Introduction to Pharmacology (Speed Pharmacology)

G-proteins (3)

1. Gs 2. Gi 3. Gq

steps of pharmacokinetics (4)

1. absorption into blood 2. distribution to cells 3. metabolism of drug (liver) 4. elimination (bile, urine, and feces)

three kinds of cholinergic agonists

1. direct acting 2. indirect acting reversible 3. indirect acting irreversible

receptor types

1. ligand-gated ion channels 2. G-protein coupled receptors 3. enzyme-linked receptors 4. intracellular receptors

factors that determine distribution (4)

1. lipophilicity (high for lipophilic) 2. blood flow (high in brain; low in skin) 3. capillary permeability (high in liver; low in brain) 4. plasma and tissue binding (low in drugs that bind albumin)

two locations of nicotinic receptors

1. neuromuscular junction 2. central nervous system

two kinds of neuromuscular blockers

1. non-depolarizing agents 2. depolarizing agents

How are (non-IV) drugs absorbed?

1. passive diffusion 2. facilitated diffusion 3. active transport 4. endocytosis

depolarization a. stimulus causes neuron to reach ______________ voltage b. ______________ channels open, allowing the ions to flow ______________ the cell membrane

depolarization a. stimulus causes neuron to reach threshold voltage b. sodium channels open, allowing sodium ions to flow inside the cell membrane

direct acting cholinergic agonists: 1. ______________ 2. ______________ol 3. ______________ine 4. ______________ol

direct acting cholinergic agonists: 1. acetylcholine 2. carbachol 3. pilocarpine 4. bethanechol

What happens when most of a cell's receptors are occupied?

downregulation

inhibitors (GPACMAN)

grapefruit protease inhibitors azole antifungals cimetidine macrolides amiodorone non-DHP CCBs

3 common routes of elimination

hepatic renal biliary

pharmacodynamics

how drug affects body

hyperpolarization - ____________ channels continue to allow ions to flow ____________ the cell membrane; voltage becomes ____________ negative than at rest

hyperpolarization - potassium channels continue to allow ions to flow outside the cell membrane; voltage becomes more negative than at rest

cytochrome p450

large family of liver enzymes used to metabolize drugs

E max

maximum effect

action potential

movement of ions across the membrane of a neuron

two kinds of cholinergic receptors

muscarinic (affinity for muscarine) and nicotinic (affinity for nicotine)

neurons in the parasympathetic: 1. ________________ - long; release ________________ 2. ________________ - short; release ________________

neurons in the parasympathetic: 1. preganglionic - long; release acetylcholine 2. post-ganglionic - short; release acetylecholine

neurons in the sympathetic: 1. _______________ - short; release _______________; directly off of spinal cord; synapse with post ganglionic 2. _______________ - long; release _______________; synapse with preganglionic

neurons in the sympathetic: 1. preganglionic - short; release acetylcholine; directly off of spinal cord; synapse with post ganglionic 2. post ganglionic - long; release norepinephrine; synapse with preganglionic

_______-__________________ agents: -cisatracurium (90 min) -pancuronium (90 min) -rocuronium (40 min) -vecuronium (40 min) -atracurium (40 min); adverse effects

non-depolarizing agents: -cisatracurium (90 min) -pancuronium (90 min) -rocuronium (40 min) -vecuronium (40 min) -atracurium (40 min); adverse effects

inducers of cytochrome p450 (PCRABS)

phenytoin carbamazepine rifampin alcohol barbiturates st. john's wort

steady state concentration

rate of administration = rate of elimination; flattening of graph; typically maintained through therapeutic range; if needed rapidly, large loading dose may be needed

zero order kinetics

rate of elimination = constant; straight line; aspirin

first order kinetics

rate of elimination proportional to concentration of drug in the body; curved graph; most drugs

refractory period - time between action potentials when Na is pumped to the ____________ and K to the ____________ by the ____________ in order to restore the resting membrane potential

refractory period - time between action potentials when Na is pumped to the outside and K to the inside by the Na-K pump in order to restore the resting membrane potential

repolarization - ____________ channels open, allowing the ions to flow ____________ the cell membrane; voltage becomes negative

repolarization - potassium channels open, allowing the ions to flow outside the cell membrane; voltage becomes negative

Antimuscarinic agents block _____________ receptors.

Antimuscarinic agents block muscarinic receptors.

CHOLINERGIC AGONISTS

CHOLINERGIC AGONISTS

CHOLINERGIC ANTAGONISTS

CHOLINERGIC ANTAGONISTS

divided into two parts

CNS and PNS

efferent neurons

carry movement messages to PNS

afferent neurons

carry sensory messages to CNS

types of neurons in CNS (2)

cholinergic - use acetylcholine to send messages adrenergic - use norepinephrine and epinephrine to send messages

cholinergic antagonists 1. _____________ agents 2. _____________ agents a. _____________ blockers b. _____________ blockers

cholinergic antagonists 1. antimuscarinic agents 2. "antinicotinic" agents a. ganglionic blockers b. neuromuscular blockers

elimination

clearing of a drug from body

EC 50

concentration of drug that produces 50% of maximal effect

threshold voltage (caused by stimulus)

-55mV

voltage of neuron at rest

-70mV

cholinergic adverse effects due to overstimulation of cholinergic receptors - DUMBBELS

-diarrhea -urination -miosis/muscle weakness -bronchorrhea -bradycardia -emesis -lacrimation -salivation/sweating

sympathetic effects (parasympathetic = opposite)

-dilation of pupils -no salivation -relaxation of airways -increased heart rate -no digestion -stimulation of glucose release from liver -no gall bladder -stimulation of adrenal medulla (stimulated by long preganglionic neuron) -relaxation of bladder -ejaculation

ion channels in neuron membrane

-sodium -potassium

2 kinds of alpha receptors alpha 1 - G_____________ protein; sympathetic response; found on _____________, _____________ sphincter, liver (_____________), and kidney (_____________ inhibition) alpha 2 - G_____________ protein; inhibitory response; found on _____________ (inhibition of NE release) and pancreas (_____________)

2 kinds of alpha receptors alpha 1 - Gq protein; sympathetic response; found on vessels, urinary sphincter, liver (glycogenolysis), and kidney (renin inhibition) alpha 2 - Gi protein; inhibitory response; found on presynaptic nerve endings (inhibition of NE release) and pancreas (decreased insulin secretion)

ADRENERGIC RECEPTORS AND AGONISTS

ADRENERGIC RECEPTORS AND AGONISTS

bioavailability

AUC oral / AUC IV times 100

Adrenergic agonists mimic the effects of ______________ (noradrenaline) and ______________ (adrenaline).

Adrenergic agonists mimic the effects of norepinephrine (noradrenaline) and epinephrine (adrenaline).

anticholinergic adverse effects (ABCDs)

Agitation Blurred vision Constipation and Confusion Dry mouth Stasis of urine and sweating

Cholinergic neurons are primarily found within the parasympathetic system, but they also participate in sympathetic ____________, ____________, and ____________ activity.

Cholinergic neurons are primarily found within the parasympathetic system, but they also participate in sympathetic sweat gland, blood vessel, and skeletal muscle activity.

Depolarizing agents are acetylcholine receptor ________________; they mimic acetylecholine.

Depolarizing agents are acetylcholine receptor agonists; they mimic acetylecholine.

____________ acting cholinergic agonists mimic effects of acetylcholine by binding to muscarinic or nicotinic receptors.

Direct acting cholinergic agonists mimic effects of acetylcholine by binding to muscarinic or nicotinic receptors.

Ganglionic blockers block _____________ receptors.

Ganglionic blockers block nicotinic receptors.

Gi receptor stimulation deactivates adenylyl cyclase and thus cAMP production. This causes smooth muscle _____________.

Gi receptor stimulation deactivates adenylyl cyclase and thus cAMP production. This causes smooth muscle contraction.

Gq receptor stimulation activate an enzyme class, phospholipases, to produce the second messengers, DAG and IP3. This causes the release of Ca from the sarcoplasmic reticulum and thus, smooth muscle ____________.

Gq receptor stimulation activate an enzyme class, phospholipases, to produce the second messengers, DAG and IP3. This causes the release of Ca from the sarcoplasmic reticulum and thus, smooth muscle contraction.

Gs receptor stimulation activates the enzyme, adenylyl cyclase, which uses ATP to activate cAMP. This causes smooth muscle _____________ and heart muscle _____________.

Gs receptor stimulation activates the enzyme, adenylyl cyclase, which uses ATP to activate cAMP. This causes smooth muscle relaxation and heart muscle contraction.

____________ acting cholinergic agonists bind acetylcholinesterase, resulting in buildup of Ach in synaptic cleft.

Indirect acting cholinergic agonists bind acetylcholinesterase, resulting in buildup of Ach in synaptic cleft.

Indirect acting _____________ cholinergic agonists are rarely used due to extreme effects.

Indirect acting irreversible cholinergic agonists are rarely used due to extreme effects.

five kinds of muscarinic receptors

M1 - gastric glands M2 - cardiac cells M3 - smooth muscle in eye, lung, GI, sweat glands, and salivary glands M4 M5

interneurons

between efferent and afferent neurons

Muscarinic receptors are _______________ coupled receptors.

Muscarinic receptors are G-protein coupled receptors.

NERVOUS SYSTEM

NERVOUS SYSTEM

NEURON ACTION POTENTIAL

NEURON ACTION POTENTIAL

Neuromuscular blockers block _____________ receptors.

Neuromuscular blockers block nicotinic receptors.

__________________ blockers block the transmission between motor nerve endings and the nicotinic receptors on __________________ muscles.

Neuromuscular blockers block the transmission between motor nerve endings and the nicotinic receptors on skeletal muscles.

Nicotinic receptors are ____________ gated ion channels.

Nicotinic receptors are ligand gated ion channels.

Non-depolarizing agents are competitive ____________ that bind to ____________ receptors but do not cause ion channel opening. Thus, they prevent ____________ of the muscle fiber/muscle contraction. They can be used for intubation and muscular relaxation during surgery.

Non-depolarizing agents are competitive antagonists that bind to Ach receptors but do not cause ion channel opening. Thus, they prevent depolarization of the muscle fiber/muscle contraction. They can be used for intubation and muscular relaxation during surgery.

PHARMACODYNAMICS

PHARMACODYNAMICS

PHARMACOKINETICS

PHARMACOKINETICS

______________ is a depolarizing agent that binds to ______________ receptors, causing ion channels to ______________. Since it is resistant to degradation, the ion channel remains open too long. Eventually, the receptor becomes desensitized to Ach, thus preventing further action potentials.

Succinylcholine is a depolarizing agent that binds to Ach receptors, causing ion channels to open. Since it is resistant to degradation, the ion channel remains open too long. Eventually, the receptor becomes desensitized to Ach, thus preventing further action potentials.

How do the liver and kidneys work together to accomplish elimination?

The liver modifies molecules to become hydrophilic through phase 1 reactions using cytochrome p450 enzymes. If molecules are not hydrophilic enough after phase 1, then they move on to phase 2 to become even more hydrophilic. The kidneys then eliminate the hydrophilic products.

G-protein coupled receptor (seven-transmembrane)

a. 3-part G protein (with GDP) attached to receptor b. ligand binds to receptor and GTP replaces GDP c. 3-part G protein breaks up d. broken parts cause response

ligand-gated ion channels

a. ligand (any molecule) binds to receptor b. receptor opens c. ion passes through membrane

enzyme-linked receptors

a. ligand binds to two receptors b. causes conformational change in receptors c. receptors come together d. receptors phosphorylated e. protein attaches to phosphorylated receptor f. protein changes to produce cellular response

intracellular receptors

a. ligand crosses membrane b. binds to receptor inside the cell c. ligand-receptor complex moves into nucleus, binds to DNA, and expresses specific genes/proteins

adrenergic neuron transmission a. __________ (amino acid) transported into __________ by Na-dependent transporter; enzymes convert to L-DOPA; enzymes convert to __________ b. transport of dopamine into synaptic vesicle; enzymes convert to __________ c. arrival of action potential causes opening of __________ channels and Ca influx; causes vesicle to release NE into synapse d. NE binds to postsynaptic receptor, triggering response; NE binds to presynaptic receptors, decreasing release e. NE removed by diffusing into systemic circulation, destruction by enzyme COMT, and transport back into neuron through norepinephrine transporter (NET)

adrenergic neuron transmission a. tyrosine (amino acid) transported into neuron by Na-dependent transporter; enzymes convert to L-DOPA; enzymes convert to dopamine b. transport of dopamine into synaptic vesicle; enzymes convert to norepinephrine c. arrival of action potential causes opening of Ca channels and Ca influx; causes vesicle to release NE into synapse d. NE binds to postsynaptic receptor, triggering response; NE binds to presynaptic receptors, decreasing release e. NE removed by diffusing into systemic circulation, destruction by enzyme COMT, and transport back into neuron through norepinephrine transporter (NET)

2 kinds of adrenergic receptors

alpha and beta

volume of distribution

amount of drug in body / concentration of drug in plasma

antimuscarinic agents and their effects 1. _____________ine - reduces M2 and M3 effects 2 . _____________ine - reduces nausea and vomiting 3. _____________pium and _____________pium - bronchodilation (COPD)

antimuscarinic agents and their effects 1. atropine - reduces M2 and M3 effects 2 . scoplamine - reduces nausea and vomiting 3. ipratropium and tiotropium - bronchodilation (COPD)

antimuscarinics used for _________________-like disorders: -benzotropine -trihexyphenidyl

antimuscarinics used for Parkinson's-like disorders: -benzotropine -trihexyphenidyl

____________ used for ____________ control (M____): -tolterodine -darifenacin -solifenacin -oxybutynin -trospium -fesoterodine

antimuscarinics used for bladder control (M3): -tolterodine -darifenacin -solifenacin -oxybutynin -trospium -fesoterodine

AUC

area under curve; plasma drug concentration vs. time

facilitated diffusion

drug moves from high to low concentration with help of carrier protein

passive diffusion

drug moves from high to low concentration; water soluble through pore; lipid soluble through membrane

active transport

drug moves from low to high concentration with help of ATP

endocytosis

drug moves into cell through engulfment of cell membrane

allosteric antagonist

drug that binds and changes the receptor so that the agonist can no longer bind; decreases E max

competitive antagonist

drug that binds to the same site as the agonist; shifts curve to right

inverse agonist

drug that eliminates agonist activity

irreversible antagonist

drug that permanently binds to the same site as the agonist; decreases E max

full agonist

drug that produces maximum effect

partial agonist

drug that produces some effect of baseline but not maximal effect

therapeutic index

ed50:td50 (effective dose: toxic dose)

indirect acting reversible cholinergic agonists 1. _________ium 2. _________mine 3. _________mine 4. _________mine

indirect acting reversible cholinergic agonists 1. edrophonium 2. physostigmine 3. neostigmine 4. pyridostigmine

steps of cholinergic muscle fiber stimulation a. ______________ released into synaptic cleft b. binds to ______________ receptor on skeletal muscle fiber c. ______________ receptor opens d. ______________ flows into the fiber, causing an action potential e. Ca release from sarcoplasmic reticulum causes ______________ ______________

steps of cholinergic muscle fiber stimulation a. acetylcholine released into synaptic cleft b. binds to nicotinic receptor on skeletal muscle fiber c. nicotinic receptor opens d. Na flows into the fiber, causing an action potential e. Ca release from sarcoplasmic reticulum causes muscle contraction

steps of cholinergic neurotransmission a. ____________ delivered into presynaptic neuron by ATP-Na transport system and reacts with enzymes to make ____________ b. ____________ enters ____________ to avoid degradation c. action potential causes voltage sensitive ____________ channels to open, allowing the ion to enter the axon; influx causes vesicle to fuse with membrane and Ach to enter ____________ d. Ach binds to ____________ receptor, causing cholinergic response; Ach binds to ____________ receptors, inhibiting more Ach release e. ____________ breaks Ach into choline and acetate f. free choline taken up by presynaptic neuron

steps of cholinergic neurotransmission a. choline delivered into presynaptic neuron by ATP-Na transport system and reacts with enzymes to make Ach b. Ach enters vesicle to avoid degradation c. action potential causes voltage sensitive Ca channels to open, allowing the ion to enter the axon; influx causes vesicle to fuse with membrane and Ach to enter synapse d. Ach binds to postsynaptic receptor, causing cholinergic response; Ach binds to presynaptic receptors, inhibiting more Ach release e. acetylcholinesterase breaks Ach into choline and acetate f. free choline taken up by presynaptic neuron

CNS divided into two parts

sympathetic and parasympathetic

agents that block adrenergic receptors

sympatholytics

agents that activate adrenergic receptors

sympathomimetics

What happens when most of a cell's receptors are blocked?

upregulation

pharmacokinetics

what the body does to a drug