood

renal clearance = plasma conc = urine conc (1:1:1)

tubular secreation

active transport ob substances from blood to urine to be excreted

- very important elim process for drugs

- increases CL

tubular reabsorption

transport substances from urine to blood

- lipid solubility --> lipophilic drugs reabsorbed

- pka

- urinary pH --> basic drug ionized in acidic urine, acidic drug ionized in basic urine = polar, water soluble (dissolves in urine --> excreted)

- body needs component that was filtered --> reabsorbed in tubules

- decreases CL

intestinal clearance

drug not absorbed and eliminated in feces

- may be enterohepatic elimination

* half life

time it takes for concentration of drug in plasma to decrease by 50%

- determines when to redose

graph--> time it takes for plasma conc of blood to reach 50%

t1/2 x 4.7 = time to reach steady state

withdrawal times

time needed to elapse after administration to ensure drug residues are below max

* pharmacodynamic

manner in which a drug acts on the animal

1. onset

2. peak

3. duration

protein targets

1. ion channels

2. enzymes

3. receptors

4. carrier protein

receptor site hypothesis

drug must act w/ receptor in/on cell to produce pharmacological resp

- agonist/antagonist actions --> enzymes, NT, hormones

* agonist

activates/mimics --> binds to receptor to elicit response

- open ion channel

- activate G protein

- activate enzyme

- on does response curve --> less potent = takes more to reach max response, full agonist mimics same effect of drug, partial agonist = 50% max response

- full agonist = reaches 100% response

- one substance in body = agonist

- all competitive --> prolongs effect

* antagonist

inhibits/block

- physio --> 2 drugs exert opposing actions on same system through diff mech

- chem --> interaction of drugs leads to inactivation of 1 or both

antagonism on pharmacokinetic

- reduces absorption

- increases elimination

- alters distribution & metabolism

antagonism on pharmacodynamic

decreases effect of drug due to action of another drug on the same pathway

- reversible competitive antagonism

- irreversible competitive antagonism

- noncompetitive antagonism

* competitive can be overwhelmed by adding more agonist, non competitive removed & becomes 0% response

reversible competitive antagonism

antagonist competes w/ agonist for same receptor

- on dose response curve --> curve shifts right but max response not changed

irreversible competitive antagonism

antagonist competes w/ agonist for same receptor but w/ infinitely greater affinity

- on dose response curve --> curves shift right, max response decreases

noncompetitive antagonism

antagonist affects cellular response of agonist but does not interfere w/ receptor

- on dose response curve --> curves shift right, max response decreases

receptors

- want to reach nucleus --> small & lipophilic

- on/ w/i cells

- agonist/antagonist receptor

- channel linked (Ach nicotinic)

- G protein (Ach muscarinic)

channel linked receptors

open/close channel

- influx sodium --> depolarize (more positive) = causes action potential

- efflux potassium & influx chloride --> repolarize/prevents depolarization (flows opposite of sodium) --> hyperpolarize (more negative) = inhibits action potential

G protein receptors

2nd messengers

signal transduction

binding of drug (ligand/signal) to receptor results in signal transduction in cell

- Ca ions responsible

ligands

signaling molecules

1. agonist

2. antagonist

3. partial agonist - antagonist

dose response curve

response vs concentration

- administer more drug = increase response

- plateau = constant response but may be toxic --> receptors part of response saturated/full

- response = efficacy

* look at response first

sensitivity

refers to steepness of dose response curve

- steeper = more sensitive --> takes less to produce effect

potency

amt of drug req to produce a response

- larger concentration = less potent

affinity

attraction between drug & receptor

- degree to which the drug is bound to receptor vs unbound

- degree of association or dissociation

- higher affinity = highly bound

efficacy

ability of drug to induce a response

- full agonist will elicit max response = max efficacy (emax)

- how agonist or antagonist is the drug

- 100% response = 100% efficacy

* central nervous system

brain & spinal cord

- inter neurons

- efferent neurons

* peripheral nervous system

cranial & spinal nerves

1. afferent divison

2. efferent division

afferent neuron

PNS to CNS

- sensory stimuli

- visceral stimula (organs)

efferent neuron

CNS to PNS

- autonomic nervous system

- somatic nervous system

* autonomic nervous system

involuntary

1. sympathetic

2. parasympathetic

tissue targets

- smooth muscle

- cardiac muscle

- glands

side effects: SLUDVB

Salivation

Lacrimation

Urination

Defication

Vomiting

Bradycardia

autonomic nervous system drugs

- mostly refers to agonize muscarinic --> direct acting

- acts like acetylcholine --> effect on muscarinic effect on tissues

- agonize nicotinic

- give acetylcholine

= contract

- take away

acetylcholine =

relax

-antagonize acetylcholinerase --> indirect acting

- inhibits breaking

down of

acetylcholine -->

concentration

increase

* sympathetic autonomic nervous system

fight and flight response

- short pre ganglionic neuron

- long post ganglionic neuron

- increases HR & heart contraction

- surpasses GI motility --> treat colic

- open airways

- dilate pupils

-adrenergic drugs

* parasympathetic autonomic nervous system

rest & digest response

- long pre ganglionic neuron

- short post ganglionic neuron

- homeostasis

- decreases HR

- stimulate GI motility

- constrict pupil

cholinergic agonist = parasympathomimetic

sympatholytic drugs

block actions of sympathetic nervous system

-adrenergic antagonist

- block receptor --> inhibit release of NT

parasympatholytic

-anticholinergic (antimuscarinic)

-blocks acetylcholine

somatic nervous system

voluntary

- targets skeletal muscle

- nicotinic

signaling

1. action potential propagated down presynaptic neuron

2. Ca enters synapse

3. NT released from pre synapse

4. NT binds to receptors on post synapse

5. ion channels open & produces/inhibits action potential

synapse

NT pre-synaptic signals excitatory or inhibitory receptors post-synaptic

excitatory response

depolarize

- influx of sodium ions

inhibitory response

hyperpolarize

- influx of potassium/chloride

adrenergic receptors

1. alpha 1

2. alpha 2

3. beta 1

4. beta 2

5. beta 3

- sympathetic nervous sys

- autonomic ligand receptor: norepinephrine

- uses epinephrine & norepinephrine

- in smooth muscles, cardiac muscles, glands